1
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Taba N, Fischer K, Estonian Biobank Research Team, Org E, Aasmets O. A novel framework for assessing causal effect of microbiome on health: long-term antibiotic usage as an instrument. Gut Microbes 2025; 17:2453616. [PMID: 39849320 PMCID: PMC11776458 DOI: 10.1080/19490976.2025.2453616] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/28/2024] [Revised: 07/25/2024] [Accepted: 01/02/2025] [Indexed: 01/25/2025] Open
Abstract
Assessing causality is undoubtedly one of the key questions in microbiome studies for the upcoming years. Since randomized trials in human subjects are often unethical or difficult to pursue, analytical methods to derive causal effects from observational data deserve attention. As simple covariate adjustment is not likely to account for all potential confounders, the idea of instrumental variable (IV) analysis is worth exploiting. Here we propose a novel framework of antibiotic instrumental variable regression (AB-IVR) for estimating the causal relationships between microbiome and various diseases. We rely on the recent studies showing that antibiotic treatment has a cumulative long-term effect on the microbiome, resulting in individuals with higher antibiotic usage to have a more perturbed microbiome. We apply the AB-IVR method on the Estonian Biobank data and show that the microbiome has a causal role in numerous diseases including migraine, depression and irritable bowel syndrome. We show with a plethora of sensitivity analyses that the identified causal effects are robust and propose ways for further methodological developments.
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Affiliation(s)
- Nele Taba
- Estonian Genome Center, Institute of Genomics, University of Tartu, Tartu, Estonia
| | - Krista Fischer
- Estonian Genome Center, Institute of Genomics, University of Tartu, Tartu, Estonia
- Institute of Mathematics and Statistics, Faculty of Science and Technology, University of Tartu, Tartu, Estonia
| | | | - Elin Org
- Estonian Genome Center, Institute of Genomics, University of Tartu, Tartu, Estonia
| | - Oliver Aasmets
- Estonian Genome Center, Institute of Genomics, University of Tartu, Tartu, Estonia
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2
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Li P, Li M, Chen WH. Best practices for developing microbiome-based disease diagnostic classifiers through machine learning. Gut Microbes 2025; 17:2489074. [PMID: 40186338 PMCID: PMC11980492 DOI: 10.1080/19490976.2025.2489074] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/05/2024] [Revised: 03/13/2025] [Accepted: 03/28/2025] [Indexed: 04/07/2025] Open
Abstract
The human gut microbiome, crucial in various diseases, can be utilized to develop diagnostic models through machine learning (ML). The specific tools and parameters used in model construction such as data preprocessing, batch effect removal and modeling algorithms can impact model performance and generalizability. To establish an generally applicable workflow, we divided the ML process into three above-mentioned steps and optimized each sequentially using 83 gut microbiome cohorts across 20 diseases. We tested a total of 156 tool-parameter-algorithm combinations and benchmarked them according to internal- and external- AUCs. At the data preprocessing step, we identified four data preprocessing methods that performed well for regression-type algorithms and one method that excelled for non-regression-type algorithms. At the batch effect removal step, we identified the "ComBat" function from the sva R package as an effective batch effect removal method and compared the performance of various algorithms. Finally, at the ML algorithm selection step, we found that Ridge and Random Forest ranked the best. Our optimized work flow performed similarly comparing with previous exhaustive methods for disease-specific optimizations, thus is generally applicable and can provide a comprehensive guideline for constructing diagnostic models for a range of diseases, potentially serving as a powerful tool for future medical diagnostics.
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Affiliation(s)
- Peikun Li
- Key Laboratory of Molecular Biophysics of the Ministry of Education, Hubei Key Laboratory of Bioinformatics and Molecular Imaging, Center for Artificial Intelligence Biology, Department of Bioinformatics and Systems Biology, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Min Li
- Key Laboratory of Molecular Biophysics of the Ministry of Education, Hubei Key Laboratory of Bioinformatics and Molecular Imaging, Center for Artificial Intelligence Biology, Department of Bioinformatics and Systems Biology, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Wei-Hua Chen
- Key Laboratory of Molecular Biophysics of the Ministry of Education, Hubei Key Laboratory of Bioinformatics and Molecular Imaging, Center for Artificial Intelligence Biology, Department of Bioinformatics and Systems Biology, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan, Hubei, China
- School of Biological Science, Jining Medical University, Rizhao, China
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3
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Snelson M, Muralitharan RR, Liu CF, Markó L, Forslund SK, Marques FZ, Tang WHW. Gut-Heart Axis: The Role of Gut Microbiota and Metabolites in Heart Failure. Circ Res 2025; 136:1382-1406. [PMID: 40403109 PMCID: PMC12101525 DOI: 10.1161/circresaha.125.325516] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/31/2025] [Revised: 04/03/2025] [Accepted: 04/06/2025] [Indexed: 05/24/2025]
Abstract
Heart failure is a global health issue with significant mortality and morbidity. There is increasing evidence that alterations in the gastrointestinal microbiome, gut epithelial permeability, and gastrointestinal disorders contribute to heart failure progression through various pathways, including systemic inflammation, metabolic dysregulation, and modulation of cardiac function. Moreover, several medications used to treat heart failure directly impact the microbiome. The relationship between the gastrointestinal tract and the heart is bidirectional, termed the gut-heart axis. It is increasingly understood that diet-derived microbial metabolites are key mechanistic drivers of the gut-heart axis. This includes, for example, trimethylamine N-oxide and short-chain fatty acids. This review discusses current insights into the interplay between heart failure, its associated risk factors, and the gut microbiome, focusing on key metabolic pathways, the role of dietary interventions, and the potential for gut-targeted therapies. Understanding these complex interactions could pave the way for novel strategies to mitigate heart failure progression and improve patient outcomes.
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Affiliation(s)
- Matthew Snelson
- Hypertension Research Laboratory, Department of Pharmacology, Biomedical Discovery Institute, Faculty of Medicine, Nursing and Health Sciences, Monash University, Melbourne, Australia
- Victorian Heart Institute, Monash University, Melbourne, Australia
| | - Rikeish R. Muralitharan
- Hypertension Research Laboratory, Department of Pharmacology, Biomedical Discovery Institute, Faculty of Medicine, Nursing and Health Sciences, Monash University, Melbourne, Australia
- Victorian Heart Institute, Monash University, Melbourne, Australia
| | - Chia-Feng Liu
- Center for Microbiome and Human Health, Department of Cardiovascular and Metabolic Sciences, Lerner Research Institute, Cleveland Clinic, Cleveland OH, USA
- Department of Cardiovascular Medicine, Heart Vascular and Thoracic Institute, Cleveland Clinic, Cleveland OH, USA
| | - Lajos Markó
- Charité – Universitätsmedizin Berlin, Germany
- Max Delbrück Center for Molecular Medicine, Berlin, Germany
- Experimental and Clinical Research Center ( ECRC), Berlin, Germany
| | - Sofia K. Forslund
- Charité – Universitätsmedizin Berlin, Germany
- Max Delbrück Center for Molecular Medicine, Berlin, Germany
- Experimental and Clinical Research Center ( ECRC), Berlin, Germany
- DZHK (German Centre for Cardiovascular Research), Berlin, Germany
| | - Francine Z. Marques
- Hypertension Research Laboratory, Department of Pharmacology, Biomedical Discovery Institute, Faculty of Medicine, Nursing and Health Sciences, Monash University, Melbourne, Australia
- Victorian Heart Institute, Monash University, Melbourne, Australia
- Baker Heart and Diabetes Institute, Melbourne, Australia
| | - W. H. Wilson Tang
- Center for Microbiome and Human Health, Department of Cardiovascular and Metabolic Sciences, Lerner Research Institute, Cleveland Clinic, Cleveland OH, USA
- Department of Cardiovascular Medicine, Heart Vascular and Thoracic Institute, Cleveland Clinic, Cleveland OH, USA
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4
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Rademacher J, Poddubnyy D, Rios Rodriguez V. [Microbial and genetic factors in the pathogenesis of spondyloarthritis]. Z Rheumatol 2025; 84:268-275. [PMID: 39621045 DOI: 10.1007/s00393-024-01593-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 04/18/2024] [Indexed: 04/30/2025]
Abstract
Spondyloarthritis (SpA) is a heterogenous group of diseases with an yet unknown exact pathogenesis. An interplay between genetic predispositionw (mainly HLA-B*27 positivity), a barrier leakage (of skin and gut) and environmental influences, such as the contact to certain microbiota are suspected to lead to an activation of the immune system and through this to the development and maintenance of the disease.
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Affiliation(s)
- Judith Rademacher
- Medizinische Klinik für Gastroenterologie, Infektiologie und Rheumatologie, (including Nutrition Medicine), Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Campus Benjamin Franklin, Hindenburgdamm 30, 12203, Berlin, Deutschland.
- Berlin Institute of Health, Charité - Universitätsmedizin Berlin, Berlin, Deutschland.
| | - Denis Poddubnyy
- Medizinische Klinik für Gastroenterologie, Infektiologie und Rheumatologie, (including Nutrition Medicine), Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Campus Benjamin Franklin, Hindenburgdamm 30, 12203, Berlin, Deutschland
- Epidemiology unit, German Rheumatism Research Centre, Berlin, Deutschland
| | - Valeria Rios Rodriguez
- Medizinische Klinik für Gastroenterologie, Infektiologie und Rheumatologie, (including Nutrition Medicine), Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Campus Benjamin Franklin, Hindenburgdamm 30, 12203, Berlin, Deutschland
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5
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Holle J, Bartolomaeus H. Gut-derived metabolites as treatment targets in chronic kidney disease-an avenue toward personalized medicine. Pediatr Nephrol 2025; 40:1505-1510. [PMID: 39820506 PMCID: PMC11947041 DOI: 10.1007/s00467-024-06609-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/08/2024] [Revised: 11/08/2024] [Accepted: 11/08/2024] [Indexed: 01/19/2025]
Affiliation(s)
- Johannes Holle
- Department of Pediatric Gastroenterology, Nephrology and Metabolic Diseases, Charité - Universitätsmedizin Berlin, Berlin, Germany.
- Experimental and Clinical Research Center, a Cooperation of Charité - Universitätsmedizin Berlin and Max Delbrück Center for Molecular Medicine, Berlin, Germany.
- German Centre for Cardiovascular Research (DZHK), Partner Site Berlin, Berlin, Germany.
- Max Delbrück Center for Molecular Medicine in the Helmholtz Association, Berlin, Germany.
| | - Hendrik Bartolomaeus
- German Centre for Cardiovascular Research (DZHK), Partner Site Berlin, Berlin, Germany
- Max Delbrück Center for Molecular Medicine in the Helmholtz Association, Berlin, Germany
- Institute of Experimental Biomedicine, University Hospital Würzburg, Würzburg, Germany
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6
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Beaudoin CA, Norget S, Omran Z, Hala S, Daqeeq AH, Burnet PWJ, Blundell TL, van Tonder AJ. Similarity of drug targets to human microbiome metaproteome promotes pharmacological promiscuity. THE PHARMACOGENOMICS JOURNAL 2025; 25:9. [PMID: 40246834 PMCID: PMC12006021 DOI: 10.1038/s41397-025-00367-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/15/2024] [Revised: 02/27/2025] [Accepted: 03/24/2025] [Indexed: 04/19/2025]
Abstract
Similarity between candidate drug targets and human proteins is commonly assessed to minimize the occurrence of side effects. Although numerous drugs have been found to disrupt the health of the human microbiome, no comprehensive comparison between established drug targets and the human microbiome metaproteome has yet been conducted. Therefore, herein, sequence and structure alignments between human and pathogen drug targets and representative human gut, oral, and vaginal microbiome metaproteomes were performed. Both human and pathogen drug targets were found to be similar in sequence, function, structure, and drug binding capacity to proteins in diverse pathogenic and non-pathogenic bacteria from all three microbiomes. The gut metaproteome was identified as particularly susceptible overall to off-target effects. Certain symptoms, such as infections and immune disorders, may be more common among drugs that non-selectively target host microbiota. These findings suggest that similarities between human microbiome metaproteomes and drug target candidates should be routinely checked.
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Affiliation(s)
| | - Shannon Norget
- Department of Psychology, Health & Technology, University of Twente, Enschede, the Netherlands
| | - Ziad Omran
- King Abdullah International Medical Research Center, King Saud Bin Abdelaziz University for Health Sciences, Jeddah, Saudi Arabia
| | - Sharif Hala
- Biothreat Department, Public Health Laboratory, Public Health Authority, Riyadh, Saudi Arabia
- Pathogen Genomics Laboratory, Biological and Environmental Sciences and Engineering, King Abdullah University of Science and Technology, Thuwal, Saudi Arabia
| | - Abdullah H Daqeeq
- Department of Anesthesia, International Medical Center, Jeddah, Kingdom of Saudi Arabia
| | | | - Tom L Blundell
- Victor Phillip Dahdaleh Heart and Lung Research Institute, Biomedical Campus, Trumpington, Cambridge, UK
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7
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Zhang Y, Zhang Y, Chen Z, Jia Z, Yu Y, Wang J, Liang H. Global burden, subtype, risk factors and etiological analysis of enteric infections from 1990-2021: population based study. Front Cell Infect Microbiol 2025; 15:1527765. [PMID: 40182771 PMCID: PMC11965617 DOI: 10.3389/fcimb.2025.1527765] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2024] [Accepted: 02/26/2025] [Indexed: 04/05/2025] Open
Abstract
Background Enteric infections represent a prevalent global health issue and contribute significantly to the global disease burden. This study aims to investigate the patterns and trends of enteric infections from 1990 to 2021, providing valuable insights for health policy formulation, medical resource allocation, and the optimization of patient management plans. Methods We analyzed the Global Burden of Disease (GBD) 2021 for 21 regions and 204 countries to understand better the health burden using prevalence, incidence, mortality, and disability-adjusted life years (DALYs), subtype, risk factors, and etiology. We tested correlations with the Socio-demographic Index (SDI), and using decomposition analysis to dissect the reasons behind changes in epidemiological indicators of the disease. Results In 2021, the age-standardized rates of prevalence, incidence, deaths, and DALYs per 100,000 population for enteric infections were 879.58, 577.21, 17.83, and 1020.15, respectively. Compared to 1990, these rates exhibited -0.18, -0.12, -0.73, and -0.72 changes. Gender and age analyses revealed a higher burden among females, those under 15 years old, and the elderly. Regions with low SDI had higher epidemiological indicators. The burden of Typhoid fever declines in high-development regions. Unsafe water sources were identified as the primary risk factor globally in both 1990 and 2021. Rotavirus was the leading cause of deaths and DALYs. Conclusion This study highlights the complex epidemiological landscape of enteric infections, revealing variations in burden, risk factors, and etiological characteristics across age, gender, and geographical regions. It underscores the urgent need for healthcare professionals and policymakers to develop innovative prevention and healthcare strategies based on the current and evolving burden of enteric infections, to alleviate the global disease burden.
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Affiliation(s)
- Youao Zhang
- Department of Urology, People’s Hospital of Longhua, Shenzhen, Guangdong, China
- Nanfang Hospital, The First Clinical Medical College of Southern Medical University, Guangzhou, Guangdong, China
| | - Yuran Zhang
- Nanfang Hospital, The First Clinical Medical College of Southern Medical University, Guangzhou, Guangdong, China
| | - Zhifeng Chen
- Nanfang Hospital, The First Clinical Medical College of Southern Medical University, Guangzhou, Guangdong, China
| | - Zixuan Jia
- School of Chinese Medicine, Southern Medical University, Guangzhou, China
| | - Yulan Yu
- Nanfang Hospital, The First Clinical Medical College of Southern Medical University, Guangzhou, Guangdong, China
| | - Jieyan Wang
- Department of Urology, People’s Hospital of Longhua, Shenzhen, Guangdong, China
| | - Hui Liang
- Department of Urology, People’s Hospital of Longhua, Shenzhen, Guangdong, China
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8
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de la Cuesta-Zuluaga J, Müller P, Maier L. Balancing act: counteracting adverse drug effects on the microbiome. Trends Microbiol 2025; 33:268-276. [PMID: 39395850 DOI: 10.1016/j.tim.2024.09.011] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/04/2024] [Revised: 09/24/2024] [Accepted: 09/25/2024] [Indexed: 10/14/2024]
Abstract
The human gut microbiome, a community of microbes that plays a crucial role in our wellbeing, is highly adaptable but also vulnerable to drug treatments. This vulnerability can have serious consequences for the host, for example, increasing susceptibility to infections, immune, metabolic, and cognitive disorders. However, the microbiome's adaptability also provides opportunities to prevent, protect, or even reverse drug-induced damage. Recently, several innovative approaches have emerged aimed at minimizing the collateral damage of drugs on the microbiome. Here, we outline these approaches, discuss their applicability in different treatment scenarios, highlight current challenges, and suggest avenues that may lead to an effective protection of the microbiome.
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Affiliation(s)
- Jacobo de la Cuesta-Zuluaga
- Interfaculty Institute for Microbiology and Infection Medicine Tübingen, University of Tübingen, Tübingen, Germany; Cluster of Excellence EXC 2124 Controlling Microbes to Fight Infections, University of Tübingen, Tübingen, Germany; M3-Research Center for Malignome, Metabolome and Microbiome, University of Tübingen, Tübingen, Germany
| | - Patrick Müller
- Interfaculty Institute for Microbiology and Infection Medicine Tübingen, University of Tübingen, Tübingen, Germany; Cluster of Excellence EXC 2124 Controlling Microbes to Fight Infections, University of Tübingen, Tübingen, Germany; M3-Research Center for Malignome, Metabolome and Microbiome, University of Tübingen, Tübingen, Germany
| | - Lisa Maier
- Interfaculty Institute for Microbiology and Infection Medicine Tübingen, University of Tübingen, Tübingen, Germany; Cluster of Excellence EXC 2124 Controlling Microbes to Fight Infections, University of Tübingen, Tübingen, Germany; M3-Research Center for Malignome, Metabolome and Microbiome, University of Tübingen, Tübingen, Germany.
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9
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Caesar R. The impact of novel probiotics isolated from the human gut on the gut microbiota and health. Diabetes Obes Metab 2025; 27 Suppl 1:3-14. [PMID: 39726216 PMCID: PMC11894790 DOI: 10.1111/dom.16129] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/25/2024] [Revised: 12/02/2024] [Accepted: 12/02/2024] [Indexed: 12/28/2024]
Abstract
The gut microbiota plays a pivotal role in influencing the metabolism and immune responses of the body. A balanced microbial composition promotes metabolic health through various mechanisms, including the production of beneficial metabolites, which help regulate inflammation and support immune functions. In contrast, imbalance in the gut microbiota, known as dysbiosis, can disrupt metabolic processes and increase the risk of developing diseases, such as obesity, type 2 diabetes, and inflammatory disorders. The composition of the gut microbiota is dynamic and can be influenced by environmental factors such as diet, medication, and the consumption of live bacteria. Since the early 1900s, bacteria isolated from food and have been used as probiotics. However, the human gut also offers an enormous reservoir of bacterial strains, and recent advances in microbiota research have led to the discovery of strains with probiotic potentials. These strains, derived from a broad spectrum of microbial taxa, differ in their ecological properties and how they interact with their hosts. For most probiotics bacterial structural components and metabolites, such as short-chain fatty acids, contribute to the maintenance of metabolic and immunological homeostasis by regulating inflammation and reinforcing gut barrier integrity. Metabolites produced by probiotic strains can also be used for bacterial cross-feeding to promote a balanced microbiota. Despite the challenges related to safety, stability, and strain-specific properties, several newly identified strains offer great potential for personalized probiotic interventions, allowing for targeted health strategies.
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Affiliation(s)
- Robert Caesar
- The Wallenberg Laboratory, Department of Molecular and Clinical MedicineUniversity of GothenburgGothenburgSweden
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10
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Szajewska H, Scott KP, de Meij T, Forslund-Startceva SK, Knight R, Koren O, Little P, Johnston BC, Łukasik J, Suez J, Tancredi DJ, Sanders ME. Antibiotic-perturbed microbiota and the role of probiotics. Nat Rev Gastroenterol Hepatol 2025; 22:155-172. [PMID: 39663462 DOI: 10.1038/s41575-024-01023-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 11/08/2024] [Indexed: 12/13/2024]
Abstract
The disruptive effect of antibiotics on the composition and function of the human microbiota is well established. However, the hypothesis that probiotics can help restore the antibiotic-disrupted microbiota has been advanced, with little consideration of the strength of evidence supporting it. Some clinical data suggest that probiotics can reduce antibiotic-related side effects, including Clostridioides difficile-associated diarrhoea, but there are no data that causally link these clinical effects to microbiota protection or recovery. Substantial challenges hinder attempts to address this hypothesis, including the absence of consensus on the composition of a 'normal' microbiota, non-standardized and evolving microbiome measurement methods, and substantial inter-individual microbiota variation. In this Review, we explore these complexities. First, we review the known benefits and risks of antibiotics, the effect of antibiotics on the human microbiota, the resilience and adaptability of the microbiota, and how microbiota restoration might be defined and measured. Subsequently, we explore the evidence for the efficacy of probiotics in preventing disruption or aiding microbiota recovery post-antibiotic treatment. Finally, we offer insights into the current state of research and suggest directions for future research.
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Affiliation(s)
- Hania Szajewska
- Department of Paediatrics, The Medical University of Warsaw, Warsaw, Poland
| | - Karen P Scott
- Rowett Institute, University of Aberdeen, Aberdeen, UK
| | - Tim de Meij
- Department of Paediatric Gastroenterology, Emma Children's Hospital, Amsterdam UMC, Academic Medical Centre, Amsterdam, The Netherlands
| | - Sofia K Forslund-Startceva
- Experimental and Clinical Research Center, a joint cooperation of Max Delbruck Center for Molecular Medicine and Charité - Universitätsmedizin Berlin, Berlin, Germany
- Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany
- Max Delbruck Center for Molecular Medicine in the Helmholtz Association (MDC), Berlin, Germany
- DZHK (German Centre for Cardiovascular Research), Berlin, Germany
| | - Rob Knight
- Department of Pediatrics, University of California San Diego, San Diego, CA, USA
- Department of Computer Science & Engineering, University of California San Diego, San Diego, CA, USA
- Shu Chien - Gene Lay Department of Bioengineering, University of California San Diego, San Diego, CA, USA
- Halıcıoğlu Data Science Institute, University of California San Diego, San Diego, CA, USA
- Center for Microbiome Innovation, University of California San Diego, San Diego, CA, USA
| | - Omry Koren
- Azrieli Faculty of Medicine, Bar Ilan University, Safed, Israel
| | - Paul Little
- Primary Care Research Centre, University of Southampton, Southampton, UK
| | - Bradley C Johnston
- Department of Nutrition, College of Agriculture and Life Sciences, Texas A&M University, College Station, TX, USA
- Department of Epidemiology and Biostatistics, School of Public Health, Texas A&M University, College Station, TX, USA
| | - Jan Łukasik
- Department of Paediatrics, The Medical University of Warsaw, Warsaw, Poland
| | - Jotham Suez
- W. Harry Feinstone Department of Molecular Microbiology and Immunology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA
| | - Daniel J Tancredi
- Department of Pediatrics, School of Medicine, University of California Davis, Sacramento, CA, USA
| | - Mary Ellen Sanders
- International Scientific Association for Probiotics and Prebiotics, Consulting Scientific Advisor, Centennial, CO, USA.
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11
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Holle J, Reitmeir R, Behrens F, Singh D, Schindler D, Potapenko O, McParland V, Anandakumar H, Kanzelmeyer N, Sommerer C, Hartleif S, Andrassy J, Heemann U, Neuenhahn M, Forslund-Startceva SK, Gerhard M, Oh J, Wilck N, Löber U, Bartolomaeus H. Gut microbiome alterations precede graft rejection in kidney transplantation patients. Am J Transplant 2025:S1600-6135(25)00093-0. [PMID: 39978595 DOI: 10.1016/j.ajt.2025.02.010] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2024] [Revised: 01/22/2025] [Accepted: 02/12/2025] [Indexed: 02/22/2025]
Abstract
Kidney transplantation (KT) is the best treatment for end-stage kidney disease, with graft survival critically affected by the recipient's immune response. The role of the gut microbiome in modulating this immune response remains underexplored. Our study investigates how microbiome alterations might associate with allograft rejection by analyzing the gut microbiome using 16S rRNA gene amplicon sequencing of a multicenter prospective study involving 562 samples from 245 individuals of which 217 received KT. Overall, gut microbiome composition showed gradual recovery post-KT, mirroring CKD-to-health transition as indicated by an increase of Shannon diversity. Prior to graft rejection, we observed a decrease in microbial diversity and SCFA-producing taxa. Functional analysis highlighted a decreased potential for SCFA production in patients preceding the rejection event, validated by quantitative PCR for the production potential of propionate and butyrate. Post-rejection analysis revealed normalization of these microbiome features. Comparison to published microbiome signatures from CKD patients demonstrated a partial overlap of the microbiome alterations preceding graft rejection with the alterations typically found in CKD. Our findings suggest that alterations in gut microbiome composition and function may precede and influence KT rejection, suggesting potential implications as biomarkers or for early therapeutic microbiome-targeting interventions.
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Affiliation(s)
- Johannes Holle
- Department of Pediatric Gastroenterology, Nephrology and Metabolic Diseases, Charité - Universitätsmedizin Berlin, Berlin, Germany; Experimental and Clinical Research Center, a cooperation of Charité - Universitätsmedizin Berlin and Max Delbrück Center for Molecular Medicine, Berlin, Germany; German Centre for Cardiovascular Research (DZHK), Partner Site Berlin, Berlin, Germany; Max Delbrück Center for Molecular Medicine in the Helmholtz Association, Berlin, Germany; Department of General Pediatrics and Hematology/Oncology, University Children's Hospital, University Hospital Tübingen, Tübingen, Germany.
| | - Rosa Reitmeir
- Department of Pediatric Gastroenterology, Nephrology and Metabolic Diseases, Charité - Universitätsmedizin Berlin, Berlin, Germany; Experimental and Clinical Research Center, a cooperation of Charité - Universitätsmedizin Berlin and Max Delbrück Center for Molecular Medicine, Berlin, Germany; German Centre for Cardiovascular Research (DZHK), Partner Site Berlin, Berlin, Germany; Max Delbrück Center for Molecular Medicine in the Helmholtz Association, Berlin, Germany
| | - Felix Behrens
- Department of Pediatric Gastroenterology, Nephrology and Metabolic Diseases, Charité - Universitätsmedizin Berlin, Berlin, Germany; Experimental and Clinical Research Center, a cooperation of Charité - Universitätsmedizin Berlin and Max Delbrück Center for Molecular Medicine, Berlin, Germany; German Centre for Cardiovascular Research (DZHK), Partner Site Berlin, Berlin, Germany; Max Delbrück Center for Molecular Medicine in the Helmholtz Association, Berlin, Germany
| | - Dharmesh Singh
- Department of Preclinical Medicine, Institute for Medical Microbiology, Immunology and Hygiene, Technical University of Munich (TUM), TUM School of Medicine and Health, Munich, Germany; German Center for Infection Research (DZIF), Partner Site München, Germany
| | - Daniela Schindler
- German Center for Infection Research (DZIF), Partner Site Braunschweig, Germany
| | - Olena Potapenko
- Experimental and Clinical Research Center, a cooperation of Charité - Universitätsmedizin Berlin and Max Delbrück Center for Molecular Medicine, Berlin, Germany; Max Delbrück Center for Molecular Medicine in the Helmholtz Association, Berlin, Germany; Department of Nephrology and Medical Intensive Care, Charité - Universitätsmedizin Berlin, Germany
| | - Victoria McParland
- Experimental and Clinical Research Center, a cooperation of Charité - Universitätsmedizin Berlin and Max Delbrück Center for Molecular Medicine, Berlin, Germany; Max Delbrück Center for Molecular Medicine in the Helmholtz Association, Berlin, Germany; Department of Nephrology and Medical Intensive Care, Charité - Universitätsmedizin Berlin, Germany
| | - Harithaa Anandakumar
- Experimental and Clinical Research Center, a cooperation of Charité - Universitätsmedizin Berlin and Max Delbrück Center for Molecular Medicine, Berlin, Germany; German Centre for Cardiovascular Research (DZHK), Partner Site Berlin, Berlin, Germany; Max Delbrück Center for Molecular Medicine in the Helmholtz Association, Berlin, Germany; Department of Nephrology and Medical Intensive Care, Charité - Universitätsmedizin Berlin, Germany
| | - Nele Kanzelmeyer
- Department of Pediatric Kidney, Liver and Metabolic Diseases, Hannover Medical School, Children's Hospital, Hannover, Germany; German Center for Infection Research (DZIF), Partner Site Hannover, Germany
| | - Claudia Sommerer
- Department of Nephrology, University of Heidelberg, Heidelberg, Germany; German Center for Infection Research (DZIF), Partner Site Heidelberg, Germany
| | - Steffen Hartleif
- Paediatric Gastroenterology and Hepatology, University Children's Hospital Tübingen, Tübingen, Germany; German Center for Infection Research (DZIF), Partner Site Tübingen, Germany
| | - Joachim Andrassy
- German Center for Infection Research (DZIF), Partner Site München, Germany; Klinik für Allgemeine, Viszeral, und Transplantationschirurgie, Klinikum der Universität München, Munich, Germany
| | - Uwe Heemann
- German Center for Infection Research (DZIF), Partner Site München, Germany; Department of Nephrology, Technical University of Munich, Munich, Germany
| | - Michael Neuenhahn
- Department of Preclinical Medicine, Institute for Medical Microbiology, Immunology and Hygiene, Technical University of Munich (TUM), TUM School of Medicine and Health, Munich, Germany; German Center for Infection Research (DZIF), Partner Site München, Germany
| | - Sofia K Forslund-Startceva
- Experimental and Clinical Research Center, a cooperation of Charité - Universitätsmedizin Berlin and Max Delbrück Center for Molecular Medicine, Berlin, Germany; German Centre for Cardiovascular Research (DZHK), Partner Site Berlin, Berlin, Germany; Max Delbrück Center for Molecular Medicine in the Helmholtz Association, Berlin, Germany
| | - Markus Gerhard
- Department of Preclinical Medicine, Institute for Medical Microbiology, Immunology and Hygiene, Technical University of Munich (TUM), TUM School of Medicine and Health, Munich, Germany; German Center for Infection Research (DZIF), Partner Site München, Germany
| | - Jun Oh
- Department of Pediatric Nephrology, University Children's Hospital, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Nicola Wilck
- Experimental and Clinical Research Center, a cooperation of Charité - Universitätsmedizin Berlin and Max Delbrück Center for Molecular Medicine, Berlin, Germany; German Centre for Cardiovascular Research (DZHK), Partner Site Berlin, Berlin, Germany; Max Delbrück Center for Molecular Medicine in the Helmholtz Association, Berlin, Germany; Department of Nephrology and Medical Intensive Care, Charité - Universitätsmedizin Berlin, Germany
| | - Ulrike Löber
- Experimental and Clinical Research Center, a cooperation of Charité - Universitätsmedizin Berlin and Max Delbrück Center for Molecular Medicine, Berlin, Germany; German Centre for Cardiovascular Research (DZHK), Partner Site Berlin, Berlin, Germany; Max Delbrück Center for Molecular Medicine in the Helmholtz Association, Berlin, Germany
| | - Hendrik Bartolomaeus
- German Centre for Cardiovascular Research (DZHK), Partner Site Berlin, Berlin, Germany; Max Delbrück Center for Molecular Medicine in the Helmholtz Association, Berlin, Germany; Institute of Experimental Biomedicine, University Hospital Würzburg, Germany
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12
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Juan Z, Chen J, Ding B, Yongping L, Cai H, Chen H, Wang L, Le Y, Shi J, Wu Y, Ma D, Ouyang W, Cheng Y, Tong J. Probiotics prevent pegylated liposomal doxorubicin-associated hand-foot syndrome and oral mucositis of breast cancer patients following surgery and chemotherapy: a randomized placebo-controlled trial. Int J Surg 2025; 111:2018-2030. [PMID: 39715143 DOI: 10.1097/js9.0000000000002147] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2024] [Accepted: 11/06/2024] [Indexed: 12/25/2024]
Abstract
BACKGROUND Hand-foot syndrome (HFS) and oral mucositis (OM) are common adverse events during cancer chemotherapy and can significantly decrease patients' quality of life and chemotherapy adaptation, however, prevention strategies of these complications yet to be established. METHODS Patients with stages I-III breast cancer, who had surgery and needed pegylated liposomal doxorubicin (PLD)-based adjuvant chemotherapy were screened, recruited and randomly assigned to receive either probiotics or placebo (three capsules, twice/day) treatment during the course of chemotherapy from November 2019 to August 2020. The incidence and severity of PLD related HFS and OM, and patients' quality of life were assessed. Their plasma biomarkers, metabolites and fecal microbiota compositions were measured. And the results were further verified in animal experiments. RESULTS Probiotics supplement during PLD treatment significantly decreased the incidence and the severity of HFS and OM ( P < 0.001), improved patients' life quality ( P < 0.001), increased the relative abundance of intestinal Enterococcus ( P = 0.025) and mitigated the changes of seven plasma metabolites. Among these metabolites, the changes of p-Mentha-1,8-dien-7-ol (MDO) ( B = - 0.441, P = 0.02) and L-arginine ( B = - 0.586, P = 0.002) were negatively correlated with the occurrence of severe HFS and OM. MDO can partly reproduce the preventive effects of probiotics on PLD-related skin cell proliferating inhibition, DNA damage, and local inflammation in rats. CONCLUSION Probiotics supplement during PLD-based chemotherapy prevents the incidence and severity of HFS and OM, which may be associated with modulating plasma metabolites including the MDO.
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Affiliation(s)
- Zhang Juan
- Department of Anesthesiology
- Department of Breast Surgery, Tangshan People's Hospital, Tangshan, Hebei, China
| | - Jie Chen
- Center for Experimental Medicine
- Department of Anatomy and Neurobiology, School of Basic Medical Sciences, Central South University, Changsha, Hunan, PR China
| | - Boni Ding
- Department of Breast and Thyroid Surgery, Third Xiangya Hospital, Central South University, Changsha, Hunan, PR China
| | - Liang Yongping
- Department of Anesthesiology
- Department of Breast Surgery, Tangshan People's Hospital, Tangshan, Hebei, China
| | - Haifeng Cai
- Department of Breast Surgery, Tangshan People's Hospital, Tangshan, Hebei, China
| | - Hui Chen
- Department of Anesthesiology
- Hunan Province Key Laboratory of Brain Homeostasis, Third Xiangya Hospital, Central South University, Changsha, Hunan, PR China
| | - Ling Wang
- Department of Breast and Thyroid Surgery, Third Xiangya Hospital, Central South University, Changsha, Hunan, PR China
| | - Yuan Le
- Department of Anesthesiology
- Hunan Province Key Laboratory of Brain Homeostasis, Third Xiangya Hospital, Central South University, Changsha, Hunan, PR China
| | - Jingcheng Shi
- Department of Epidemiology and Health Statistics, Xiangya School of Public Health, Central South University, Changsha, Hunan, PR China
| | - Yuhui Wu
- Department of Breast Surgery, Xiangya Hospital, Central South University, Changsha, Hunan, PR China
| | - Daqing Ma
- Division of Anaesthetics, Pain Medicine and Intensive Care, Department of Surgery and Cancer, Faculty of Medicine, Imperial College London, Chelsea and Westminster Hospital, London, UK
| | - Wen Ouyang
- Department of Anesthesiology
- Hunan Province Key Laboratory of Brain Homeostasis, Third Xiangya Hospital, Central South University, Changsha, Hunan, PR China
| | - Yong Cheng
- Department of Plastic and Burns Surgery, Huazhong University of Science and Technology Union Shenzhen Hospital, Shenzhen, Guangdong, PR China
| | - Jianbin Tong
- Department of Anesthesiology
- Hunan Province Key Laboratory of Brain Homeostasis, Third Xiangya Hospital, Central South University, Changsha, Hunan, PR China
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13
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Castells-Nobau A, Moreno-Navarrete JM, de la Vega-Correa L, Puig I, Federici M, Sun J, Burcelin R, Guzylack-Piriou L, Gourdy P, Cazals L, Arnoriaga-Rodríguez M, Frühbeck G, Seoane LM, López-Miranda J, Tinahones FJ, Dieguez C, Dumas ME, Pérez-Brocal V, Moya A, Perakakis N, Mingrone G, Bornstein S, Rodriguez Hermosa JI, Castro E, Fernández-Real JM, Mayneris-Perxachs J. Multiomics of the intestine-liver-adipose axis in multiple studies unveils a consistent link of the gut microbiota and the antiviral response with systemic glucose metabolism. Gut 2025; 74:229-245. [PMID: 39358003 PMCID: PMC11874369 DOI: 10.1136/gutjnl-2024-332602] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/10/2024] [Accepted: 09/06/2024] [Indexed: 10/04/2024]
Abstract
BACKGROUND The microbiota is emerging as a key factor in the predisposition to insulin resistance and obesity. OBJECTIVE To understand the interplay among gut microbiota and insulin sensitivity in multiple tissues. DESIGN Integrative multiomics and multitissue approach across six studies, combining euglycaemic clamp measurements (used in four of the six studies) with other measurements of glucose metabolism and insulin resistance (glycated haemoglobin (HbA1c) and fasting glucose). RESULTS Several genera and species from the Proteobacteria phylum were consistently negatively associated with insulin sensitivity in four studies (ADIPOINST, n=15; IRONMET, n=121, FLORINASH, n=67 and FLOROMIDIA, n=24). Transcriptomic analysis of the jejunum, ileum and colon revealed T cell-related signatures positively linked to insulin sensitivity. Proteobacteria in the ileum and colon were positively associated with HbA1c but negatively with the number of T cells. Jejunal deoxycholic acid was negatively associated with insulin sensitivity. Transcriptomics of subcutaneous adipose tissue (ADIPOMIT, n=740) and visceral adipose tissue (VAT) (ADIPOINST, n=29) revealed T cell-related signatures linked to HbA1c and insulin sensitivity, respectively. VAT Proteobacteria were negatively associated with insulin sensitivity. Multiomics and multitissue integration in the ADIPOINST and FLORINASH studies linked faecal Proteobacteria with jejunal and liver deoxycholic acid, as well as jejunal, VAT and liver transcriptomic signatures involved in the actin cytoskeleton, insulin and T cell signalling. Fasting glucose was consistently linked to interferon-induced genes and antiviral responses in the intestine and VAT. Studies in Drosophila melanogaster validated these human insulin sensitivity-associated changes. CONCLUSION These data provide comprehensive insights into the microbiome-gut-adipose-liver axis and its impact on systemic insulin action, suggesting potential therapeutic targets.Cite Now.
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Affiliation(s)
- Anna Castells-Nobau
- Department of Diabetes, Endocrinology and Nutrition, Dr. Josep Trueta University Hospital, Girona, Spain
- Nutrition, Eumetabolism and Health Group, Girona Biomedical Research Institute (IDIBGI-CERCA), Girona, Spain
- Integrative Systems Medicine and Biology Group, Girona Biomedical Research Institute (IDIBGI-CERCA), Parc Hospitalari Martí i Julià, Edifici M2, Salt, Spain
- CIBER Fisiopatología de la Obesidad y Nutrición (CIBERobn), Instituto de Salud Carlos III, Madrid, Spain
| | - José Maria Moreno-Navarrete
- Department of Diabetes, Endocrinology and Nutrition, Dr. Josep Trueta University Hospital, Girona, Spain
- Nutrition, Eumetabolism and Health Group, Girona Biomedical Research Institute (IDIBGI-CERCA), Girona, Spain
- CIBER Fisiopatología de la Obesidad y Nutrición (CIBERobn), Instituto de Salud Carlos III, Madrid, Spain
- Department of Medical Sciences, School of Medicine, University of Girona, Girona, Spain
| | - Lisset de la Vega-Correa
- Department of Diabetes, Endocrinology and Nutrition, Dr. Josep Trueta University Hospital, Girona, Spain
- Nutrition, Eumetabolism and Health Group, Girona Biomedical Research Institute (IDIBGI-CERCA), Girona, Spain
- CIBER Fisiopatología de la Obesidad y Nutrición (CIBERobn), Instituto de Salud Carlos III, Madrid, Spain
| | - Irene Puig
- Department of Diabetes, Endocrinology and Nutrition, Dr. Josep Trueta University Hospital, Girona, Spain
- Nutrition, Eumetabolism and Health Group, Girona Biomedical Research Institute (IDIBGI-CERCA), Girona, Spain
- CIBER Fisiopatología de la Obesidad y Nutrición (CIBERobn), Instituto de Salud Carlos III, Madrid, Spain
| | - Massimo Federici
- Department of Systems Medicine, University of Rome Tor Vergata, Via Montpellier 1, Rome, Italy
| | - Jiuwen Sun
- Integrative Systems Medicine and Biology Group, Girona Biomedical Research Institute (IDIBGI-CERCA), Parc Hospitalari Martí i Julià, Edifici M2, Salt, Spain
- Institut National de la Santé et de la Recherche Médicale (INSERM), Toulouse, France
- Université Paul Sabatier (UPS), Unité Mixte de Recherche (UMR), Toulouse, France
- Institut des Maladies Métaboliques et Cardiovasculaires (I2MC), Team 2: 'Intestinal Risk Factors, Diabetes, Dyslipidemia, and Heart Failure', F-31432, Toulouse, France
| | - Remy Burcelin
- Institut National de la Santé et de la Recherche Médicale (INSERM), Toulouse, France
- Université Paul Sabatier (UPS), Unité Mixte de Recherche (UMR), Toulouse, France
- Institut des Maladies Métaboliques et Cardiovasculaires (I2MC), Team 2: 'Intestinal Risk Factors, Diabetes, Dyslipidemia, and Heart Failure', F-31432, Toulouse, France
| | - Laurence Guzylack-Piriou
- Team "Immunité et ALTernatives aux Antibiotiques (IALTA)", Laboratory of host to pathogens Interactions (IHAP), UMR INRAE 1225 / ENVT, Toulouse, France
| | - Pierre Gourdy
- Department of Diabetology, metabolic Diseases and Nutrition, CHU de Toulouse, Toulouse, France
- Institute of Metabolic and Cardiovascular Diseases, UMR1297 I2MC, INSERM, Toulouse 3 University, Toulouse, France
| | - Laurent Cazals
- Department of Diabetology, metabolic Diseases and Nutrition, CHU de Toulouse, Toulouse, France
- Institute of Metabolic and Cardiovascular Diseases, UMR1297 I2MC, INSERM, Toulouse 3 University, Toulouse, France
| | - María Arnoriaga-Rodríguez
- Department of Diabetes, Endocrinology and Nutrition, Dr. Josep Trueta University Hospital, Girona, Spain
- Nutrition, Eumetabolism and Health Group, Girona Biomedical Research Institute (IDIBGI-CERCA), Girona, Spain
- CIBER Fisiopatología de la Obesidad y Nutrición (CIBERobn), Instituto de Salud Carlos III, Madrid, Spain
- Department of Medical Sciences, School of Medicine, University of Girona, Girona, Spain
| | - Gema Frühbeck
- CIBER Fisiopatología de la Obesidad y Nutrición (CIBERobn), Instituto de Salud Carlos III, Madrid, Spain
- Department of Endocrinology & Nutrition, Clínica Universidad de Navarra, IdiSNA, Pamplona, Spain
| | - Luisa Maria Seoane
- CIBER Fisiopatología de la Obesidad y Nutrición (CIBERobn), Instituto de Salud Carlos III, Madrid, Spain
- Fisiopatología Endocrina Instituto de Investigación Sanitaria de Santiago de Compostela (IDIS), Complejo Hospitalario Universitario de Santiago de Compostela (CHUS/SERGAS), Santiago de Compostela, Spain
| | - José López-Miranda
- CIBER Fisiopatología de la Obesidad y Nutrición (CIBERobn), Instituto de Salud Carlos III, Madrid, Spain
- Department of Internal Medicine, Hospital Universitario Reina Sofía, Maimonides Institute for Biomedical Research in Cordoba (IMIBIC), Universidad de Córdoba, Córdoba, Spain
| | - Francisco J Tinahones
- CIBER Fisiopatología de la Obesidad y Nutrición (CIBERobn), Instituto de Salud Carlos III, Madrid, Spain
- Virgen de la Victoria Hospital, Department of Endocrinology, Instituto de Investigación Biomédica de Málaga (IBIMA), University of Málaga, Málaga, Spain
| | - Carlos Dieguez
- CIBER Fisiopatología de la Obesidad y Nutrición (CIBERobn), Instituto de Salud Carlos III, Madrid, Spain
- Department of Physiology, CIMUS, University of Santiago de Compostela, Instituto de Investigación Sanitaria, Santiago de Compostela, Spain
| | - Marc-Emmanuel Dumas
- Section of Biomolecular Medicine, Division of Systems Medicine, Department of Metabolism, Digestion and Reproduction, Imperial College London, London, UK
- Section of Genomic and Environmental Medicine, National Heart & Lung Institute, Imperial College London, London, UK
- European Genomic Institute for Diabetes, CNRS UMR 8199, INSERM UMR 1283, Institut Pasteur de Lille, Lille University Hospital; University of Lille, Lille, France
- McGill Genome Centre, Mc Gill University, Montréal, Quebec, Canada
| | - Vicente Pérez-Brocal
- Department of Genomics and Health, Foundation for the Promotion of Health and Biomedical Research of Valencia Region (FISABIO-Public Health), Valencia, Spain
- Biomedical Research Networking Center for Epidemiology and Public Health (CIBERESP), Madrid, Spain
| | - Andrés Moya
- Department of Genomics and Health, Foundation for the Promotion of Health and Biomedical Research of Valencia Region (FISABIO-Public Health), Valencia, Spain
- Biomedical Research Networking Center for Epidemiology and Public Health (CIBERESP), Madrid, Spain
- Institute for Integrative Systems Biology (I2SysBio), University of Valencia, Spanish National Research Council (CSIC-UVEG), Valencia, Spain
| | - Nikolaos Perakakis
- Department of Internal Medicine III, University Hospital Carl Gustav Carus, TU Dresden, Paul Langerhans Institute Dresden (PLID), Helmholtz Center Munich, Dresden, Germany
| | - Geltrude Mingrone
- Department of Translational Medicine and Surgery, Università Cattolica del Sacro Cuore, Rome, Italy
| | - Stefan Bornstein
- Department of Internal Medicine III, University Hospital Carl Gustav Carus, TU Dresden, Paul Langerhans Institute Dresden (PLID), Helmholtz Center Munich, Dresden, Germany
| | | | - Ernesto Castro
- General and Digestive Surgery Service, Dr. Josep Trueta University Hospital, Girona, Spain
| | - Jose Manuel Fernández-Real
- Department of Diabetes, Endocrinology and Nutrition, Dr. Josep Trueta University Hospital, Girona, Spain
- Nutrition, Eumetabolism and Health Group, Girona Biomedical Research Institute (IDIBGI-CERCA), Girona, Spain
- CIBER Fisiopatología de la Obesidad y Nutrición (CIBERobn), Instituto de Salud Carlos III, Madrid, Spain
- Department of Medical Sciences, School of Medicine, University of Girona, Girona, Spain
| | - Jordi Mayneris-Perxachs
- Department of Diabetes, Endocrinology and Nutrition, Dr. Josep Trueta University Hospital, Girona, Spain
- Integrative Systems Medicine and Biology Group, Girona Biomedical Research Institute (IDIBGI-CERCA), Parc Hospitalari Martí i Julià, Edifici M2, Salt, Spain
- CIBER Fisiopatología de la Obesidad y Nutrición (CIBERobn), Instituto de Salud Carlos III, Madrid, Spain
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14
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Franz K, Markó L, Mähler A, Chakaroun R, Heinitz S, Schlögl H, Sacher J, Steckhan N, Dechend R, Adams N, Andersen M, Glintborg D, Viehweger M, Bahr LS, Forslund-Startceva SK. Sex hormone-dependent host-microbiome interactions and cardiovascular risk (XCVD): design of a longitudinal multi-omics cohort study. BMJ Open 2025; 15:e087982. [PMID: 39788783 PMCID: PMC11751863 DOI: 10.1136/bmjopen-2024-087982] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/24/2024] [Accepted: 12/23/2024] [Indexed: 01/12/2025] Open
Abstract
INTRODUCTION Cardiovascular diseases (CVDs) present differently in women and men, influenced by host-microbiome interactions. The roles of sex hormones in CVD outcomes and gut microbiome in modifying these effects are poorly understood. The XCVD study examines gut microbiome mediation of sex hormone effects on CVD risk markers by observing transgender participants undergoing gender-affirming hormone therapy (GAHT), with findings expected to extrapolate to cisgender populations. METHODS AND ANALYSES This observational, longitudinal cohort study includes baseline, 1- and 2-year follow-ups with transgender participants beginning GAHT. It involves comprehensive phenotyping and microbiome genotyping, integrating computational analyses of high-dimensional data. Microbial diversity will be assessed using gut, skin, and oral samples via 16S rRNA and shotgun metagenomic sequencing of gut samples. Blood measurements will include sex hormones, CVD risk markers, cardiometabolic parameters, cytokines, and immune cell counts. Hair samples will be analysed for cortisol. Participants will complete online questionnaires on physical activity, mental health, stress, quality of life, fatigue, sleep, pain, and gender dysphoria, tracking medication use and diet to control for confounders. Statistical analyses will integrate phenomic, lifestyle, and multi-omic data to model health effects, testing gut microbiome mediation of CVD risk as the endocrine environment shifts between that typical for cisgender men to women and vice versa. ETHICS AND DISSEMINATION The study adheres to Good Clinical Practice and the Declaration of Helsinki. The protocol was approved by the Charité Ethical Committee (EA1/339/21). Signed informed consent will be obtained. Results will be published in peer-reviewed journals and conferences and shared as accessible summaries for participants, community groups, and the public, with participants able to view their data securely after public and patient involvement review for accessibility. TRIAL REGISTRATION NUMBER The XCVD study was registered on ClinicalTrials.gov (NCT05334888) as 'Sex-differential host-microbiome CVD risk - a longitudinal cohort approach (XCVD)" on 4 April 2022. Data set link can be found at https://classic. CLINICALTRIALS gov/ct2/show/NCT05334888.
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Affiliation(s)
- Kristina Franz
- Experimental and Clinical Research Center, Charité - Universitätsmedizin Berlin and Max Delbrück Center for Molecular Medicine, Berlin, Germany
- Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC), Berlin, Germany
- German Centre for Cardiovascular Research (DZHK) partner site Berlin, DZHK, Berlin, Germany
- Deutsches Herzzentrum der Charité - Medical Heart Center of Charité and German Heart Institute Berlin, Department of Cardiology, Angiology and Intensive Care Medicine, Berlin, Germany
- Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany
| | - Lajos Markó
- Experimental and Clinical Research Center, Charité - Universitätsmedizin Berlin and Max Delbrück Center for Molecular Medicine, Berlin, Germany
- Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC), Berlin, Germany
- German Centre for Cardiovascular Research (DZHK) partner site Berlin, DZHK, Berlin, Germany
- Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany
- Berlin Institute of Health (BIH), Berlin, Germany
| | - Anja Mähler
- Experimental and Clinical Research Center, Charité - Universitätsmedizin Berlin and Max Delbrück Center for Molecular Medicine, Berlin, Germany
- Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC), Berlin, Germany
- Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany
| | - Rima Chakaroun
- Medical Department III Endocrinology Nephrology Rheumatology, University of Leipzig Medical Center, Leipzig, Germany
- Sahlgrenska Center for Cardiovascular and Metabolic Research, University of Gothenburg Wallenberg Laboratory for Cardiovascular and Metabolic Research, Goteborg, Sweden
| | - Sascha Heinitz
- Medical Department III Endocrinology Nephrology Rheumatology, University of Leipzig Medical Center, Leipzig, Germany
| | - Haiko Schlögl
- Medical Department III Endocrinology Nephrology Rheumatology, University of Leipzig Medical Center, Leipzig, Germany
- HI-MAG, Helmholtz Institute for Metabolic Obesity and Vascular Research, Leipzig, Germany
| | - Julia Sacher
- Clinic for Cognitive Neurology, University of Leipzig Medical Center, and Department of Neurology, Max Planck Institute for Human Cognitive and Brain Sciences, Max-Planck-Institut fur molekulare Physiologie, Dortmund, Germany
| | - Nico Steckhan
- Digital Health - Connected Healthcare, Hasso Plattner Institute, University of Potsdam, Potsdam, Germany
| | - Ralf Dechend
- Experimental and Clinical Research Center, Charité - Universitätsmedizin Berlin and Max Delbrück Center for Molecular Medicine, Berlin, Germany
- Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC), Berlin, Germany
- German Centre for Cardiovascular Research (DZHK) partner site Berlin, DZHK, Berlin, Germany
- Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany
- Helios Clinic Berlin-Buch, Berlin, Germany
| | - Noah Adams
- University of Toronto, Toronto, Ontario, Canada
- Center for Applied Transgender Studies (CATS), Chicago, Illinois, USA
- Transgender Professional Association for Transgender Health, TPATH, Toronto, Ontario, Canada
| | - Marianne Andersen
- Department of Endocrinology, Odense Universitetshospital, Odense, Denmark
- Institute of Clinical Research, University of Southern Denmark, Odense, Syddanmark, Denmark
| | - Dorte Glintborg
- Institute of Clinical Research, University of Southern Denmark, Odense, Syddanmark, Denmark
- Body Identity Clinic, Odense Universitetshospital Endokrinologisk Afdeling M, Odense, Denmark
| | | | - Lina Samira Bahr
- Experimental and Clinical Research Center, Charité - Universitätsmedizin Berlin and Max Delbrück Center for Molecular Medicine, Berlin, Germany
- Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC), Berlin, Germany
- German Centre for Cardiovascular Research (DZHK) partner site Berlin, DZHK, Berlin, Germany
- Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany
| | - Sofia Kirke Forslund-Startceva
- Experimental and Clinical Research Center, Charité - Universitätsmedizin Berlin and Max Delbrück Center for Molecular Medicine, Berlin, Germany
- Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC), Berlin, Germany
- German Centre for Cardiovascular Research (DZHK) partner site Berlin, DZHK, Berlin, Germany
- Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany
- Transgender Professional Association for Transgender Health, TPATH, Toronto, Ontario, Canada
- European Molecular Biology Laboratory Structural and Computational Biology Unit, Heidelberg, Baden-Württemberg, Germany
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15
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Nishijima S, Stankevic E, Aasmets O, Schmidt TSB, Nagata N, Keller MI, Ferretti P, Juel HB, Fullam A, Robbani SM, Schudoma C, Hansen JK, Holm LA, Israelsen M, Schierwagen R, Torp N, Telzerow A, Hercog R, Kandels S, Hazenbrink DHM, Arumugam M, Bendtsen F, Brøns C, Fonvig CE, Holm JC, Nielsen T, Pedersen JS, Thiele MS, Trebicka J, Org E, Krag A, Hansen T, Kuhn M, Bork P. Fecal microbial load is a major determinant of gut microbiome variation and a confounder for disease associations. Cell 2025; 188:222-236.e15. [PMID: 39541968 DOI: 10.1016/j.cell.2024.10.022] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2024] [Revised: 07/12/2024] [Accepted: 10/14/2024] [Indexed: 11/17/2024]
Abstract
The microbiota in individual habitats differ in both relative composition and absolute abundance. While sequencing approaches determine the relative abundances of taxa and genes, they do not provide information on their absolute abundances. Here, we developed a machine-learning approach to predict fecal microbial loads (microbial cells per gram) solely from relative abundance data. Applying our prediction model to a large-scale metagenomic dataset (n = 34,539), we demonstrated that microbial load is the major determinant of gut microbiome variation and is associated with numerous host factors, including age, diet, and medication. We further found that for several diseases, changes in microbial load, rather than the disease condition itself, more strongly explained alterations in patients' gut microbiome. Adjusting for this effect substantially reduced the statistical significance of the majority of disease-associated species. Our analysis reveals that the fecal microbial load is a major confounder in microbiome studies, highlighting its importance for understanding microbiome variation in health and disease.
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Affiliation(s)
- Suguru Nishijima
- Molecular Systems Biology Unit, European Molecular Biology Laboratory, Heidelberg, Germany
| | - Evelina Stankevic
- Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen, Copenhagen, Denmark
| | - Oliver Aasmets
- Institute of Genomics, University of Tartu, Tartu, Estonia
| | - Thomas S B Schmidt
- Molecular Systems Biology Unit, European Molecular Biology Laboratory, Heidelberg, Germany
| | - Naoyoshi Nagata
- Department of Gastroenterological Endoscopy, Tokyo Medical University, Tokyo, Japan
| | - Marisa Isabell Keller
- Molecular Systems Biology Unit, European Molecular Biology Laboratory, Heidelberg, Germany
| | - Pamela Ferretti
- Molecular Systems Biology Unit, European Molecular Biology Laboratory, Heidelberg, Germany
| | - Helene Bæk Juel
- Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen, Copenhagen, Denmark
| | - Anthony Fullam
- Molecular Systems Biology Unit, European Molecular Biology Laboratory, Heidelberg, Germany
| | | | - Christian Schudoma
- Molecular Systems Biology Unit, European Molecular Biology Laboratory, Heidelberg, Germany
| | - Johanne Kragh Hansen
- Faculty of Health Sciences, University of Southern Denmark, Odense, Denmark; Department of Gastroenterology and Hepatology, Odense University Hospital, Odense, Denmark
| | - Louise Aas Holm
- Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen, Copenhagen, Denmark; The Children's Obesity Clinic, Department of Pediatrics, Copenhagen University Hospital Holbæk, Holbæk, Denmark
| | - Mads Israelsen
- Faculty of Health Sciences, University of Southern Denmark, Odense, Denmark; Department of Gastroenterology and Hepatology, Odense University Hospital, Odense, Denmark
| | - Robert Schierwagen
- Department of Internal Medicine B, University of Münster, Münster, Germany
| | - Nikolaj Torp
- Faculty of Health Sciences, University of Southern Denmark, Odense, Denmark; Department of Gastroenterology and Hepatology, Odense University Hospital, Odense, Denmark
| | - Anja Telzerow
- Molecular Systems Biology Unit, European Molecular Biology Laboratory, Heidelberg, Germany
| | - Rajna Hercog
- Molecular Systems Biology Unit, European Molecular Biology Laboratory, Heidelberg, Germany
| | - Stefanie Kandels
- Molecular Systems Biology Unit, European Molecular Biology Laboratory, Heidelberg, Germany
| | - Diënty H M Hazenbrink
- Molecular Systems Biology Unit, European Molecular Biology Laboratory, Heidelberg, Germany
| | - Manimozhiyan Arumugam
- Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen, Copenhagen, Denmark
| | - Flemming Bendtsen
- Gastrounit, Medical Division, Copenhagen University Hospital Hvidovre, Hvidovre, Denmark
| | - Charlotte Brøns
- Clinical Research, Steno Diabetes Center Copenhagen, Herlev, Denmark
| | - Cilius Esmann Fonvig
- Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen, Copenhagen, Denmark; The Children's Obesity Clinic, Department of Pediatrics, Copenhagen University Hospital Holbæk, Holbæk, Denmark; Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Jens-Christian Holm
- Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen, Copenhagen, Denmark; The Children's Obesity Clinic, Department of Pediatrics, Copenhagen University Hospital Holbæk, Holbæk, Denmark; Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Trine Nielsen
- Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen, Copenhagen, Denmark; Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark; Medical department, University Hospital Zeeland, Køge, Denmark
| | - Julie Steen Pedersen
- Gastrounit, Medical Division, Copenhagen University Hospital Hvidovre, Hvidovre, Denmark
| | - Maja Sofie Thiele
- Faculty of Health Sciences, University of Southern Denmark, Odense, Denmark; Department of Gastroenterology and Hepatology, Odense University Hospital, Odense, Denmark
| | - Jonel Trebicka
- Department of Internal Medicine B, University of Münster, Münster, Germany; European Foundation for the Study of Chronic Liver Failure, EFCLIF, Barcelona, Spain
| | - Elin Org
- Institute of Genomics, University of Tartu, Tartu, Estonia
| | - Aleksander Krag
- Faculty of Health Sciences, University of Southern Denmark, Odense, Denmark; Department of Gastroenterology and Hepatology, Odense University Hospital, Odense, Denmark
| | - Torben Hansen
- Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen, Copenhagen, Denmark
| | - Michael Kuhn
- Molecular Systems Biology Unit, European Molecular Biology Laboratory, Heidelberg, Germany.
| | - Peer Bork
- Molecular Systems Biology Unit, European Molecular Biology Laboratory, Heidelberg, Germany; Max Delbrück Centre for Molecular Medicine, Berlin, Germany; Department of Bioinformatics, Biocenter, University of Würzburg, Würzburg, Germany.
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16
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Duan D, Wang M, Han J, Li M, Wang Z, Zhou S, Xin W, Li X. Advances in multi-omics integrated analysis methods based on the gut microbiome and their applications. Front Microbiol 2025; 15:1509117. [PMID: 39831120 PMCID: PMC11739165 DOI: 10.3389/fmicb.2024.1509117] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2024] [Accepted: 12/13/2024] [Indexed: 01/22/2025] Open
Abstract
The gut microbiota actually shares the host's physical space and affects the host's physiological functions and health indicators through a complex network of interactions with the host. However, its role as a determinant of host health and disease is often underestimated. With the emergence of new technologies including next-generation sequencing (NGS) and advanced techniques such as microbial community sequencing, people have begun to explore the interaction mechanisms between microorganisms and hosts at various omics levels such as genomics, transcriptomics, metabolomics, and proteomics. With the enrichment of multi-omics integrated analysis methods based on the microbiome, an increasing number of complex statistical analysis methods have also been proposed. In this review, we summarized the multi-omics research analysis methods currently used to study the interaction between the microbiome and the host. We analyzed the advantages and limitations of various methods and briefly introduced their application progress.
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Affiliation(s)
- Dongdong Duan
- Sanya Institute, Hainan Academy of Agricultural, Sanya, China
| | - Mingyu Wang
- College of Animal Sciences and Technology, Henan Agricultural University, Zhengzhou, China
| | - Jinyi Han
- Sanya Institute, Hainan Academy of Agricultural, Sanya, China
| | - Mengyu Li
- Sanya Institute, Hainan Academy of Agricultural, Sanya, China
| | - Zhenyu Wang
- Sanya Institute, Hainan Academy of Agricultural, Sanya, China
| | - Shenping Zhou
- Sanya Institute, Hainan Academy of Agricultural, Sanya, China
| | - Wenshui Xin
- Sanya Institute, Hainan Academy of Agricultural, Sanya, China
| | - Xinjian Li
- Sanya Institute, Hainan Academy of Agricultural, Sanya, China
- College of Animal Sciences and Technology, Henan Agricultural University, Zhengzhou, China
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17
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Kullberg RFJ, Haak BW, Chanderraj R, Prescott HC, Dickson RP, Wiersinga WJ. Empirical antibiotic therapy for sepsis: save the anaerobic microbiota. THE LANCET. RESPIRATORY MEDICINE 2025; 13:92-100. [PMID: 39401510 DOI: 10.1016/s2213-2600(24)00257-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/28/2024] [Revised: 07/23/2024] [Accepted: 08/06/2024] [Indexed: 01/07/2025]
Abstract
Antibiotics are fundamental in sepsis management; however, the optimal empirical treatment remains debated. Despite anaerobes rarely being the causative pathogen of sepsis, antibiotics targeting them are frequently used, which might lead to unintended consequences. Multiple studies have shown that depletion of commensal anaerobic gut microbes by anti-anaerobic antibiotics influences systemic immunity and is associated with increased mortality in patients with sepsis. However, this knowledge has not yet been translated into clinical practice. When considering empirical coverage of anaerobic pathogens in sepsis, most physicians advocate for a better-safe-than-sorry approach. In this Viewpoint, we argue that anti-anaerobic antibiotics could often result in being sorry rather than safe. We provide an overview of the limited necessity of anaerobic coverage and the potential detrimental effects of anaerobic depletion in sepsis. We aim to raise anaerobic awareness to reduce the unnecessary use of anti-anaerobic antibiotics in empirical sepsis treatment and improve patient outcomes.
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Affiliation(s)
- Robert F J Kullberg
- Center for Experimental and Molecular Medicine, Amsterdam UMC, University of Amsterdam, Amsterdam, Netherlands.
| | - Bastiaan W Haak
- Center for Experimental and Molecular Medicine, Amsterdam UMC, University of Amsterdam, Amsterdam, Netherlands
| | - Rishi Chanderraj
- Division of Infectious Diseases, Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, MI, USA; Medicine Service, Infectious Diseases Section, Veterans Affairs Ann Arbor Healthcare System, Ann Arbor, MI, USA; Weil Institute for Critical Care Research and Innovation, Ann Arbor, MI, USA
| | - Hallie C Prescott
- Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, MI, USA; Veterans Affairs Center for Clinical Management Research, Ann Arbor, MI, USA
| | - Robert P Dickson
- Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, MI, USA; Department of Microbiology and Immunology, University of Michigan Medical School, Ann Arbor, MI, USA; Weil Institute for Critical Care Research and Innovation, Ann Arbor, MI, USA
| | - W Joost Wiersinga
- Center for Experimental and Molecular Medicine, Amsterdam UMC, University of Amsterdam, Amsterdam, Netherlands; Division of Infectious Diseases, Department of Internal Medicine, Amsterdam UMC, University of Amsterdam, Amsterdam, Netherlands
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18
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Mishra A, McNichol J, Fuhrman J, Blei D, Müller CL. Variational inference for microbiome survey data with application to global ocean data. ISME COMMUNICATIONS 2025; 5:ycaf062. [PMID: 40352106 PMCID: PMC12064564 DOI: 10.1093/ismeco/ycaf062] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 03/18/2024] [Revised: 01/21/2025] [Accepted: 04/08/2025] [Indexed: 05/14/2025]
Abstract
Linking sequence-derived microbial taxa abundances to host (patho-)physiology or habitat characteristics in a reproducible and interpretable manner has remained a formidable challenge for the analysis of microbiome survey data. Here, we introduce a flexible probabilistic modeling framework, VI-MIDAS (variational inference for microbiome survey data analysis), that enables joint estimation of context-dependent drivers and broad patterns of associations of microbial taxon abundances from microbiome survey data. VI-MIDAS comprises mechanisms for direct coupling of taxon abundances with covariates and taxa-specific latent coupling, which can incorporate spatio-temporal information and taxon-taxon interactions. We leverage mean-field variational inference for posterior VI-MIDAS model parameter estimation and illustrate model building and analysis using Tara Ocean Expedition survey data. Using VI-MIDAS' latent embedding model and tools from network analysis, we show that marine microbial communities can be broadly categorized into five modules, including SAR11-, nitrosopumilus-, and alteromondales-dominated communities, each associated with specific environmental and spatiotemporal signatures. VI-MIDAS also finds evidence for largely positive taxon-taxon associations in SAR11 or Rhodospirillales clades, and negative associations with Alteromonadales and Flavobacteriales classes. Our results indicate that VI-MIDAS provides a powerful integrative statistical analysis framework for discovering broad patterns of associations between microbial taxa and context-specific covariate data from microbiome survey data.
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Affiliation(s)
- Aditya Mishra
- Department of Statistics, University of Georgia, Athens, GA, 30606, United States
| | - Jesse McNichol
- Department of Biology, St. Francis Xavier University, Antigonish, NS, B2G 2W5, Canada
- Department of Biological Sciences, University of Southern California, LA, 90007, United States
| | - Jed Fuhrman
- Department of Biological Sciences, University of Southern California, LA, 90007, United States
| | - David Blei
- Center for Computational Mathematics, Flatiron Institute, New York, NY, 10010, United States
- Department of Statistics and Computer Science, Columbia University, New York, NY, 10027, United States
| | - Christian L Müller
- Center for Computational Mathematics, Flatiron Institute, New York, NY, 10010, United States
- Computational Health Center, Helmholtz Zentrum München, Munich, 85764, Germany
- Department of Statistics, LMU München, Munich, 80539, Germany
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19
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Patt M, Karkossa I, Krieg L, Massier L, Makki K, Tabei S, Karlas T, Dietrich A, Gericke M, Stumvoll M, Blüher M, von Bergen M, Schubert K, Kovacs P, Chakaroun RM. FGF21 and its underlying adipose tissue-liver axis inform cardiometabolic burden and improvement in obesity after metabolic surgery. EBioMedicine 2024; 110:105458. [PMID: 39608059 PMCID: PMC11638646 DOI: 10.1016/j.ebiom.2024.105458] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/17/2024] [Revised: 10/20/2024] [Accepted: 11/04/2024] [Indexed: 11/30/2024] Open
Abstract
BACKGROUND This research investigates the determinants of circulating FGF21 levels in a cohort reflecting metabolic disease progression, examining the associations of circulating FGF21 with morphology and function of adipose tissue (AT), and with metabolic adjustments following metabolic surgery. METHODS We measured serum FGF21 in 678 individuals cross-sectionally and in 189 undergoing metabolic surgery longitudinally. Relationships between FGF21 levels, AT histology, transcriptomes and proteomes, cardiometabolic risk factors, and post-surgery metabolic adjustments were assessed using univariate and multivariate analyses, causal mediation analysis, and network integration of AT transcriptomes and proteomes. FINDINGS FGF21 levels were linked to central adiposity, subclinical inflammation, insulin resistance, and cardiometabolic risk, and were driven by circulating leptin and liver enzymes. Higher FGF21 were linked with AT dysfunction reflected in fibro-inflammatory and lipid dysmetabolism pathways. Specifically, visceral AT inflammation was tied to both FGF21 elevation and liver dysfunction. Post-surgery, FGF21 peaked transitorily at three months. Mediation analysis highlighted an underlying increased AT catabolic state with elevated free fatty acids (FFA), contributing to higher liver stress and FGF21 levels (total effect of free fatty acids on FGF21 levels: 0.38, p < 0.01; proportion mediation via liver 32%, p < 0.01). In line with this, histological AT fibrosis linked with less pronounced FGF21 responses and reduced fat loss post-surgery (FFA and visceral AT fibrosis: rho = -0.31, p = 0.030; FFA and fat-mass loss: rho = 0.17, p = 0.020). INTERPRETATION FGF21 reflects the liver's disproportionate metabolic stress response in both central adiposity and after metabolic surgery, with its dynamics reflecting an AT-liver crosstalk. FUNDING This work was supported by the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) through CRC 1052, project number 209933838, CRC1382 and a Walther-Benjamin Fellowship and by a junior research grant by the Medical Faculty, University of Leipzig, and by the Federal Ministry of Education and Research (BMBF), Germany, FKZ: 01EO1501. Part of this work was supported by the European Union's Seventh Framework Program for research, technological development and demonstration under grant agreement HEALTH-F4-2012-305312 and by the CRC1382 and the Novo Nordisk Foundation and by the Deutsche Forschungsgemeinschaft (DFG, German Research foundation) project number 530364326.
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Affiliation(s)
- Marie Patt
- University of Leipzig Medical Centre, Medical Department III-Endocrinology, Nephrology, Rheumatology, Leipzig, Germany
| | - Isabel Karkossa
- Department of Molecular Systems Biology, Helmholtz-Centre for Environmental Research - UFZ, Leipzig, Germany
| | - Laura Krieg
- Department of Molecular Systems Biology, Helmholtz-Centre for Environmental Research - UFZ, Leipzig, Germany
| | - Lucas Massier
- University of Leipzig Medical Centre, Medical Department III-Endocrinology, Nephrology, Rheumatology, Leipzig, Germany; Department of Medicine (H7), Karolinska Institutet, Stockholm, Sweden
| | - Kassem Makki
- INSERM U1060, INRAE UMR1397, Université de Lyon, France
| | - Shirin Tabei
- Institute of Endocrinology and Diabetes, University of Lübeck, Lübeck, Germany; Centre of Brain, Behaviour, and Metabolism (CBBM), University of Lübeck, Lübeck, Germany
| | - Thomas Karlas
- Division of Gastroenterology, Medical Department II, University of Leipzig Medical Centre, Leipzig, Germany
| | - Arne Dietrich
- Department of Visceral, Transplant, Thoracic and Vascular Surgery, University of Leipzig Medical Centre, Leipzig, Germany
| | - Martin Gericke
- Leipzig University, Institute of Anatomy, Leipzig, Germany
| | - Michael Stumvoll
- University of Leipzig Medical Centre, Medical Department III-Endocrinology, Nephrology, Rheumatology, Leipzig, Germany; Helmholtz Institute for Metabolic Obesity and Vascular Research (HI-MAG), Helmholtz Zentrum München, University of Leipzig and University Hospital Leipzig, Leipzig, Germany
| | - Matthias Blüher
- University of Leipzig Medical Centre, Medical Department III-Endocrinology, Nephrology, Rheumatology, Leipzig, Germany; Helmholtz Institute for Metabolic Obesity and Vascular Research (HI-MAG), Helmholtz Zentrum München, University of Leipzig and University Hospital Leipzig, Leipzig, Germany
| | - Martin von Bergen
- Department of Molecular Systems Biology, Helmholtz-Centre for Environmental Research - UFZ, Leipzig, Germany; Institute of Biochemistry, Leipzig University, Leipzig, Germany; German Centre for Integrative Biodiversity Research (iDiv) Halle-Jena-Leipzig, Leipzig, Germany
| | - Kristin Schubert
- Department of Molecular Systems Biology, Helmholtz-Centre for Environmental Research - UFZ, Leipzig, Germany
| | - Peter Kovacs
- University of Leipzig Medical Centre, Medical Department III-Endocrinology, Nephrology, Rheumatology, Leipzig, Germany; Deutsches Zentrum für Diabetesforschung e.V., 85764, Neuherberg, Germany
| | - Rima M Chakaroun
- University of Leipzig Medical Centre, Medical Department III-Endocrinology, Nephrology, Rheumatology, Leipzig, Germany; Wallenberg Laboratory, Department of Molecular and Clinical Medicine and Sahlgrenska Centre for Cardiovascular and Metabolic Research, University of Gothenburg, Gothenburg, Sweden.
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20
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Pan X, Song Y, Liang Y, Feng G, Wang Z. Roseburia intestinalis: A possible target for vascular calcification. Heliyon 2024; 10:e39865. [PMID: 39524709 PMCID: PMC11550659 DOI: 10.1016/j.heliyon.2024.e39865] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/21/2024] [Revised: 10/22/2024] [Accepted: 10/25/2024] [Indexed: 11/16/2024] Open
Abstract
With the advancement of metagenomics and metabolomics techniques, the crucial role of the gut microbiome in intestinal, cardiovascular, and metabolic disorders has been extensively explored. Vascular calcification (VC) is common in atherosclerosis, hypertension, diabetes mellitus, and chronic kidney disease. Moreover, it is a significant cause of cardiovascular diseases and mortality. Roseburia intestinalis, as a promising candidate for the next generation of probiotics, plays a substantial role in inhibiting the systemic inflammatory response and holds great potential in the treatment of intestinal diseases, cardiovascular diseases, and metabolic disorders. Its primary metabolite, butyrate, acts on specific receptors (GPR43, GPR41, GPR109a). It enters cells via transporters (MCT1, SMCT1), affecting gene expression through HDACs, PPARγ and Nrf2, promoting energy metabolism and changing the concentration of other metabolites (including AGEs, LPS, BHB) in the circulation to affect the body's life activities. In this paper, we focus on the possible mechanism of the primary metabolite butyrate of Roseburia intestinalis in inhibiting VC, which may become a potential therapeutic target for the treatment of VC and the ways to enhance its effect.
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Affiliation(s)
- Xinyun Pan
- Department of Cardiology, Affiliated Hospital of Jiangsu University, Zhenjiang, 212001, China
- Institue of Cardiovascular Diseases, Jiangsu University, Zhenjiang, 21200, China
| | - Yunjian Song
- Institue of Cardiovascular Diseases, Jiangsu University, Zhenjiang, 21200, China
| | - Yapeng Liang
- Department of Emergency, Affiliated Hospital of Jiangsu University, Zhenjiang, 212001, China
| | - Guoquan Feng
- Department of Imaging, Affiliated Hospital of Jiangsu University, Zhenjiang, 212001, China
| | - Zhongqun Wang
- Department of Cardiology, Affiliated Hospital of Jiangsu University, Zhenjiang, 212001, China
- Institue of Cardiovascular Diseases, Jiangsu University, Zhenjiang, 21200, China
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21
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Jeyaraman N, Jeyaraman M, Mariappan T, Muthu S, Ramasubramanian S, Sharma S, Santos GS, da Fonseca LF, Lana JF. Insights of gut-liver axis in hepatic diseases: Mechanisms, clinical implications, and therapeutic potentials. World J Gastrointest Pharmacol Ther 2024; 15:98146. [PMID: 39534519 PMCID: PMC11551618 DOI: 10.4292/wjgpt.v15.i6.98146] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/18/2024] [Revised: 08/06/2024] [Accepted: 09/10/2024] [Indexed: 10/25/2024] Open
Abstract
With the rising prevalence of chronic liver diseases worldwide, there exists a need to diversify our artillery to incorporate a plethora of diagnostic and therapeutic methods to combat this disease. Currently, the most common causes of liver disease are non-alcoholic fatty liver disease, hepatitis, and alcoholic liver disease. Some of these chronic diseases have the potential to transform into hepatocellular carcinoma with advancing fibrosis. In this review, we analyse the relationship between the gut and liver and their significance in liver disease. This two-way relationship has interesting effects on each other in liver diseases. The gut microbiota, through its metabolites, influences the metabolism in numerous ways. Careful manipulation of its composition can lead to the discovery of numerous therapeutic potentials that can be applied in the treatment of various liver diseases. Numerous cohort studies with a pan-omics approach are required to understand the association between the gut microbiome and hepatic disease progression through which we can identify effective ways to deal with this issue.
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Affiliation(s)
- Naveen Jeyaraman
- Department of Orthopaedics, ACS Medical College and Hospital, Dr MGR Educational and Research Institute, Chennai 600077, Tamil Nadu, India
- Department of Research Methods, Orthopaedic Research Group, Coimbatore 641045, Tamil Nadu, India
| | - Madhan Jeyaraman
- Department of Orthopaedics, ACS Medical College and Hospital, Dr MGR Educational and Research Institute, Chennai 600077, Tamil Nadu, India
- Department of Research Methods, Orthopaedic Research Group, Coimbatore 641045, Tamil Nadu, India
- Department of Orthopaedics, Brazilian Institute of Regenerative Medicine, Indaiatuba 13334-170, São Paulo, Brazil
| | - Tejaswin Mariappan
- Department of Community Medicine, Government Stanley Medical College and Hospital, Chennai 600001, Tamil Nadu, India
| | - Sathish Muthu
- Department of Research Methods, Orthopaedic Research Group, Coimbatore 641045, Tamil Nadu, India
- Department of Orthopaedics, Government Medical College, Karur 639004, Tamil Nadu, India
- Department of Biotechnology, Faculty of Engineering, Karpagam Academy of Higher Education, Coimbatore 641021, Tamil Nadu, India
| | - Swaminathan Ramasubramanian
- Department of Orthopaedics, Government Medical College, Omandurar Government Estate, Chennai 600002, Tamil Nadu, India
| | - Shilpa Sharma
- Department of Paediatric Surgery, All India Institute of Medical Sciences, New Delhi 110029, India
| | - Gabriel Silva Santos
- Department of Orthopaedics, Brazilian Institute of Regenerative Medicine, Indaiatuba 13334-170, São Paulo, Brazil
| | - Lucas Furtado da Fonseca
- Department of Orthopaedics, Brazilian Institute of Regenerative Medicine, Indaiatuba 13334-170, São Paulo, Brazil
| | - José Fábio Lana
- Department of Orthopaedics, Brazilian Institute of Regenerative Medicine, Indaiatuba 13334-170, São Paulo, Brazil
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22
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Larsson A, Ericson U, Jönsson D, Miari M, Athanasiadis P, Baldanzi G, Brunkwall L, Hellstrand S, Klinge B, Melander O, Nilsson PM, Fall T, Maziarz M, Orho-Melander M. New connections of medication use and polypharmacy with the gut microbiota composition and functional potential in a large population. Sci Rep 2024; 14:23723. [PMID: 39390025 PMCID: PMC11467196 DOI: 10.1038/s41598-024-71571-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/07/2024] [Accepted: 08/29/2024] [Indexed: 10/12/2024] Open
Abstract
Medication can affect the gut microbiota composition and function. The aim of this study was to investigate connections between use of common non-antibiotic medicines and the gut microbiota composition and function in a large Swedish cohort (N = 2223). Use of 67 medications and polypharmacy (≥ 5 medications), based on self-reported and prescription registry data, were associated with the relative abundance of 881 gut metagenomic species (> 5% prevalence) and 103 gut metabolic modules (GMMs). Altogether, 97 associations of 26 medications with 40 species and of four medications with five GMMs were observed (false discovery rate < 5%). Several earlier findings were replicated like the positive associations of proton pump inhibitors (PPIs) with numerous oral species, and those of metformin with Escherichia species and with lactate consumption I and arginine degradation II. Several new associations were observed between, among others, use of antidepressants, beta-blockers, nonsteroidal anti-inflammatory drugs and calcium channel blockers, and specific species. Polypharmacy was positively associated with Enterococcus faecalis, Bacteroides uniformis, Rothia mucilaginosa, Escherichia coli and Limosilactobacillus vaginalis, and with 13 GMMs. We confirmed several previous findings and identified numerous new associations between use of medications/polypharmacy and the gut microbiota composition and functional potential. Further studies are needed to confirm the new findings.
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Affiliation(s)
- Anna Larsson
- Department of Clinical Sciences in Malmö, Lund University Diabetes Center, Lund University, Malmö, Sweden
| | - Ulrika Ericson
- Department of Clinical Sciences in Malmö, Lund University Diabetes Center, Lund University, Malmö, Sweden
| | - Daniel Jönsson
- Department of Clinical Sciences in Malmö, Lund University Diabetes Center, Lund University, Malmö, Sweden
- Public Dental Service of Skåne, Lund, Sweden
- Department of Periodontology, Faculty of Odontology, Malmö University, Malmö, Sweden
| | - Mariam Miari
- Department of Clinical Sciences in Malmö, Lund University Diabetes Center, Lund University, Malmö, Sweden
| | - Paschalis Athanasiadis
- Department of Clinical Sciences in Malmö, Lund University Diabetes Center, Lund University, Malmö, Sweden
| | - Gabriel Baldanzi
- Molecular Epidemiology, Department of Medical Sciences, Uppsala University, Uppsala, Sweden
| | - Louise Brunkwall
- Department of Clinical Sciences in Malmö, Lund University Diabetes Center, Lund University, Malmö, Sweden
| | - Sophie Hellstrand
- Department of Clinical Sciences in Malmö, Lund University Diabetes Center, Lund University, Malmö, Sweden
| | - Björn Klinge
- Department of Periodontology, Faculty of Odontology, Malmö University, Malmö, Sweden
- Division of Oral Health and Periodontology, Department of Dental Medicine, Karolinska Institutet, Solna, Sweden
| | - Olle Melander
- Department of Clinical Sciences in Malmö, Lund University Diabetes Center, Lund University, Malmö, Sweden
| | - Peter M Nilsson
- Department of Clinical Sciences in Malmö, Lund University Diabetes Center, Lund University, Malmö, Sweden
| | - Tove Fall
- Molecular Epidemiology, Department of Medical Sciences, Uppsala University, Uppsala, Sweden
- SciLifeLab, Uppsala University, Uppsala, Sweden
| | - Marlena Maziarz
- Department of Clinical Sciences in Malmö, Lund University Diabetes Center, Lund University, Malmö, Sweden
| | - Marju Orho-Melander
- Department of Clinical Sciences in Malmö, Lund University Diabetes Center, Lund University, Malmö, Sweden.
- Clinical Research Center, Diabetes and Cardiovascular Disease, Box 50332, 202 13, Malmö, Sweden.
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23
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Thänert R, Schwartz DJ, Keen EC, Hall-Moore C, Wang B, Shaikh N, Ning J, Rouggly-Nickless LC, Thänert A, Ferreiro A, Fishbein SRS, Sullivan JE, Radmacher P, Escobedo M, Warner BB, Tarr PI, Dantas G. Clinical sequelae of gut microbiome development and disruption in hospitalized preterm infants. Cell Host Microbe 2024; 32:1822-1837.e5. [PMID: 39197454 PMCID: PMC11466706 DOI: 10.1016/j.chom.2024.07.027] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2024] [Revised: 06/24/2024] [Accepted: 07/31/2024] [Indexed: 09/01/2024]
Abstract
Aberrant preterm infant gut microbiota assembly predisposes to early-life disorders and persistent health problems. Here, we characterize gut microbiome dynamics over the first 3 months of life in 236 preterm infants hospitalized in three neonatal intensive care units using shotgun metagenomics of 2,512 stools and metatranscriptomics of 1,381 stools. Strain tracking, taxonomic and functional profiling, and comprehensive clinical metadata identify Enterobacteriaceae, enterococci, and staphylococci as primarily exploiting available niches to populate the gut microbiome. Clostridioides difficile lineages persist between individuals in single centers, and Staphylococcus epidermidis lineages persist within and, unexpectedly, between centers. Collectively, antibiotic and non-antibiotic medications influence gut microbiome composition to greater extents than maternal or baseline variables. Finally, we identify a persistent low-diversity gut microbiome in neonates who develop necrotizing enterocolitis after day of life 40. Overall, we comprehensively describe gut microbiome dynamics in response to medical interventions in preterm, hospitalized neonates.
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Affiliation(s)
- Robert Thänert
- The Edison Family Center for Genome Sciences and Systems Biology, Washington University School of Medicine, St. Louis, MO 63110, USA; Department of Pathology and Immunology, Division of Laboratory and Genomic Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA
| | - Drew J Schwartz
- The Edison Family Center for Genome Sciences and Systems Biology, Washington University School of Medicine, St. Louis, MO 63110, USA; Department of Pediatrics, Washington University School of Medicine, St. Louis, MO 63110, USA; Department of Molecular Microbiology, Washington University School of Medicine, St. Louis, MO 63110, USA; Department of Obstetrics and Gynecology, Washington University School of Medicine, St. Louis, MO 63110, USA; Center for Women's Infectious Diseases Research, Washington University School of Medicine, St. Louis, MO 63110, USA
| | - Eric C Keen
- The Edison Family Center for Genome Sciences and Systems Biology, Washington University School of Medicine, St. Louis, MO 63110, USA
| | - Carla Hall-Moore
- Department of Pediatrics, Washington University School of Medicine, St. Louis, MO 63110, USA
| | - Bin Wang
- The Edison Family Center for Genome Sciences and Systems Biology, Washington University School of Medicine, St. Louis, MO 63110, USA; Department of Pathology and Immunology, Division of Laboratory and Genomic Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA
| | - Nurmohammad Shaikh
- Department of Pediatrics, Washington University School of Medicine, St. Louis, MO 63110, USA
| | - Jie Ning
- The Edison Family Center for Genome Sciences and Systems Biology, Washington University School of Medicine, St. Louis, MO 63110, USA; Department of Pathology and Immunology, Division of Laboratory and Genomic Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA
| | | | - Anna Thänert
- The Edison Family Center for Genome Sciences and Systems Biology, Washington University School of Medicine, St. Louis, MO 63110, USA; Department of Pathology and Immunology, Division of Laboratory and Genomic Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA
| | - Aura Ferreiro
- The Edison Family Center for Genome Sciences and Systems Biology, Washington University School of Medicine, St. Louis, MO 63110, USA; Department of Pathology and Immunology, Division of Laboratory and Genomic Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA
| | - Skye R S Fishbein
- The Edison Family Center for Genome Sciences and Systems Biology, Washington University School of Medicine, St. Louis, MO 63110, USA; Department of Pathology and Immunology, Division of Laboratory and Genomic Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA
| | - Janice E Sullivan
- Department of Pediatrics, University of Louisville School of Medicine, Norton Children's Hospital, Louisville, KY 40202, USA
| | - Paula Radmacher
- Department of Pediatrics, University of Louisville School of Medicine, Norton Children's Hospital, Louisville, KY 40202, USA
| | - Marilyn Escobedo
- Department of Pediatrics, University of Oklahoma, Oklahoma City, OK 73104, USA
| | - Barbara B Warner
- Department of Pediatrics, Washington University School of Medicine, St. Louis, MO 63110, USA.
| | - Phillip I Tarr
- Department of Pediatrics, Washington University School of Medicine, St. Louis, MO 63110, USA; Department of Molecular Microbiology, Washington University School of Medicine, St. Louis, MO 63110, USA.
| | - Gautam Dantas
- The Edison Family Center for Genome Sciences and Systems Biology, Washington University School of Medicine, St. Louis, MO 63110, USA; Department of Pathology and Immunology, Division of Laboratory and Genomic Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA; Department of Pediatrics, Washington University School of Medicine, St. Louis, MO 63110, USA; Department of Molecular Microbiology, Washington University School of Medicine, St. Louis, MO 63110, USA; Department of Biomedical Engineering, Washington University in St. Louis, St. Louis, MO 63130, USA.
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24
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Wirbel J, Essex M, Forslund SK, Zeller G. A realistic benchmark for differential abundance testing and confounder adjustment in human microbiome studies. Genome Biol 2024; 25:247. [PMID: 39322959 PMCID: PMC11423519 DOI: 10.1186/s13059-024-03390-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2023] [Accepted: 09/06/2024] [Indexed: 09/27/2024] Open
Abstract
BACKGROUND In microbiome disease association studies, it is a fundamental task to test which microbes differ in their abundance between groups. Yet, consensus on suitable or optimal statistical methods for differential abundance testing is lacking, and it remains unexplored how these cope with confounding. Previous differential abundance benchmarks relying on simulated datasets did not quantitatively evaluate the similarity to real data, which undermines their recommendations. RESULTS Our simulation framework implants calibrated signals into real taxonomic profiles, including signals mimicking confounders. Using several whole meta-genome and 16S rRNA gene amplicon datasets, we validate that our simulated data resembles real data from disease association studies much more than in previous benchmarks. With extensively parametrized simulations, we benchmark the performance of nineteen differential abundance methods and further evaluate the best ones on confounded simulations. Only classic statistical methods (linear models, the Wilcoxon test, t-test), limma, and fastANCOM properly control false discoveries at relatively high sensitivity. When additionally considering confounders, these issues are exacerbated, but we find that adjusted differential abundance testing can effectively mitigate them. In a large cardiometabolic disease dataset, we showcase that failure to account for covariates such as medication causes spurious association in real-world applications. CONCLUSIONS Tight error control is critical for microbiome association studies. The unsatisfactory performance of many differential abundance methods and the persistent danger of unchecked confounding suggest these contribute to a lack of reproducibility among such studies. We have open-sourced our simulation and benchmarking software to foster a much-needed consolidation of statistical methodology for microbiome research.
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Affiliation(s)
- Jakob Wirbel
- Structural and Computational Biology Unit (SCB), European Molecular Biology Laboratory (EMBL), Heidelberg, Germany
| | - Morgan Essex
- Experimental and Clinical Research Center (ECRC), a cooperation of the Max-Delbrück Center and Charité-Universitätsmedizin, Berlin, Germany
- Max-Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC), Berlin, Germany
- Charité-Universitätsmedizin Berlin (a corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin), Berlin, Germany
| | - Sofia Kirke Forslund
- Structural and Computational Biology Unit (SCB), European Molecular Biology Laboratory (EMBL), Heidelberg, Germany.
- Experimental and Clinical Research Center (ECRC), a cooperation of the Max-Delbrück Center and Charité-Universitätsmedizin, Berlin, Germany.
- Max-Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC), Berlin, Germany.
- Charité-Universitätsmedizin Berlin (a corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin), Berlin, Germany.
- German Center for Cardiovascular Research (DZHK), Partner Site Berlin, Berlin, Germany.
| | - Georg Zeller
- Structural and Computational Biology Unit (SCB), European Molecular Biology Laboratory (EMBL), Heidelberg, Germany.
- Center for Infectious Diseases (LUCID), Leiden University, Leiden University Medical Center (LUMC), Leiden, Netherlands.
- Center for Microbiome Analyses and Therapeutics (CMAT), Leiden University Medical Center, Leiden, Netherlands.
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25
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Boverhoff D, Kool J, Pijnacker R, Ducarmon QR, Zeller G, Shetty S, Sie S, Mulder AC, van der Klis F, Franz E, Mughini-Gras L, van Baarle D, Fuentes S. Profiling the fecal microbiome and its modulators across the lifespan in the Netherlands. Cell Rep 2024; 43:114729. [PMID: 39264809 DOI: 10.1016/j.celrep.2024.114729] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2024] [Revised: 05/23/2024] [Accepted: 08/22/2024] [Indexed: 09/14/2024] Open
Abstract
Defining what constitutes a healthy microbiome throughout our lives remains an ongoing challenge. Understanding to what extent host and environmental factors can influence it has been the primary motivation for large population studies worldwide. Here, we describe the fecal microbiome of 3,746 individuals (0-87 years of age) in a nationwide study in the Netherlands, in association with extensive questionnaires. We validate previous findings, such as infant-adult trajectories, and explore the collective impact of our variables, which explain over 40% of the variation in microbiome composition. We identify associations with less explored factors, particularly those ethnic related, which show the largest impact on the adult microbiome composition, diversity, metabolic profiles, and CAZy (carbohydrate-active enzyme) repertoires. Understanding the sources of microbiome variability is crucial, given its potential as a modifiable target with therapeutic possibilities. With this work, we aim to serve as a foundational element for the design of health interventions and fundamental research.
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Affiliation(s)
- David Boverhoff
- Centre for Infectious Disease Control, National Institute for Public Health and the Environment, Bilthoven, the Netherlands; Virology & Immunology Research, Department of Medical Microbiology and Infection Prevention, University Medical Center Groningen, Groningen, the Netherlands
| | - Jolanda Kool
- Centre for Infectious Disease Control, National Institute for Public Health and the Environment, Bilthoven, the Netherlands
| | - Roan Pijnacker
- Centre for Infectious Disease Control, National Institute for Public Health and the Environment, Bilthoven, the Netherlands
| | - Quinten R Ducarmon
- Structural and Computational Biology Unit, European Molecular Biology Laboratory, Heidelberg, Germany
| | - Georg Zeller
- Structural and Computational Biology Unit, European Molecular Biology Laboratory, Heidelberg, Germany
| | - Sudarshan Shetty
- Centre for Infectious Disease Control, National Institute for Public Health and the Environment, Bilthoven, the Netherlands; Virology & Immunology Research, Department of Medical Microbiology and Infection Prevention, University Medical Center Groningen, Groningen, the Netherlands
| | - Stephan Sie
- Centre for Infectious Disease Control, National Institute for Public Health and the Environment, Bilthoven, the Netherlands
| | - Annemieke Christine Mulder
- Centre for Infectious Disease Control, National Institute for Public Health and the Environment, Bilthoven, the Netherlands
| | - Fiona van der Klis
- Centre for Infectious Disease Control, National Institute for Public Health and the Environment, Bilthoven, the Netherlands
| | - Eelco Franz
- Centre for Infectious Disease Control, National Institute for Public Health and the Environment, Bilthoven, the Netherlands
| | - Lapo Mughini-Gras
- Centre for Infectious Disease Control, National Institute for Public Health and the Environment, Bilthoven, the Netherlands; Institute for Risk Assessment Sciences, Utrecht University, Utrecht, the Netherlands
| | - Debbie van Baarle
- Centre for Infectious Disease Control, National Institute for Public Health and the Environment, Bilthoven, the Netherlands; Virology & Immunology Research, Department of Medical Microbiology and Infection Prevention, University Medical Center Groningen, Groningen, the Netherlands
| | - Susana Fuentes
- Centre for Infectious Disease Control, National Institute for Public Health and the Environment, Bilthoven, the Netherlands.
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26
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Ma Z, Zuo T, Frey N, Rangrez AY. A systematic framework for understanding the microbiome in human health and disease: from basic principles to clinical translation. Signal Transduct Target Ther 2024; 9:237. [PMID: 39307902 PMCID: PMC11418828 DOI: 10.1038/s41392-024-01946-6] [Citation(s) in RCA: 18] [Impact Index Per Article: 18.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/05/2024] [Revised: 07/03/2024] [Accepted: 08/01/2024] [Indexed: 09/26/2024] Open
Abstract
The human microbiome is a complex and dynamic system that plays important roles in human health and disease. However, there remain limitations and theoretical gaps in our current understanding of the intricate relationship between microbes and humans. In this narrative review, we integrate the knowledge and insights from various fields, including anatomy, physiology, immunology, histology, genetics, and evolution, to propose a systematic framework. It introduces key concepts such as the 'innate and adaptive genomes', which enhance genetic and evolutionary comprehension of the human genome. The 'germ-free syndrome' challenges the traditional 'microbes as pathogens' view, advocating for the necessity of microbes for health. The 'slave tissue' concept underscores the symbiotic intricacies between human tissues and their microbial counterparts, highlighting the dynamic health implications of microbial interactions. 'Acquired microbial immunity' positions the microbiome as an adjunct to human immune systems, providing a rationale for probiotic therapies and prudent antibiotic use. The 'homeostatic reprogramming hypothesis' integrates the microbiome into the internal environment theory, potentially explaining the change in homeostatic indicators post-industrialization. The 'cell-microbe co-ecology model' elucidates the symbiotic regulation affecting cellular balance, while the 'meta-host model' broadens the host definition to include symbiotic microbes. The 'health-illness conversion model' encapsulates the innate and adaptive genomes' interplay and dysbiosis patterns. The aim here is to provide a more focused and coherent understanding of microbiome and highlight future research avenues that could lead to a more effective and efficient healthcare system.
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Affiliation(s)
- Ziqi Ma
- Department of Cardiology, Angiology and Pneumology, University Hospital Heidelberg, Heidelberg, Germany.
- DZHK (German Centre for Cardiovascular Research), partner site Heidelberg/Mannheim, Heidelberg, Germany.
| | - Tao Zuo
- Key Laboratory of Human Microbiome and Chronic Diseases (Sun Yat-sen University), Ministry of Education, Guangzhou, China
- Guangdong Institute of Gastroenterology, The Sixth Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Norbert Frey
- Department of Cardiology, Angiology and Pneumology, University Hospital Heidelberg, Heidelberg, Germany.
- DZHK (German Centre for Cardiovascular Research), partner site Heidelberg/Mannheim, Heidelberg, Germany.
| | - Ashraf Yusuf Rangrez
- Department of Cardiology, Angiology and Pneumology, University Hospital Heidelberg, Heidelberg, Germany.
- DZHK (German Centre for Cardiovascular Research), partner site Heidelberg/Mannheim, Heidelberg, Germany.
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27
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Matsumoto H, Sasahira M, Go TT, Yo S, Ninomiya T, Osawa M, Handa O, Umegami E, Inoue R, Shiotani A. Characteristics of Mucosa-Associated Microbiota in Ulcerative Colitis Patients with 5-Aminosalicylic Acid Intolerance. Biomedicines 2024; 12:2125. [PMID: 39335641 PMCID: PMC11428711 DOI: 10.3390/biomedicines12092125] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2024] [Revised: 09/15/2024] [Accepted: 09/16/2024] [Indexed: 09/30/2024] Open
Abstract
BACKGROUND/OBJECTIVES 5-Aminosalicylic acid (5-ASA) is a first-line therapy for ulcerative colitis (UC). This study examined the mucosa-associated microbiota (MAM) in UC patients, distinguishing between those who were 5-ASA tolerant and intolerant. METHODS Brushing samples were collected from the sigmoid and ileal end of patients with UC during endoscopic procedures. The samples were profiled by using the Illumina MiSeq platform. The V3-V4 regions of the 16S rRNA gene (460 bp) were amplified by using tailed PCR. RESULTS A total of 15 patients with 5-ASA intolerance, 38 patients with 5-ASA tolerance, and 19 healthy controls were recruited in this study. The α-diversity indices were remarkably different among the three groups in the ileum mucosa but not in the sigmoid colon. In the ileum mucosa, Alistipes, Ruminococcaceae, and Odoribacter were less abundant in the 5-ASA-intolerant group than in the control and 5-ASA-tolerant groups. On the contrary, Merdibacter, Brevundimonas, and Porphyromonas were more abundant in the 5-ASA-intolerant group than in other groups. CONCLUSIONS The present study showed that the changes in MAM were characterized by a decrease in mucoprotective bacteria rather than an increase in harmful bacteria.
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Affiliation(s)
- Hiroshi Matsumoto
- Department of Gastroenterology, Kawasaki Medical School, Okayama 701-0192, Japan; (M.S.); (T.T.G.); (S.Y.); (T.N.); (M.O.); (O.H.); (E.U.); (A.S.)
| | - Momoyo Sasahira
- Department of Gastroenterology, Kawasaki Medical School, Okayama 701-0192, Japan; (M.S.); (T.T.G.); (S.Y.); (T.N.); (M.O.); (O.H.); (E.U.); (A.S.)
| | - Tei Tei Go
- Department of Gastroenterology, Kawasaki Medical School, Okayama 701-0192, Japan; (M.S.); (T.T.G.); (S.Y.); (T.N.); (M.O.); (O.H.); (E.U.); (A.S.)
| | - Shogen Yo
- Department of Gastroenterology, Kawasaki Medical School, Okayama 701-0192, Japan; (M.S.); (T.T.G.); (S.Y.); (T.N.); (M.O.); (O.H.); (E.U.); (A.S.)
| | - Takehiro Ninomiya
- Department of Gastroenterology, Kawasaki Medical School, Okayama 701-0192, Japan; (M.S.); (T.T.G.); (S.Y.); (T.N.); (M.O.); (O.H.); (E.U.); (A.S.)
| | - Motoyasu Osawa
- Department of Gastroenterology, Kawasaki Medical School, Okayama 701-0192, Japan; (M.S.); (T.T.G.); (S.Y.); (T.N.); (M.O.); (O.H.); (E.U.); (A.S.)
| | - Osamu Handa
- Department of Gastroenterology, Kawasaki Medical School, Okayama 701-0192, Japan; (M.S.); (T.T.G.); (S.Y.); (T.N.); (M.O.); (O.H.); (E.U.); (A.S.)
| | - Eiji Umegami
- Department of Gastroenterology, Kawasaki Medical School, Okayama 701-0192, Japan; (M.S.); (T.T.G.); (S.Y.); (T.N.); (M.O.); (O.H.); (E.U.); (A.S.)
| | - Ryo Inoue
- Faculty of Agriculture, Setsunan University, 45-1 Nagaotoge-cho, Hirakata 573-0101, Japan;
| | - Akiko Shiotani
- Department of Gastroenterology, Kawasaki Medical School, Okayama 701-0192, Japan; (M.S.); (T.T.G.); (S.Y.); (T.N.); (M.O.); (O.H.); (E.U.); (A.S.)
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28
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Hartmann CR, Khan R, Schöning J, Richter M, Willers M, Pirr S, Heckmann J, Dirks J, Morbach H, Konrad M, Fries E, Winkler M, Büchel J, Seidenspinner S, Fischer J, Vollmuth C, Meinhardt M, Marissen J, Schmolke M, Haid S, Pietschmann T, Backes S, Dölken L, Löber U, Keil T, Heuschmann PU, Wöckel A, Sagar, Ulas T, Forslund-Startceva SK, Härtel C, Viemann D. A clinical protocol for a German birth cohort study of the Maturation of Immunity Against respiratory viral Infections (MIAI). Front Immunol 2024; 15:1443665. [PMID: 39355253 PMCID: PMC11442434 DOI: 10.3389/fimmu.2024.1443665] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/05/2024] [Accepted: 08/29/2024] [Indexed: 10/03/2024] Open
Abstract
Introduction Respiratory viral infections (RVIs) are a major global contributor to morbidity and mortality. The susceptibility and outcome of RVIs are strongly age-dependent and show considerable inter-population differences, pointing to genetically and/or environmentally driven developmental variability. The factors determining the age-dependency and shaping the age-related changes of human anti-RVI immunity after birth are still elusive. Methods We are conducting a prospective birth cohort study aiming at identifying endogenous and environmental factors associated with the susceptibility to RVIs and their impact on cellular and humoral immune responses against the influenza A virus (IAV), respiratory syncytial virus (RSV) and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The MIAI birth cohort enrolls healthy, full-term neonates born at the University Hospital Würzburg, Germany, with follow-up at four defined time-points during the first year of life. At each study visit, clinical metadata including diet, lifestyle, sociodemographic information, and physical examinations, are collected along with extensive biomaterial sampling. Biomaterials are used to generate comprehensive, integrated multi-omics datasets including transcriptomic, epigenomic, proteomic, metabolomic and microbiomic methods. Discussion The results are expected to capture a holistic picture of the variability of immune trajectories with a focus on cellular and humoral key players involved in the defense of RVIs and the impact of host and environmental factors thereon. Thereby, MIAI aims at providing insights that allow unraveling molecular mechanisms that can be targeted to promote the development of competent anti-RVI immunity in early life and prevent severe RVIs. Clinical trial registration https://drks.de/search/de/trial/, identifier DRKS00034278.
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Affiliation(s)
- Carina R. Hartmann
- Department of Pediatrics, University Hospital Würzburg, Würzburg, Germany
| | - Robin Khan
- Department of Pediatrics, University Hospital Würzburg, Würzburg, Germany
| | - Jennifer Schöning
- Department of Pediatrics, University Hospital Würzburg, Würzburg, Germany
| | - Maximilian Richter
- Department of Pediatrics, University Hospital Würzburg, Würzburg, Germany
| | - Maike Willers
- Department of Pediatric Pneumology, Allergology and Neonatology, Hannover Medical School, Hannover, Germany
| | - Sabine Pirr
- Department of Pediatric Pneumology, Allergology and Neonatology, Hannover Medical School, Hannover, Germany
- Cluster of Excellence RESIST (EXC 2155), Hannover Medical School, Hannover, Germany
| | - Julia Heckmann
- Department of Pediatrics, University Hospital Würzburg, Würzburg, Germany
| | - Johannes Dirks
- Department of Pediatrics, University Hospital Würzburg, Würzburg, Germany
- German Center for Infection Research, Site Hamburg-Lübeck-Borstel-Riems, Hamburg, Germany
| | - Henner Morbach
- Department of Pediatrics, University Hospital Würzburg, Würzburg, Germany
- Center for Primary Immunodeficiencies and Autoinflammatory Diseases (CIDA), University Hospital Würzburg, Würzburg, Germany
| | - Monika Konrad
- Department of Pediatrics, University Hospital Würzburg, Würzburg, Germany
| | - Elena Fries
- Department of Pediatrics, University Hospital Würzburg, Würzburg, Germany
| | - Magdalene Winkler
- Department of Gynecology and Obstetrics, University Hospital Würzburg, Würzburg, Germany
| | - Johanna Büchel
- Department of Gynecology and Obstetrics, University Hospital Würzburg, Würzburg, Germany
| | | | - Jonas Fischer
- Department of Pediatrics, University Hospital Würzburg, Würzburg, Germany
| | - Claudia Vollmuth
- Department of Pediatrics, University Hospital Würzburg, Würzburg, Germany
| | - Martin Meinhardt
- Department of Pediatrics, University Hospital Würzburg, Würzburg, Germany
| | - Janina Marissen
- Department of Pediatrics, University Hospital Würzburg, Würzburg, Germany
| | - Mirco Schmolke
- Department of Microbiology and Molecular Medicine, University of Geneva, Geneva, Switzerland
- Center for Inflammation Research, Faculty of Medicine, University of Geneva, Geneva, Switzerland
| | - Sibylle Haid
- Institute for Experimental Virology, Centre for Experimental and Clinical Infection Research (TWINCORE), a joint venture between the Helmholtz Centre for Infection Research and The Hannover Medical School, Hannover, Germany
| | - Thomas Pietschmann
- Cluster of Excellence RESIST (EXC 2155), Hannover Medical School, Hannover, Germany
- Institute for Experimental Virology, Centre for Experimental and Clinical Infection Research (TWINCORE), a joint venture between the Helmholtz Centre for Infection Research and The Hannover Medical School, Hannover, Germany
- German Centre for Infection Research, Partner Site Braunschweig-Hannover, Braunschweig, Germany
| | - Simone Backes
- Institute for Virology and Immunobiology, University of Würzburg, Würzburg, Germany
| | - Lars Dölken
- Cluster of Excellence RESIST (EXC 2155), Hannover Medical School, Hannover, Germany
- Institute of Virology, Hannover Medical School, Hannover, Germany
| | - Ulrike Löber
- Max-Delbrück-Center for Molecular Medicine in the Helmholtz Association, Berlin, Germany
- Experimental and Clinical Research Center, a cooperation of Charité - Universitätsmedizin Berlin and Max-Delbrück-Center for Molecular Medicine, Berlin, Germany
- Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin, Germany
- German Centre for Cardiovascular Research (DZHK), Partner site Berlin, Berlin, Germany
| | - Thomas Keil
- Institute of Social Medicine, Epidemiology and Health Economics, Charité - Universitätsmedizin Berlin, Berlin, Germany
- Institute of Clinical Epidemiology and Biometry, University of Würzburg, Würzburg, Germany
- State Institute of Health I, Bavarian Health and Food Safety Authority, Erlangen, Germany
| | - Peter U. Heuschmann
- Institute of Clinical Epidemiology and Biometry, University of Würzburg, Würzburg, Germany
- Institute for Medical Data Science, University Hospital Würzburg, Würzburg, Germany
- Clinical Trial Centre Würzburg, University Hospital Würzburg, Würzburg, Germany
| | - Achim Wöckel
- Department of Gynecology and Obstetrics, University Hospital Würzburg, Würzburg, Germany
| | - Sagar
- Department of Medicine II (Gastroenterology, Hepatology, Endocrinology, and Infectious Diseases), Freiburg University Medical Center, University of Freiburg, Freiburg, Germany
| | - Thomas Ulas
- Systems Medicine, German Center for Neurodegenerative Diseases Deutsches Zentrum für Neurodegenerative Erkrankungen (DZNE), Bonn, Germany
- PRECISE Platform for Single Cell Genomics and Epigenomics, Deutsches Zentrum für Neurodegenerative Erkrankungen (DZNE) and University of Bonn, Bonn, Germany
- Genomics and Immunoregulation, Life and Medical Sciences (LIMES) Institute, University of Bonn, Bonn, Germany
| | - Sofia K. Forslund-Startceva
- Max-Delbrück-Center for Molecular Medicine in the Helmholtz Association, Berlin, Germany
- Experimental and Clinical Research Center, a cooperation of Charité - Universitätsmedizin Berlin and Max-Delbrück-Center for Molecular Medicine, Berlin, Germany
- Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin, Germany
- Structural and Computational Biology Unit, European Molecular Biology Laboratory (EMBL), Heidelberg, Germany
| | - Christoph Härtel
- Department of Pediatrics, University Hospital Würzburg, Würzburg, Germany
| | - Dorothee Viemann
- Department of Pediatrics, University Hospital Würzburg, Würzburg, Germany
- Department of Pediatric Pneumology, Allergology and Neonatology, Hannover Medical School, Hannover, Germany
- Cluster of Excellence RESIST (EXC 2155), Hannover Medical School, Hannover, Germany
- Center for Infection Research, University Würzburg, Würzburg, Germany
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29
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R Muralitharan R, Nakai ME, Snelson M, Zheng T, Dinakis E, Xie L, Jama H, Paterson M, Shihata W, Wassef F, Vinh A, Drummond GR, Kaye DM, Mackay CR, Marques FZ. Influence of angiotensin II on the gut microbiome: modest effects in comparison to experimental factors. Cardiovasc Res 2024; 120:1155-1163. [PMID: 38518247 PMCID: PMC11368123 DOI: 10.1093/cvr/cvae062] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/18/2023] [Revised: 12/12/2023] [Accepted: 01/08/2024] [Indexed: 03/24/2024] Open
Abstract
AIMS Animal models are regularly used to test the role of the gut microbiome in hypertension. Small-scale pre-clinical studies have investigated changes to the gut microbiome in the angiotensin II hypertensive model. However, the gut microbiome is influenced by internal and external experimental factors, which are not regularly considered in the study design. Once these factors are accounted for, it is unclear if microbiome signatures are reproduceable. We aimed to determine the influence of angiotensin II treatment on the gut microbiome using a large and diverse cohort of mice and to quantify the magnitude by which other factors contribute to microbiome variations. METHODS AND RESULTS We conducted a retrospective study to establish a diverse mouse cohort resembling large human studies. We sequenced the V4 region of the 16S rRNA gene from 538 samples across the gastrointestinal tract of 303 male and female C57BL/6J mice randomized into sham or angiotensin II treatment from different genotypes, diets, animal facilities, and age groups. Analysing over 17 million sequencing reads, we observed that angiotensin II treatment influenced α-diversity (P = 0.0137) and β-diversity (i.e. composition of the microbiome, P < 0.001). Bacterial abundance analysis revealed patterns consistent with a reduction in short-chain fatty acid producers, microbial metabolites that lower blood pressure. Furthermore, animal facility, genotype, diet, age, sex, intestinal sampling site, and sequencing batch had significant effects on both α- and β-diversity (all P < 0.001). Sampling site (6.8%) and diet (6%) had the largest impact on the microbiome, while angiotensin II and sex had the smallest effect (each 0.4%). CONCLUSION Our large-scale data confirmed findings from small-scale studies that angiotensin II impacted the gut microbiome. However, this effect was modest relative to most of the other factors studied. Accounting for these factors in future pre-clinical hypertensive studies will increase the likelihood that microbiome findings are replicable and translatable.
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Affiliation(s)
- Rikeish R Muralitharan
- Hypertension Research Laboratory, School of Biological Sciences, Faculty of Science, Monash University, 18 Innovation Walk, Clayton, 3800 Melbourne, Australia
- Institute for Medical Research, Ministry of Health Malaysia, Kuala Lumpur, Malaysia
- Victorian Heart Institute, Monash University, 631 Blackburn Road, Clayton, 3800 Melbourne, Australia
| | - Michael E Nakai
- Hypertension Research Laboratory, School of Biological Sciences, Faculty of Science, Monash University, 18 Innovation Walk, Clayton, 3800 Melbourne, Australia
| | - Matthew Snelson
- Hypertension Research Laboratory, School of Biological Sciences, Faculty of Science, Monash University, 18 Innovation Walk, Clayton, 3800 Melbourne, Australia
- Victorian Heart Institute, Monash University, 631 Blackburn Road, Clayton, 3800 Melbourne, Australia
| | - Tenghao Zheng
- Hypertension Research Laboratory, School of Biological Sciences, Faculty of Science, Monash University, 18 Innovation Walk, Clayton, 3800 Melbourne, Australia
| | - Evany Dinakis
- Hypertension Research Laboratory, School of Biological Sciences, Faculty of Science, Monash University, 18 Innovation Walk, Clayton, 3800 Melbourne, Australia
| | - Liang Xie
- Hypertension Research Laboratory, School of Biological Sciences, Faculty of Science, Monash University, 18 Innovation Walk, Clayton, 3800 Melbourne, Australia
| | - Hamdi Jama
- Hypertension Research Laboratory, School of Biological Sciences, Faculty of Science, Monash University, 18 Innovation Walk, Clayton, 3800 Melbourne, Australia
| | - Madeleine Paterson
- Hypertension Research Laboratory, School of Biological Sciences, Faculty of Science, Monash University, 18 Innovation Walk, Clayton, 3800 Melbourne, Australia
| | - Waled Shihata
- Heart Failure Research Group, Baker Heart and Diabetes Institute, 75 Commercial Road, 3004 Melbourne, Australia
| | - Flavia Wassef
- Centre for Cardiovascular Biology and Disease Research (CCBDR), La Trobe Institute of Medical Science (LIMS), Bundoora, Victoria, Australia
- Department of Microbiology, Anatomy, Physiology and Pharmacology, School of Agriculture, Biomedicine and Environment, La Trobe University, Bundoora, Victoria, Australia
| | - Antony Vinh
- Centre for Cardiovascular Biology and Disease Research (CCBDR), La Trobe Institute of Medical Science (LIMS), Bundoora, Victoria, Australia
- Department of Microbiology, Anatomy, Physiology and Pharmacology, School of Agriculture, Biomedicine and Environment, La Trobe University, Bundoora, Victoria, Australia
| | - Grant R Drummond
- Centre for Cardiovascular Biology and Disease Research (CCBDR), La Trobe Institute of Medical Science (LIMS), Bundoora, Victoria, Australia
- Department of Microbiology, Anatomy, Physiology and Pharmacology, School of Agriculture, Biomedicine and Environment, La Trobe University, Bundoora, Victoria, Australia
| | - David M Kaye
- Heart Failure Research Group, Baker Heart and Diabetes Institute, 75 Commercial Road, 3004 Melbourne, Australia
- Department of Cardiology, Alfred Hospital, Melbourne, Australia
- Central Clinical School, Faculty of Medicine Nursing and Health Sciences, Monash University, Melbourne, Australia
| | - Charles R Mackay
- Infection and Immunity Program, Monash Biodiscovery Institute, Monash University, Melbourne, Australia
- Department of Biochemistry, Monash University, Melbourne, Australia
- School of Pharmaceutical Sciences, Shandong Analysis and Test Center, Qilu University of Technology (Shandong Academy of Sciences), Jinan 250014, China
| | - Francine Z Marques
- Hypertension Research Laboratory, School of Biological Sciences, Faculty of Science, Monash University, 18 Innovation Walk, Clayton, 3800 Melbourne, Australia
- Victorian Heart Institute, Monash University, 631 Blackburn Road, Clayton, 3800 Melbourne, Australia
- Heart Failure Research Group, Baker Heart and Diabetes Institute, 75 Commercial Road, 3004 Melbourne, Australia
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30
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González-Correa C, Moleón J, Miñano S, Robles-Vera I, Toral M, Barranco AM, Martín-Morales N, O'Valle F, Guerra-Hernández E, Sánchez M, Gómez-Guzmán M, Jiménez R, Romero M, Duarte J. Differing contributions of the gut microbiota to the blood pressure lowering effects induced by first-line antihypertensive drugs. Br J Pharmacol 2024; 181:3420-3444. [PMID: 38770714 DOI: 10.1111/bph.16410] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/23/2023] [Revised: 01/31/2024] [Accepted: 02/07/2024] [Indexed: 05/22/2024] Open
Abstract
BACKGROUND AND PURPOSE This study analyses whether first-line antihypertensive drugs ameliorate the dysbiosis state in hypertension, and to test if this modification contributes to their blood pressure (BP) lowering properties in a genetic model of neurogenic hypertension. EXPERIMENTAL APPROACH Twenty-week-old male Wistar Kyoto rats (WKY) and spontaneously hypertensive rats (SHR) were untreated or treated with captopril, amlodipine or hydrochlorothiazide. A faecal microbiota transplantation (FMT) experiment was also performed by gavage of faecal content from donor SHR-treated groups to SHR recipients for 3 weeks. KEY RESULTS Faeces from SHR showed gut dysbiosis, characterized by lower acetate- and higher lactate-producing bacteria and lower strict anaerobic bacteria. All three drugs increased the anaerobic bacteria proportion, captopril and amlodipine restored the proportion of acetate-producing bacterial populations to WKY levels, whereas hydrochlorothiazide decreased butyrate-producing bacteria. Captopril and amlodipine decreased gut pathology and permeability and attenuated sympathetic drive in the gut. Both drugs decreased neuroinflammation and oxidative stress in the hypothalamic paraventricular nuclei. Hydrochlorothiazide was unable to reduce neuroinflammation, gut sympathetic tone and gut integrity. FMT from SHR-amlodipine to SHR decreased BP, ameliorated aortic endothelium-dependent relaxation to acetylcholine, lowered NADPH oxidase activity, aortic Th17 infiltration and reduced neuroinflammation, whereas FMT from SHR-hydrochlorothiazide did not have these effects. CONCLUSIONS AND IMPLICATIONS First-line antihypertensive drugs induced different modifications of gut integrity and gut dysbiosis in SHR, which result in no contribution of microbiota in the BP lowering effects of hydrochlorothiazide, whereas the vasculo-protective effect induced by amlodipine involves gut microbiota reshaping and gut-immune system communication.
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Affiliation(s)
- Cristina González-Correa
- Department of Pharmacology, School of Pharmacy and Center for Biomedical Research (CIBM), University of Granada, Granada, Spain
- Instituto de Investigación Biosanitaria de Granada, ibs. GRANADA, Granada, Spain
| | - Javier Moleón
- Department of Pharmacology, School of Pharmacy and Center for Biomedical Research (CIBM), University of Granada, Granada, Spain
- Instituto de Investigación Biosanitaria de Granada, ibs. GRANADA, Granada, Spain
| | - Sofía Miñano
- Department of Pharmacology, School of Pharmacy and Center for Biomedical Research (CIBM), University of Granada, Granada, Spain
| | - Iñaki Robles-Vera
- Centro Nacional de Investigaciones Cardiovasculares (CNIC), Madrid, Spain
| | - Marta Toral
- Department of Pharmacology, School of Pharmacy and Center for Biomedical Research (CIBM), University of Granada, Granada, Spain
- Instituto de Investigación Biosanitaria de Granada, ibs. GRANADA, Granada, Spain
- Ciber de Enfermedades Cardiovasculares (CIBERCV), Madrid, Spain
| | - Antonio Manuel Barranco
- Department of Pharmacology, School of Pharmacy and Center for Biomedical Research (CIBM), University of Granada, Granada, Spain
- Instituto de Investigación Biosanitaria de Granada, ibs. GRANADA, Granada, Spain
| | | | - Francisco O'Valle
- Instituto de Investigación Biosanitaria de Granada, ibs. GRANADA, Granada, Spain
- Department of Pathology, School of Medicine, University of Granada, Granada, Spain
| | | | - Manuel Sánchez
- Department of Pharmacology, School of Pharmacy and Center for Biomedical Research (CIBM), University of Granada, Granada, Spain
- Instituto de Investigación Biosanitaria de Granada, ibs. GRANADA, Granada, Spain
| | - Manuel Gómez-Guzmán
- Department of Pharmacology, School of Pharmacy and Center for Biomedical Research (CIBM), University of Granada, Granada, Spain
- Instituto de Investigación Biosanitaria de Granada, ibs. GRANADA, Granada, Spain
| | - Rosario Jiménez
- Department of Pharmacology, School of Pharmacy and Center for Biomedical Research (CIBM), University of Granada, Granada, Spain
- Instituto de Investigación Biosanitaria de Granada, ibs. GRANADA, Granada, Spain
- Ciber de Enfermedades Cardiovasculares (CIBERCV), Madrid, Spain
| | - Miguel Romero
- Department of Pharmacology, School of Pharmacy and Center for Biomedical Research (CIBM), University of Granada, Granada, Spain
- Instituto de Investigación Biosanitaria de Granada, ibs. GRANADA, Granada, Spain
| | - Juan Duarte
- Department of Pharmacology, School of Pharmacy and Center for Biomedical Research (CIBM), University of Granada, Granada, Spain
- Instituto de Investigación Biosanitaria de Granada, ibs. GRANADA, Granada, Spain
- Ciber de Enfermedades Cardiovasculares (CIBERCV), Madrid, Spain
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31
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Abstract
'Westernization', which incorporates industrial, cultural and dietary trends, has paralleled the rise of noncommunicable diseases across the globe. Today, the Western-style diet emerges as a key stimulus for gut microbial vulnerability, chronic inflammation and chronic diseases, affecting mainly the cardiovascular system, systemic metabolism and the gut. Here we review the diet of modern times and evaluate the threat it poses for human health by summarizing recent epidemiological, translational and clinical studies. We discuss the links between diet and disease in the context of obesity and type 2 diabetes, cardiovascular diseases, gut and liver diseases and solid malignancies. We collectively interpret the evidence and its limitations and discuss future challenges and strategies to overcome these. We argue that healthcare professionals and societies must react today to the detrimental effects of the Western diet to bring about sustainable change and improved outcomes in the future.
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Affiliation(s)
- Timon E Adolph
- Department of Internal Medicine I, Gastroenterology, Hepatology, Endocrinology and Metabolism, Medical University of Innsbruck, Innsbruck, Austria.
| | - Herbert Tilg
- Department of Internal Medicine I, Gastroenterology, Hepatology, Endocrinology and Metabolism, Medical University of Innsbruck, Innsbruck, Austria.
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32
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Essex M, Millet Pascual-Leone B, Löber U, Kuhring M, Zhang B, Brüning U, Fritsche-Guenther R, Krzanowski M, Fiocca Vernengo F, Brumhard S, Röwekamp I, Anna Bielecka A, Lesker TR, Wyler E, Landthaler M, Mantei A, Meisel C, Caesar S, Thibeault C, Corman VM, Marko L, Suttorp N, Strowig T, Kurth F, Sander LE, Li Y, Kirwan JA, Forslund SK, Opitz B. Gut microbiota dysbiosis is associated with altered tryptophan metabolism and dysregulated inflammatory response in COVID-19. NPJ Biofilms Microbiomes 2024; 10:66. [PMID: 39085233 PMCID: PMC11291933 DOI: 10.1038/s41522-024-00538-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2023] [Accepted: 07/22/2024] [Indexed: 08/02/2024] Open
Abstract
The clinical course of COVID-19 is variable and often unpredictable. To test the hypothesis that disease progression and inflammatory responses associate with alterations in the microbiome and metabolome, we analyzed metagenome, metabolome, cytokine, and transcriptome profiles of repeated samples from hospitalized COVID-19 patients and uninfected controls, and leveraged clinical information and post-hoc confounder analysis. Severe COVID-19 was associated with a depletion of beneficial intestinal microbes, whereas oropharyngeal microbiota disturbance was mainly linked to antibiotic use. COVID-19 severity was also associated with enhanced plasma concentrations of kynurenine and reduced levels of several other tryptophan metabolites, lysophosphatidylcholines, and secondary bile acids. Moreover, reduced concentrations of various tryptophan metabolites were associated with depletion of Faecalibacterium, and tryptophan decrease and kynurenine increase were linked to enhanced production of inflammatory cytokines. Collectively, our study identifies correlated microbiome and metabolome alterations as a potential contributor to inflammatory dysregulation in severe COVID-19.
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Affiliation(s)
- Morgan Essex
- Experimental and Clinical Research Center (ECRC), a cooperation of the Max Delbrück Center and Charité-Universitätsmedizin, Berlin, Germany
- Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC), Berlin, Germany
- Charité-Universitätsmedizin Berlin, a corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany
| | - Belén Millet Pascual-Leone
- Department of Infectious Diseases, Respiratory Medicine and Critical Care, Charité-Universitätsmedizin Berlin, a corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany
| | - Ulrike Löber
- Experimental and Clinical Research Center (ECRC), a cooperation of the Max Delbrück Center and Charité-Universitätsmedizin, Berlin, Germany
- Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC), Berlin, Germany
- Charité-Universitätsmedizin Berlin, a corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany
| | - Mathias Kuhring
- Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC), Berlin, Germany
- Berlin Institute of Health (BIH) at Charité, BIH Metabolomics Platform, Berlin, Germany
- Berlin Institute of Health (BIH) at Charité, Core Unit Bioinformatics, Berlin, Germany
| | - Bowen Zhang
- Department of Computational Biology for Individualized Infection Medicine, Center for Individualized Infection Medicine (CiiM), a joint venture between the Helmholtz-Center for Infection Research (HZI) and the Hannover Medical School (MHH), Hannover, Germany
- TWINCORE, joint ventures between the Helmholtz Center for Infection Research (HZI) and the Hannover Medical School (MHH), Hannover, Germany
- College of Life Sciences, Beijing Normal University, Beijing, China
| | - Ulrike Brüning
- Berlin Institute of Health (BIH) at Charité, BIH Metabolomics Platform, Berlin, Germany
| | | | - Marta Krzanowski
- Department of Infectious Diseases, Respiratory Medicine and Critical Care, Charité-Universitätsmedizin Berlin, a corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany
| | - Facundo Fiocca Vernengo
- Department of Infectious Diseases, Respiratory Medicine and Critical Care, Charité-Universitätsmedizin Berlin, a corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany
| | - Sophia Brumhard
- Department of Infectious Diseases, Respiratory Medicine and Critical Care, Charité-Universitätsmedizin Berlin, a corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany
| | - Ivo Röwekamp
- Department of Infectious Diseases, Respiratory Medicine and Critical Care, Charité-Universitätsmedizin Berlin, a corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany
| | - Agata Anna Bielecka
- Department of Microbial Immune Regulation, Helmholtz Center for Infection Research (HZI), Braunschweig, Germany
- German Center for Infection Research (DZIF), partner site Hannover-Braunschweig, Braunschweig, Germany
| | - Till Robin Lesker
- Department of Microbial Immune Regulation, Helmholtz Center for Infection Research (HZI), Braunschweig, Germany
| | - Emanuel Wyler
- Berlin Institute for Medical Systems Biology, Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC), Berlin, Germany
| | - Markus Landthaler
- Berlin Institute for Medical Systems Biology, Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC), Berlin, Germany
- Institute of Biology, Humboldt-Universität zu Berlin, Berlin, Germany
| | | | - Christian Meisel
- Labor Berlin-Charité Vivantes GmbH, Berlin, Germany
- Institute of Medical Immunology, Charité-Universitätsmedizin Berlin, a corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany
| | - Sandra Caesar
- Department of Infectious Diseases, Respiratory Medicine and Critical Care, Charité-Universitätsmedizin Berlin, a corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany
| | - Charlotte Thibeault
- Department of Infectious Diseases, Respiratory Medicine and Critical Care, Charité-Universitätsmedizin Berlin, a corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany
| | - Victor M Corman
- Labor Berlin-Charité Vivantes GmbH, Berlin, Germany
- Institute of Virology, Charité-Universitätsmedizin Berlin, a corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany
- German Center for Infection Research (DZIF), Berlin, Germany
| | - Lajos Marko
- Experimental and Clinical Research Center (ECRC), a cooperation of the Max Delbrück Center and Charité-Universitätsmedizin, Berlin, Germany
- Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC), Berlin, Germany
- Charité-Universitätsmedizin Berlin, a corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany
- German Center for Cardiovascular Research (DZHK), partner site Berlin, Berlin, Germany
| | - Norbert Suttorp
- Department of Infectious Diseases, Respiratory Medicine and Critical Care, Charité-Universitätsmedizin Berlin, a corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany
- German Center for Lung Research (DZL), Berlin, Germany
| | - Till Strowig
- Department of Computational Biology for Individualized Infection Medicine, Center for Individualized Infection Medicine (CiiM), a joint venture between the Helmholtz-Center for Infection Research (HZI) and the Hannover Medical School (MHH), Hannover, Germany
- Department of Microbial Immune Regulation, Helmholtz Center for Infection Research (HZI), Braunschweig, Germany
- German Center for Infection Research (DZIF), partner site Hannover-Braunschweig, Braunschweig, Germany
| | - Florian Kurth
- Department of Infectious Diseases, Respiratory Medicine and Critical Care, Charité-Universitätsmedizin Berlin, a corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany
| | - Leif E Sander
- Department of Infectious Diseases, Respiratory Medicine and Critical Care, Charité-Universitätsmedizin Berlin, a corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany
- German Center for Lung Research (DZL), Berlin, Germany
| | - Yang Li
- Department of Computational Biology for Individualized Infection Medicine, Center for Individualized Infection Medicine (CiiM), a joint venture between the Helmholtz-Center for Infection Research (HZI) and the Hannover Medical School (MHH), Hannover, Germany
- TWINCORE, joint ventures between the Helmholtz Center for Infection Research (HZI) and the Hannover Medical School (MHH), Hannover, Germany
| | - Jennifer A Kirwan
- Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC), Berlin, Germany
- Berlin Institute of Health (BIH) at Charité, BIH Metabolomics Platform, Berlin, Germany
- University of Nottingham School of Veterinary Medicine and Science, Loughborough, UK
| | - Sofia K Forslund
- Experimental and Clinical Research Center (ECRC), a cooperation of the Max Delbrück Center and Charité-Universitätsmedizin, Berlin, Germany
- Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC), Berlin, Germany
- Charité-Universitätsmedizin Berlin, a corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany
- German Center for Cardiovascular Research (DZHK), partner site Berlin, Berlin, Germany
- Structural and Computational Biology Unit, European Molecular Biology Laboratory (EMBL), Heidelberg, Germany
| | - Bastian Opitz
- Department of Infectious Diseases, Respiratory Medicine and Critical Care, Charité-Universitätsmedizin Berlin, a corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany.
- Labor Berlin-Charité Vivantes GmbH, Berlin, Germany.
- German Center for Lung Research (DZL), Berlin, Germany.
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33
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Mei Z, Wang F, Bhosle A, Dong D, Mehta R, Ghazi A, Zhang Y, Liu Y, Rinott E, Ma S, Rimm EB, Daviglus M, Willett WC, Knight R, Hu FB, Qi Q, Chan AT, Burk RD, Stampfer MJ, Shai I, Kaplan RC, Huttenhower C, Wang DD. Strain-specific gut microbial signatures in type 2 diabetes identified in a cross-cohort analysis of 8,117 metagenomes. Nat Med 2024; 30:2265-2276. [PMID: 38918632 PMCID: PMC11620793 DOI: 10.1038/s41591-024-03067-7] [Citation(s) in RCA: 22] [Impact Index Per Article: 22.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2023] [Accepted: 05/14/2024] [Indexed: 06/27/2024]
Abstract
The association of gut microbial features with type 2 diabetes (T2D) has been inconsistent due in part to the complexity of this disease and variation in study design. Even in cases in which individual microbial species have been associated with T2D, mechanisms have been unable to be attributed to these associations based on specific microbial strains. We conducted a comprehensive study of the T2D microbiome, analyzing 8,117 shotgun metagenomes from 10 cohorts of individuals with T2D, prediabetes, and normoglycemic status in the United States, Europe, Israel and China. Dysbiosis in 19 phylogenetically diverse species was associated with T2D (false discovery rate < 0.10), for example, enriched Clostridium bolteae and depleted Butyrivibrio crossotus. These microorganisms also contributed to community-level functional changes potentially underlying T2D pathogenesis, for example, perturbations in glucose metabolism. Our study identifies within-species phylogenetic diversity for strains of 27 species that explain inter-individual differences in T2D risk, such as Eubacterium rectale. In some cases, these were explained by strain-specific gene carriage, including loci involved in various mechanisms of horizontal gene transfer and novel biological processes underlying metabolic risk, for example, quorum sensing. In summary, our study provides robust cross-cohort microbial signatures in a strain-resolved manner and offers new mechanistic insights into T2D.
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Affiliation(s)
- Zhendong Mei
- Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA
- Broad Institute of MIT and Harvard, Cambridge, MA, USA
| | - Fenglei Wang
- Broad Institute of MIT and Harvard, Cambridge, MA, USA
- Department of Nutrition, Harvard T.H. Chan School of Public Health, Boston, MA, USA
| | - Amrisha Bhosle
- Broad Institute of MIT and Harvard, Cambridge, MA, USA
- Department of Biostatistics, Harvard T.H. Chan School of Public Health, Boston, MA, USA
| | - Danyue Dong
- Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA
- Broad Institute of MIT and Harvard, Cambridge, MA, USA
| | - Raaj Mehta
- Broad Institute of MIT and Harvard, Cambridge, MA, USA
- Division of Gastroenterology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA
- Clinical and Translational Epidemiology Unit, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA
- Department of Chemistry and Chemical Biology, Harvard University, Cambridge, MA, USA
| | - Andrew Ghazi
- Broad Institute of MIT and Harvard, Cambridge, MA, USA
- Department of Biostatistics, Harvard T.H. Chan School of Public Health, Boston, MA, USA
| | - Yancong Zhang
- Broad Institute of MIT and Harvard, Cambridge, MA, USA
- Department of Biostatistics, Harvard T.H. Chan School of Public Health, Boston, MA, USA
| | - Yuxi Liu
- Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA
- Broad Institute of MIT and Harvard, Cambridge, MA, USA
- Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, USA
| | - Ehud Rinott
- Department of Medicine, Hebrew University and Hadassah Medical Center, Jerusalem, Israel
| | - Siyuan Ma
- Department of Biostatistics, Vanderbilt University Medical Center, Nashville, TN, USA
| | - Eric B Rimm
- Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA
- Department of Nutrition, Harvard T.H. Chan School of Public Health, Boston, MA, USA
- Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, USA
| | - Martha Daviglus
- Institute for Minority Health Research, University of Illinois Chicago, Chicago, IL, USA
| | - Walter C Willett
- Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA
- Department of Nutrition, Harvard T.H. Chan School of Public Health, Boston, MA, USA
- Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, USA
| | - Rob Knight
- Center for Microbiome Innovation, Jacobs School of Engineering, University of California San Diego, La Jolla, CA, USA
- Department of Pediatrics, School of Medicine, University of California San Diego, La Jolla, CA, USA
- Department of Computer Science and Engineering, University of California San Diego, La Jolla, CA, USA
| | - Frank B Hu
- Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA
- Department of Nutrition, Harvard T.H. Chan School of Public Health, Boston, MA, USA
- Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, USA
| | - Qibin Qi
- Department of Nutrition, Harvard T.H. Chan School of Public Health, Boston, MA, USA
- Department of Epidemiology and Population Health, Albert Einstein College of Medicine, Bronx, NY, USA
| | - Andrew T Chan
- Broad Institute of MIT and Harvard, Cambridge, MA, USA
- Division of Gastroenterology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA
- Clinical and Translational Epidemiology Unit, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA
| | - Robert D Burk
- Department of Epidemiology and Population Health, Albert Einstein College of Medicine, Bronx, NY, USA
- Department of Pediatrics, Albert Einstein College of Medicine, Bronx, NY, USA
- Department of Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, NY, USA
- Department of Obstetrics, Gynecology and Women's Health, Albert Einstein College of Medicine, Bronx, NY, USA
| | - Meir J Stampfer
- Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA
- Department of Nutrition, Harvard T.H. Chan School of Public Health, Boston, MA, USA
- Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, USA
| | - Iris Shai
- Department of Nutrition, Harvard T.H. Chan School of Public Health, Boston, MA, USA
- Faculty of Health Sciences, The Health and Nutrition Innovative International Research Center, Ben-Gurion University of the Negev, Be'er Sheva, Israel
| | - Robert C Kaplan
- Department of Epidemiology and Population Health, Albert Einstein College of Medicine, Bronx, NY, USA
- Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA
| | - Curtis Huttenhower
- Broad Institute of MIT and Harvard, Cambridge, MA, USA.
- Department of Biostatistics, Harvard T.H. Chan School of Public Health, Boston, MA, USA.
- Department of Immunology and Infectious Diseases, Harvard T.H. Chan School of Public Health, Boston, MA, USA.
- Harvard Chan Microbiome in Public Health Center, Harvard T.H. Chan School of Public Health, Boston, MA, USA.
| | - Dong D Wang
- Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.
- Broad Institute of MIT and Harvard, Cambridge, MA, USA.
- Department of Nutrition, Harvard T.H. Chan School of Public Health, Boston, MA, USA.
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34
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Chen W, Li Y, Wang W, Gao S, Hu J, Xiang B, Wu D, Jiao N, Xu T, Zhi M, Zhu L, Zhu R. Enhanced microbiota profiling in patients with quiescent Crohn's disease through comparison with paired healthy first-degree relatives. Cell Rep Med 2024; 5:101624. [PMID: 38942021 PMCID: PMC11293350 DOI: 10.1016/j.xcrm.2024.101624] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2023] [Revised: 04/09/2024] [Accepted: 06/07/2024] [Indexed: 06/30/2024]
Abstract
Prior studies indicate no correlation between the gut microbes of healthy first-degree relatives (HFDRs) of patients with Crohn's disease (CD) and the development of CD. Here, we utilize HFDRs as controls to examine the microbiota and metabolome in individuals with active (CD-A) and quiescent (CD-R) CD, thereby minimizing the influence of genetic and environmental factors. When compared to non-relative controls, the use of HFDR controls identifies fewer differential taxa. Faecalibacterium, Dorea, and Fusicatenibacter are decreased in CD-R, independent of inflammation, and correlated with fecal short-chain fatty acids (SCFAs). Validation with a large multi-center cohort confirms decreased Faecalibacterium and other SCFA-producing genera in CD-R. Classification models based on these genera distinguish CD from healthy individuals and demonstrate superior diagnostic power than models constructed with markers identified using unrelated controls. Furthermore, these markers exhibited limited discriminatory capabilities for other diseases. Finally, our results are validated across multiple cohorts, underscoring their robustness and potential for diagnostic and therapeutic applications.
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Affiliation(s)
- Wanning Chen
- Department of Gastroenterology, the Shanghai Tenth People's Hospital, School of Life Sciences and Technology, Tongji University, Shanghai 200072, P.R. China
| | - Yichen Li
- Medical College, Jiaying University, Meizhou 514031, P. R. China; Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou 510080, P.R. China; Department of General Surgery (Colorectal Surgery), The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou 510655, P.R. China; Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, Guangdong Institute of Gastroenterology; Biomedical Innovation Center; The Sixth Affiliated Hospital, Sun Yat-sen University; Key Laboratory of Human Microbiome and Chronic Diseases (Sun Yat-sen University), Ministry of Education, Guangzhou 510655, P.R. China
| | - Wenxia Wang
- Department of General Surgery (Colorectal Surgery), The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou 510655, P.R. China; Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, Guangdong Institute of Gastroenterology; Biomedical Innovation Center; The Sixth Affiliated Hospital, Sun Yat-sen University; Key Laboratory of Human Microbiome and Chronic Diseases (Sun Yat-sen University), Ministry of Education, Guangzhou 510655, P.R. China
| | - Sheng Gao
- Department of Gastroenterology, the Shanghai Tenth People's Hospital, School of Life Sciences and Technology, Tongji University, Shanghai 200072, P.R. China
| | - Jun Hu
- Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, Guangdong Institute of Gastroenterology; Biomedical Innovation Center; The Sixth Affiliated Hospital, Sun Yat-sen University; Key Laboratory of Human Microbiome and Chronic Diseases (Sun Yat-sen University), Ministry of Education, Guangzhou 510655, P.R. China; Department of Gastroenterology, the Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou 510655, P.R. China
| | - Bingjie Xiang
- Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, Guangdong Institute of Gastroenterology; Biomedical Innovation Center; The Sixth Affiliated Hospital, Sun Yat-sen University; Key Laboratory of Human Microbiome and Chronic Diseases (Sun Yat-sen University), Ministry of Education, Guangzhou 510655, P.R. China; Department of Gastroenterology, the Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou 510655, P.R. China
| | - Dingfeng Wu
- Department of Nephrology, Children's Hospital, Zhejiang University School of Medicine, National Clinical Research Center for Child Health, Hangzhou 310058, Zhejiang, P.R. China
| | - Na Jiao
- Department of Nephrology, Children's Hospital, Zhejiang University School of Medicine, National Clinical Research Center for Child Health, Hangzhou 310058, Zhejiang, P.R. China
| | - Tao Xu
- Medical College, Jiaying University, Meizhou 514031, P. R. China; Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou 510080, P.R. China
| | - Min Zhi
- Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, Guangdong Institute of Gastroenterology; Biomedical Innovation Center; The Sixth Affiliated Hospital, Sun Yat-sen University; Key Laboratory of Human Microbiome and Chronic Diseases (Sun Yat-sen University), Ministry of Education, Guangzhou 510655, P.R. China; Department of Gastroenterology, the Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou 510655, P.R. China.
| | - Lixin Zhu
- Department of General Surgery (Colorectal Surgery), The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou 510655, P.R. China; Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, Guangdong Institute of Gastroenterology; Biomedical Innovation Center; The Sixth Affiliated Hospital, Sun Yat-sen University; Key Laboratory of Human Microbiome and Chronic Diseases (Sun Yat-sen University), Ministry of Education, Guangzhou 510655, P.R. China.
| | - Ruixin Zhu
- Department of Gastroenterology, the Shanghai Tenth People's Hospital, School of Life Sciences and Technology, Tongji University, Shanghai 200072, P.R. China.
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Kayongo A, Ntayi ML, Olweny G, Kyalo E, Ndawula J, Ssengooba W, Kigozi E, Kalyesubula R, Munana R, Namaganda J, Caroline M, Sekibira R, Bagaya BS, Kateete DP, Joloba ML, Jjingo D, Sande OJ, Mayanja-Kizza H. Airway microbiome signature accurately discriminates Mycobacterium tuberculosis infection status. iScience 2024; 27:110142. [PMID: 38904070 PMCID: PMC11187240 DOI: 10.1016/j.isci.2024.110142] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2024] [Revised: 03/05/2024] [Accepted: 05/27/2024] [Indexed: 06/22/2024] Open
Abstract
Mycobacterium tuberculosis remains one of the deadliest infectious agents globally. Amidst efforts to control TB, long treatment duration, drug toxicity, and resistance underscore the need for novel therapeutic strategies. Despite advances in understanding the interplay between microbiome and disease in humans, the specific role of the microbiome in predicting disease susceptibility and discriminating infection status in tuberculosis still needs to be fully investigated. We investigated the impact of M.tb infection and M.tb-specific IFNγ immune responses on airway microbiome diversity by performing TB GeneXpert and QuantiFERON-GOLD assays during the follow-up phase of a longitudinal HIV-Lung Microbiome cohort of individuals recruited from two large independent cohorts in rural Uganda. M.tb rather than IFNγ immune response mainly drove a significant reduction in airway microbiome diversity. A microbiome signature comprising Streptococcus, Neisseria, Fusobacterium, Prevotella, Schaalia, Actinomyces, Cutibacterium, Brevibacillus, Microbacterium, and Beijerinckiacea accurately discriminated active TB from Latent TB and M.tb-uninfected individuals.
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Affiliation(s)
- Alex Kayongo
- Department of Immunology and Molecular Biology, Makerere University, College of Health Sciences, Kampala 256, Uganda
- Lung Institute, Makerere University College of Health Sciences, Kampala 256, Uganda
| | - Moses Levi Ntayi
- Department of Immunology and Molecular Biology, Makerere University, College of Health Sciences, Kampala 256, Uganda
- Lung Institute, Makerere University College of Health Sciences, Kampala 256, Uganda
| | - Geoffrey Olweny
- Department of Immunology and Molecular Biology, Makerere University, College of Health Sciences, Kampala 256, Uganda
| | - Edward Kyalo
- Department of Immunology and Molecular Biology, Makerere University, College of Health Sciences, Kampala 256, Uganda
- Lung Institute, Makerere University College of Health Sciences, Kampala 256, Uganda
| | - Josephine Ndawula
- Department of Immunology and Molecular Biology, Makerere University, College of Health Sciences, Kampala 256, Uganda
- Lung Institute, Makerere University College of Health Sciences, Kampala 256, Uganda
| | - Willy Ssengooba
- Department of Immunology and Molecular Biology, Makerere University, College of Health Sciences, Kampala 256, Uganda
- Lung Institute, Makerere University College of Health Sciences, Kampala 256, Uganda
| | - Edgar Kigozi
- Department of Immunology and Molecular Biology, Makerere University, College of Health Sciences, Kampala 256, Uganda
| | - Robert Kalyesubula
- Department of Research, African Community Center for Social Sustainability (ACCESS), Nakaseke 256, Uganda
- Department of Medicine, Makerere University, College of Health Sciences, Kampala 256, Uganda
| | - Richard Munana
- Department of Research, African Community Center for Social Sustainability (ACCESS), Nakaseke 256, Uganda
| | - Jesca Namaganda
- Department of Immunology and Molecular Biology, Makerere University, College of Health Sciences, Kampala 256, Uganda
- Lung Institute, Makerere University College of Health Sciences, Kampala 256, Uganda
| | - Musiime Caroline
- Department of Immunology and Molecular Biology, Makerere University, College of Health Sciences, Kampala 256, Uganda
| | - Rogers Sekibira
- Department of Immunology and Molecular Biology, Makerere University, College of Health Sciences, Kampala 256, Uganda
| | - Bernard Sentalo Bagaya
- Department of Immunology and Molecular Biology, Makerere University, College of Health Sciences, Kampala 256, Uganda
| | - David Patrick Kateete
- Department of Immunology and Molecular Biology, Makerere University, College of Health Sciences, Kampala 256, Uganda
| | - Moses Lutaakome Joloba
- Department of Immunology and Molecular Biology, Makerere University, College of Health Sciences, Kampala 256, Uganda
| | - Daudi Jjingo
- College of Computing and Information Sciences, Computer Science, Makerere University, Kampala 256, Uganda
- African Center of Excellence in Bioinformatics and Data Science, Infectious Diseases Institute, Kampala 256, Uganda
| | - Obondo James Sande
- Department of Immunology and Molecular Biology, Makerere University, College of Health Sciences, Kampala 256, Uganda
| | - Harriet Mayanja-Kizza
- Department of Medicine, Makerere University, College of Health Sciences, Kampala 256, Uganda
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de la Cuesta-Zuluaga J, Boldt L, Maier L. Response, resistance, and recovery of gut bacteria to human-targeted drug exposure. Cell Host Microbe 2024; 32:786-793. [PMID: 38870896 DOI: 10.1016/j.chom.2024.05.009] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/29/2024] [Revised: 04/03/2024] [Accepted: 05/13/2024] [Indexed: 06/15/2024]
Abstract
Survival strategies of human-associated microbes to drug exposure have been mainly studied in the context of bona fide pathogens exposed to antibiotics. Less well understood are the survival strategies of non-pathogenic microbes and host-associated commensal communities to the variety of drugs and xenobiotics to which humans are exposed. The lifestyle of microbial commensals within complex communities offers a variety of ways to adapt to different drug-induced stresses. Here, we review the responses and survival strategies employed by gut commensals when exposed to drugs-antibiotics and non-antibiotics-at the individual and community level. We also discuss the factors influencing the recovery and establishment of a new community structure following drug exposure. These survival strategies are key to the stability and resilience of the gut microbiome, ultimately influencing the overall health and well-being of the host.
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Affiliation(s)
- Jacobo de la Cuesta-Zuluaga
- Interfaculty Institute for Microbiology and Infection Medicine Tübingen, University of Tübingen, Tübingen, Germany; Cluster of Excellence EXC 2124 Controlling Microbes to Fight Infections, University of Tübingen, Tübingen, Germany; M3-Research Center for Malignome, Metabolome and Microbiome, University of Tübingen, Tübingen, Germany
| | - Leonardo Boldt
- Interfaculty Institute for Microbiology and Infection Medicine Tübingen, University of Tübingen, Tübingen, Germany; Cluster of Excellence EXC 2124 Controlling Microbes to Fight Infections, University of Tübingen, Tübingen, Germany; M3-Research Center for Malignome, Metabolome and Microbiome, University of Tübingen, Tübingen, Germany
| | - Lisa Maier
- Interfaculty Institute for Microbiology and Infection Medicine Tübingen, University of Tübingen, Tübingen, Germany; Cluster of Excellence EXC 2124 Controlling Microbes to Fight Infections, University of Tübingen, Tübingen, Germany; M3-Research Center for Malignome, Metabolome and Microbiome, University of Tübingen, Tübingen, Germany.
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Zhu J, Sun C, Li M, Hu G, Zhao XM, Chen WH. Compared to histamine-2 receptor antagonist, proton pump inhibitor induces stronger oral-to-gut microbial transmission and gut microbiome alterations: a randomised controlled trial. Gut 2024; 73:1087-1097. [PMID: 38050061 PMCID: PMC11187400 DOI: 10.1136/gutjnl-2023-330168] [Citation(s) in RCA: 23] [Impact Index Per Article: 23.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/26/2023] [Accepted: 11/06/2023] [Indexed: 12/06/2023]
Abstract
OBJECTIVE We aim to compare the effects of proton pump inhibitors (PPIs) and histamine-2 receptor antagonists (H2RAs) on the gut microbiota through longitudinal analysis. DESIGN Healthy volunteers were randomly assigned to receive either PPI (n=23) or H2RA (n=26) daily for seven consecutive days. We collected oral (saliva) and faecal samples before and after the intervention for metagenomic next-generation sequencing. We analysed intervention-induced alterations in the oral and gut microbiome including microbial abundance and growth rates, oral-to-gut transmissions, and compared differences between the PPI and H2RA groups. RESULTS Both interventions disrupted the gut microbiota, with PPIs demonstrating more pronounced effects. PPI usage led to a significantly higher extent of oral-to-gut transmission and promoted the growth of specific oral microbes in the gut. This led to a significant increase in both the number and total abundance of oral species present in the gut, including the identification of known disease-associated species like Fusobacterium nucleatum and Streptococcus anginosus. Overall, gut microbiome-based machine learning classifiers could accurately distinguish PPI from non-PPI users, achieving an area under the receiver operating characteristic curve (AUROC) of 0.924, in contrast to an AUROC of 0.509 for H2RA versus non-H2RA users. CONCLUSION Our study provides evidence that PPIs have a greater impact on the gut microbiome and oral-to-gut transmission than H2RAs, shedding light on the mechanism underlying the higher risk of certain diseases associated with prolonged PPI use. TRIAL REGISTRATION NUMBER ChiCTR2300072310.
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Affiliation(s)
- Jiaying Zhu
- Key Laboratory of Molecular Biophysics of the Ministry of Education, Hubei Key Laboratory of Bioinformatics and Molecular-imaging, Center for Artificial Intelligence Biology, Department of Bioinformatics and Systems Biology, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan, China
| | - Chuqing Sun
- Key Laboratory of Molecular Biophysics of the Ministry of Education, Hubei Key Laboratory of Bioinformatics and Molecular-imaging, Center for Artificial Intelligence Biology, Department of Bioinformatics and Systems Biology, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan, China
| | - Min Li
- Key Laboratory of Molecular Biophysics of the Ministry of Education, Hubei Key Laboratory of Bioinformatics and Molecular-imaging, Center for Artificial Intelligence Biology, Department of Bioinformatics and Systems Biology, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan, China
| | - Guoru Hu
- Key Laboratory of Molecular Biophysics of the Ministry of Education, Hubei Key Laboratory of Bioinformatics and Molecular-imaging, Center for Artificial Intelligence Biology, Department of Bioinformatics and Systems Biology, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan, China
| | - Xing-Ming Zhao
- Department of Neurology, Zhongshan Hospital, Fudan University, Shanghai, China
- Institute of Science and Technology for Brain-Inspired Intelligence, Fudan University, Shanghai, China
- State Key Laboratory of Medical Neurobiology, Institutes of Brain Science, Fudan University, Shanghai, China
- MOE Key Laboratory of Computational Neuroscience and Brain-Inspired Intelligence, and MOE Frontiers Center for Brain Science, Fudan University, Shanghai, China
- International Human Phenome Institutes (Shanghai), Shanghai, China
| | - Wei-Hua Chen
- Key Laboratory of Molecular Biophysics of the Ministry of Education, Hubei Key Laboratory of Bioinformatics and Molecular-imaging, Center for Artificial Intelligence Biology, Department of Bioinformatics and Systems Biology, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan, China
- Department of Oncology, The First Affiliated Hospital of Zhengzhou University, Henan, China
- Medical Artificial Intelligence Research Institute, Binzhou Medical University, Yantai, China
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Wang T, Shi Z, Ren H, Xu M, Lu J, Yang F, Ye C, Wu K, Chen M, Xu X, Liu D, Kong L, Zheng R, Zheng J, Li M, Xu Y, Zhao Z, Chen Y, Yang H, Wang J, Ning G, Li J, Zhong H, Bi Y, Wang W. Divergent age-associated and metabolism-associated gut microbiome signatures modulate cardiovascular disease risk. Nat Med 2024; 30:1722-1731. [PMID: 38844795 DOI: 10.1038/s41591-024-03038-y] [Citation(s) in RCA: 13] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2023] [Accepted: 04/30/2024] [Indexed: 06/13/2024]
Abstract
Insight into associations between the gut microbiome with metabolism and aging is crucial for tailoring interventions to promote healthy longevity. In a discovery cohort of 10,207 individuals aged 40-93 years, we used 21 metabolic parameters to classify individuals into five clusters, termed metabolic multimorbidity clusters (MCs), that represent different metabolic subphenotypes. Compared to the cluster classified as metabolically healthy (MC1), clusters classified as 'obesity-related mixed' (MC4) and 'hyperglycemia' (MC5) exhibited an increased 11.1-year cardiovascular disease (CVD) risk by 75% (multivariable-adjusted hazard ratio (HR): 1.75, 95% confidence interval (CI): 1.43-2.14) and by 117% (2.17, 1.72-2.74), respectively. These associations were replicated in a second cohort of 9,061 individuals with a 10.0-year follow-up. Based on analysis of 4,491 shotgun fecal metagenomes from the discovery cohort, we found that gut microbial composition was associated with both MCs and age. Next, using 55 age-specific microbial species to capture biological age, we developed a gut microbial age (MA) metric, which was validated in four external cohorts comprising 4,425 metagenomic samples. Among individuals aged 60 years or older, the increased CVD risk associated with MC4 or MC5, as compared to MC1, MC2 or MC3, was exacerbated in individuals with high MA but diminished in individuals with low MA, independent of age, sex and other lifestyle and dietary factors. This pattern, in which younger MA appears to counteract the CVD risk attributable to metabolic dysfunction, implies a modulating role of MA in cardiovascular health for metabolically unhealthy older people.
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Affiliation(s)
- Tiange Wang
- Department of Endocrine and Metabolic Diseases, Shanghai Institute of Endocrine and Metabolic Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- Shanghai National Clinical Research Center for Metabolic Diseases, Key Laboratory for Endocrine and Metabolic Diseases of the National Health Commission of the PR China, Shanghai Key Laboratory for Endocrine Tumor, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Zhun Shi
- BGI Research, Shenzhen, China
- Institute of Intelligent Medical Research (IIMR), BGI Genomics, Shenzhen, China
| | - Huahui Ren
- BGI Research, Shenzhen, China
- Institute of Intelligent Medical Research (IIMR), BGI Genomics, Shenzhen, China
| | - Min Xu
- Department of Endocrine and Metabolic Diseases, Shanghai Institute of Endocrine and Metabolic Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- Shanghai National Clinical Research Center for Metabolic Diseases, Key Laboratory for Endocrine and Metabolic Diseases of the National Health Commission of the PR China, Shanghai Key Laboratory for Endocrine Tumor, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Jieli Lu
- Department of Endocrine and Metabolic Diseases, Shanghai Institute of Endocrine and Metabolic Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- Shanghai National Clinical Research Center for Metabolic Diseases, Key Laboratory for Endocrine and Metabolic Diseases of the National Health Commission of the PR China, Shanghai Key Laboratory for Endocrine Tumor, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | | | - Chaojie Ye
- Department of Endocrine and Metabolic Diseases, Shanghai Institute of Endocrine and Metabolic Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- Shanghai National Clinical Research Center for Metabolic Diseases, Key Laboratory for Endocrine and Metabolic Diseases of the National Health Commission of the PR China, Shanghai Key Laboratory for Endocrine Tumor, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Kui Wu
- BGI Research, Shenzhen, China
- Institute of Intelligent Medical Research (IIMR), BGI Genomics, Shenzhen, China
- Guangdong Provincial Key Laboratory of Human Disease Genomics, BGI Research, Shenzhen, China
| | - Mingling Chen
- Department of Endocrine and Metabolic Diseases, Shanghai Institute of Endocrine and Metabolic Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- Shanghai National Clinical Research Center for Metabolic Diseases, Key Laboratory for Endocrine and Metabolic Diseases of the National Health Commission of the PR China, Shanghai Key Laboratory for Endocrine Tumor, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Xun Xu
- BGI Research, Shenzhen, China
| | - Dong Liu
- Department of Endocrine and Metabolic Diseases, Shanghai Institute of Endocrine and Metabolic Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- Shanghai National Clinical Research Center for Metabolic Diseases, Key Laboratory for Endocrine and Metabolic Diseases of the National Health Commission of the PR China, Shanghai Key Laboratory for Endocrine Tumor, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Lijie Kong
- Department of Endocrine and Metabolic Diseases, Shanghai Institute of Endocrine and Metabolic Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- Shanghai National Clinical Research Center for Metabolic Diseases, Key Laboratory for Endocrine and Metabolic Diseases of the National Health Commission of the PR China, Shanghai Key Laboratory for Endocrine Tumor, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Ruizhi Zheng
- Department of Endocrine and Metabolic Diseases, Shanghai Institute of Endocrine and Metabolic Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- Shanghai National Clinical Research Center for Metabolic Diseases, Key Laboratory for Endocrine and Metabolic Diseases of the National Health Commission of the PR China, Shanghai Key Laboratory for Endocrine Tumor, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Jie Zheng
- Department of Endocrine and Metabolic Diseases, Shanghai Institute of Endocrine and Metabolic Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- Shanghai National Clinical Research Center for Metabolic Diseases, Key Laboratory for Endocrine and Metabolic Diseases of the National Health Commission of the PR China, Shanghai Key Laboratory for Endocrine Tumor, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Mian Li
- Department of Endocrine and Metabolic Diseases, Shanghai Institute of Endocrine and Metabolic Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- Shanghai National Clinical Research Center for Metabolic Diseases, Key Laboratory for Endocrine and Metabolic Diseases of the National Health Commission of the PR China, Shanghai Key Laboratory for Endocrine Tumor, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Yu Xu
- Department of Endocrine and Metabolic Diseases, Shanghai Institute of Endocrine and Metabolic Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- Shanghai National Clinical Research Center for Metabolic Diseases, Key Laboratory for Endocrine and Metabolic Diseases of the National Health Commission of the PR China, Shanghai Key Laboratory for Endocrine Tumor, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Zhiyun Zhao
- Department of Endocrine and Metabolic Diseases, Shanghai Institute of Endocrine and Metabolic Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- Shanghai National Clinical Research Center for Metabolic Diseases, Key Laboratory for Endocrine and Metabolic Diseases of the National Health Commission of the PR China, Shanghai Key Laboratory for Endocrine Tumor, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Yuhong Chen
- Department of Endocrine and Metabolic Diseases, Shanghai Institute of Endocrine and Metabolic Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- Shanghai National Clinical Research Center for Metabolic Diseases, Key Laboratory for Endocrine and Metabolic Diseases of the National Health Commission of the PR China, Shanghai Key Laboratory for Endocrine Tumor, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | | | | | - Guang Ning
- Department of Endocrine and Metabolic Diseases, Shanghai Institute of Endocrine and Metabolic Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- Shanghai National Clinical Research Center for Metabolic Diseases, Key Laboratory for Endocrine and Metabolic Diseases of the National Health Commission of the PR China, Shanghai Key Laboratory for Endocrine Tumor, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | | | - Huanzi Zhong
- BGI Research, Shenzhen, China.
- Institute of Intelligent Medical Research (IIMR), BGI Genomics, Shenzhen, China.
| | - Yufang Bi
- Department of Endocrine and Metabolic Diseases, Shanghai Institute of Endocrine and Metabolic Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
- Shanghai National Clinical Research Center for Metabolic Diseases, Key Laboratory for Endocrine and Metabolic Diseases of the National Health Commission of the PR China, Shanghai Key Laboratory for Endocrine Tumor, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
| | - Weiqing Wang
- Department of Endocrine and Metabolic Diseases, Shanghai Institute of Endocrine and Metabolic Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
- Shanghai National Clinical Research Center for Metabolic Diseases, Key Laboratory for Endocrine and Metabolic Diseases of the National Health Commission of the PR China, Shanghai Key Laboratory for Endocrine Tumor, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
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Luo K, Peters BA, Moon JY, Xue X, Wang Z, Usyk M, Hanna DB, Landay AL, Schneider MF, Gustafson D, Weber KM, French A, Sharma A, Anastos K, Wang T, Brown T, Clish CB, Kaplan RC, Knight R, Burk RD, Qi Q. Metabolic and inflammatory perturbation of diabetes associated gut dysbiosis in people living with and without HIV infection. Genome Med 2024; 16:59. [PMID: 38643166 PMCID: PMC11032597 DOI: 10.1186/s13073-024-01336-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2023] [Accepted: 04/16/2024] [Indexed: 04/22/2024] Open
Abstract
BACKGROUND Gut dysbiosis has been linked with both HIV infection and diabetes, but its interplay with metabolic and inflammatory responses in diabetes, particularly in the context of HIV infection, remains unclear. METHODS We first conducted a cross-sectional association analysis to characterize the gut microbial, circulating metabolite, and immune/inflammatory protein features associated with diabetes in up to 493 women (~ 146 with prevalent diabetes with 69.9% HIV +) of the Women's Interagency HIV Study. Prospective analyses were then conducted to determine associations of identified metabolites with incident diabetes over 12 years of follow-up in 694 participants (391 women from WIHS and 303 men from the Multicenter AIDS Cohort Study; 166 incident cases were recorded) with and without HIV infection. Mediation analyses were conducted to explore whether gut bacteria-diabetes associations are explained by altered metabolites and proteins. RESULTS Seven gut bacterial genera were identified to be associated with diabetes (FDR-q < 0.1), with positive associations for Shigella, Escherichia, Megasphaera, and Lactobacillus, and inverse associations for Adlercreutzia, Ruminococcus, and Intestinibacter. Importantly, the associations of most species, especially Adlercreutzia and Ruminococcus, were largely independent of antidiabetic medications use. Meanwhile, 18 proteins and 76 metabolites, including 3 microbially derived metabolites (trimethylamine N-oxide, phenylacetylglutamine (PAGln), imidazolepropionic acid (IMP)), 50 lipids (e.g., diradylglycerols (DGs) and triradylglycerols (TGs)) and 23 non-lipid metabolites, were associated with diabetes (FDR-q < 0.1), with the majority showing positive associations and more than half of them (59/76) associated with incident diabetes. In mediation analyses, several proteins, especially interleukin-18 receptor 1 and osteoprotegerin, IMP and PAGln partially mediate the observed bacterial genera-diabetes associations, particularly for those of Adlercreutzia and Escherichia. Many diabetes-associated metabolites and proteins were altered in HIV, but no effect modification on their associations with diabetes was observed by HIV. CONCLUSION Among individuals with and without HIV, multiple gut bacterial genera, blood metabolites, and proinflammatory proteins were associated with diabetes. The observed mediated effects by metabolites and proteins in genera-diabetes associations highlighted the potential involvement of inflammatory and metabolic perturbations in the link between gut dysbiosis and diabetes in the context of HIV infection.
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Affiliation(s)
- Kai Luo
- Department of Epidemiology and Population Health, Albert Einstein College of Medicine, Bronx, NY, USA
| | - Brandilyn A Peters
- Department of Epidemiology and Population Health, Albert Einstein College of Medicine, Bronx, NY, USA
| | - Jee-Young Moon
- Department of Epidemiology and Population Health, Albert Einstein College of Medicine, Bronx, NY, USA
| | - Xiaonan Xue
- Department of Epidemiology and Population Health, Albert Einstein College of Medicine, Bronx, NY, USA
| | - Zheng Wang
- Department of Epidemiology and Population Health, Albert Einstein College of Medicine, Bronx, NY, USA
| | - Mykhaylo Usyk
- Department of Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, NY, USA
| | - David B Hanna
- Department of Epidemiology and Population Health, Albert Einstein College of Medicine, Bronx, NY, USA
| | - Alan L Landay
- Department of Internal Medicine, Rush University Medical Center, Chicago, IL, USA
| | - Michael F Schneider
- Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA
| | - Deborah Gustafson
- Department of Neurology, State University of New York-Downstate Medical Center, Brooklyn, NY, USA
| | | | - Audrey French
- Department of Internal Medicine, Rush University Medical Center, Chicago, IL, USA
| | - Anjali Sharma
- Department of Medicine, Albert Einstein College of Medicine, Bronx, NY, USA
| | - Kathryn Anastos
- Department of Epidemiology and Population Health, Albert Einstein College of Medicine, Bronx, NY, USA
- Department of Medicine, Albert Einstein College of Medicine, Bronx, NY, USA
- Department of Obstetrics and Gynecology and Women's Health, Albert Einstein College of Medicine, Bronx, NY, USA
| | - Tao Wang
- Department of Epidemiology and Population Health, Albert Einstein College of Medicine, Bronx, NY, USA
| | - Todd Brown
- Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Clary B Clish
- Broad Institute of MIT and Harvard, Cambridge, MA, USA
| | - Robert C Kaplan
- Department of Epidemiology and Population Health, Albert Einstein College of Medicine, Bronx, NY, USA
- Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA
| | - Rob Knight
- Center for Microbiome Innovation, University of California, San Diego, La Jolla, CA, USA
- Department of Bioengineering, University of California, San Diego, La Jolla, CA, USA
- Department of Pediatrics, University of California, San Diego, La Jolla, CA, USA
- Department of Computer Science and Engineering, University of California, San Diego, La Jolla, CA, USA
| | - Robert D Burk
- Department of Epidemiology and Population Health, Albert Einstein College of Medicine, Bronx, NY, USA
- Department of Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, NY, USA
- Department of Obstetrics and Gynecology and Women's Health, Albert Einstein College of Medicine, Bronx, NY, USA
- Department of Pediatrics, Albert Einstein College of Medicine, Bronx, NY, USA
| | - Qibin Qi
- Department of Epidemiology and Population Health, Albert Einstein College of Medicine, Bronx, NY, USA.
- Department of Nutrition, Harvard T.H. Chan School of Public Health, Boston, MA, USA.
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Nakamura M. Lipotoxicity as a therapeutic target in obesity and diabetic cardiomyopathy. JOURNAL OF PHARMACY & PHARMACEUTICAL SCIENCES : A PUBLICATION OF THE CANADIAN SOCIETY FOR PHARMACEUTICAL SCIENCES, SOCIETE CANADIENNE DES SCIENCES PHARMACEUTIQUES 2024; 27:12568. [PMID: 38706718 PMCID: PMC11066298 DOI: 10.3389/jpps.2024.12568] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 12/14/2023] [Accepted: 04/09/2024] [Indexed: 05/07/2024]
Abstract
Unhealthy sources of fats, ultra-processed foods with added sugars, and a sedentary lifestyle make humans more susceptible to developing overweight and obesity. While lipids constitute an integral component of the organism, excessive and abnormal lipid accumulation that exceeds the storage capacity of lipid droplets disrupts the intracellular composition of fatty acids and results in the release of deleterious lipid species, thereby giving rise to a pathological state termed lipotoxicity. This condition induces endoplasmic reticulum stress, mitochondrial dysfunction, inflammatory responses, and cell death. Recent advances in omics technologies and analytical methodologies and clinical research have provided novel insights into the mechanisms of lipotoxicity, including gut dysbiosis, epigenetic and epitranscriptomic modifications, dysfunction of lipid droplets, post-translational modifications, and altered membrane lipid composition. In this review, we discuss the recent knowledge on the mechanisms underlying the development of lipotoxicity and lipotoxic cardiometabolic disease in obesity, with a particular focus on lipotoxic and diabetic cardiomyopathy.
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Affiliation(s)
- Michinari Nakamura
- Department of Cell Biology and Molecular Medicine, Rutgers New Jersey Medical School, Rutgers Biomedical and Health Sciences, Newark, United States
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41
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Shearer J, Shah S, Shen-Tu G, Schlicht K, Laudes M, Mu C. Microbial Features Linked to Medication Strategies in Cardiometabolic Disease Management. ACS Pharmacol Transl Sci 2024; 7:991-1001. [PMID: 38665607 PMCID: PMC11040554 DOI: 10.1021/acsptsci.3c00261] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2023] [Revised: 01/05/2024] [Accepted: 01/15/2024] [Indexed: 04/28/2024]
Abstract
Human gut microbiota are recognized as critical players in both metabolic disease and drug metabolism. However, medication-microbiota interactions in cardiometabolic diseases are not well understood. To gain a comprehensive understanding of how medication intake impacts the gut microbiota, we investigated the association of microbial structure with the use of single or multiple medications in a cohort of 134 middle-aged adults diagnosed with cardiometabolic disease, recruited from Alberta's Tomorrow Project. Predominant cardiometabolic prescription medication classes (12 total) were included in our analysis. Multivariate Association with Linear Model (MaAsLin2) was employed and results were corrected for age, BMI, sex, and diet to evaluate the relationship between microbial features and single- or multimedication use. Highly individualized microbiota profiles were observed across participants, and increasing medication use was negatively correlated with α-diversity. A total of 46 associations were identified between microbial composition and single medications, exemplified by the depletion of Akkermansia muciniphila by β-blockers and statins, and the enrichment of Escherichia/Shigella and depletion of Bacteroides xylanisolvens by metformin. Metagenomics prediction further indicated alterations in microbial functions associated with single medications such as the depletion of enzymes involved in energy metabolism encoded by Eggerthella lenta due to β-blocker use. Specific dual medication combinations also had profound impacts, including the depletion of Romboutsia and Butyriciocccus by statin plus metformin. Together, these results show reductions in bacterial diversity as well as species and microbial functional potential associated with both single- and multimedication use in cardiometabolic disease.
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Affiliation(s)
- Jane Shearer
- Department
of Biochemistry and Molecular Biology, Cumming School of Medicine,
University of Calgary, Calgary, Alberta T2N 1N4, Canada
- Libin
Cardiovascular Institute, University of Calgary, Calgary, Alberta T2N 1N4, Canada
- Faculty
of Kinesiology, University of Calgary, Calgary, Alberta T2N 1N4, Canada
| | - Shrushti Shah
- Libin
Cardiovascular Institute, University of Calgary, Calgary, Alberta T2N 1N4, Canada
- Faculty
of Kinesiology, University of Calgary, Calgary, Alberta T2N 1N4, Canada
| | - Grace Shen-Tu
- Alberta’s
Tomorrow Project, Cancer Control Alberta, Alberta Health Services, Calgary, Alberta T2T 5C7, Canada
| | - Kristina Schlicht
- Institute
of Diabetes and Clinical Metabolic Research, University Medical Center Schleswig-Holstein, Kiel 24105, Germany
| | - Matthias Laudes
- Institute
of Diabetes and Clinical Metabolic Research, University Medical Center Schleswig-Holstein, Kiel 24105, Germany
- Division
of Endocrinology, Diabetes and Clinical Nutrition, Department of Medicine, University Medical Center Schleswig-Holstein, 24105 Kiel, Germany
| | - Chunlong Mu
- Department
of Biochemistry and Molecular Biology, Cumming School of Medicine,
University of Calgary, Calgary, Alberta T2N 1N4, Canada
- Libin
Cardiovascular Institute, University of Calgary, Calgary, Alberta T2N 1N4, Canada
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Bengel F, Epstein JA, Gropler R, Haberkorn U, Kramann R, Lavine K, Leuschner F, Liu Y, Rosenthal N, Wu H. Linking immune modulation to cardiac fibrosis. NATURE CARDIOVASCULAR RESEARCH 2024; 3:414-419. [PMID: 39196217 DOI: 10.1038/s44161-024-00459-3] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 08/29/2024]
Affiliation(s)
| | | | - Robert Gropler
- Division of Radiological Sciences, Edward Mallinckrodt Institute of Radiology, Washington University School of Medicine, St Louis, MO, USA.
| | | | - Rafael Kramann
- Department of Medicine 2, RWTH Aachen University, Medical Faculty, Aachen, Germany
| | - Kory Lavine
- Center for Cardiovascular Research, Department of Medicine, Cardiovascular Division, Washington University School of Medicine, St Louis, MO, USA
- Department of Pathology and Immunology, Washington University School of Medicine, St Louis, MO, USA
- Department of Developmental Biology, Washington University School of Medicine, St Louis, MO, USA
| | - Florian Leuschner
- Department of Internal Medicine III (Cardiology, Angiology, and Pneumology), Heidelberg University Hospital, Heidelberg, Germany.
- DZHK (German Center for Cardiovascular Research), Partner Site Heidelberg/Mannheim, Heidelberg, Germany.
| | - Yongjian Liu
- Division of Radiological Sciences, Edward Mallinckrodt Institute of Radiology, Washington University School of Medicine, St Louis, MO, USA
| | - Nadia Rosenthal
- The Jackson Laboratory, Bar Harbor, ME, USA.
- National Heart and Lung Institute, Imperial College London, London, UK.
| | - Hao Wu
- University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA
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43
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Longtine AG, Greenberg NT, Bernaldo de Quirós Y, Brunt VE. The gut microbiome as a modulator of arterial function and age-related arterial dysfunction. Am J Physiol Heart Circ Physiol 2024; 326:H986-H1005. [PMID: 38363212 PMCID: PMC11279790 DOI: 10.1152/ajpheart.00764.2023] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/08/2023] [Revised: 01/26/2024] [Accepted: 02/13/2024] [Indexed: 02/17/2024]
Abstract
The arterial system is integral to the proper function of all other organs and tissues. Arterial function is impaired with aging, and arterial dysfunction contributes to the development of numerous age-related diseases, including cardiovascular diseases. The gut microbiome has emerged as an important regulator of both normal host physiological function and impairments in function with aging. The purpose of this review is to summarize more recently published literature demonstrating the role of the gut microbiome in supporting normal arterial development and function and in modulating arterial dysfunction with aging in the absence of overt disease. The gut microbiome can be altered due to a variety of exposures, including physiological aging processes. We explore mechanisms by which the gut microbiome may contribute to age-related arterial dysfunction, with a focus on changes in various gut microbiome-related compounds in circulation. In addition, we discuss how modulating circulating levels of these compounds may be a viable therapeutic approach for improving artery function with aging. Finally, we identify and discuss various experimental considerations and research gaps/areas of future research.
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Affiliation(s)
- Abigail G Longtine
- Department of Integrative Physiology, University of Colorado Boulder, Boulder, Colorado, United States
| | - Nathan T Greenberg
- Department of Integrative Physiology, University of Colorado Boulder, Boulder, Colorado, United States
| | - Yara Bernaldo de Quirós
- Department of Integrative Physiology, University of Colorado Boulder, Boulder, Colorado, United States
- Instituto Universitario de Sanidad Animal y Seguridad Alimentaria, Universidad de las Palmas de Gran Canaria, Las Palmas, Spain
| | - Vienna E Brunt
- Department of Integrative Physiology, University of Colorado Boulder, Boulder, Colorado, United States
- Division of Renal Diseases and Hypertension, Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, Colorado, United States
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44
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Muller E, Shiryan I, Borenstein E. Multi-omic integration of microbiome data for identifying disease-associated modules. Nat Commun 2024; 15:2621. [PMID: 38521774 PMCID: PMC10960825 DOI: 10.1038/s41467-024-46888-3] [Citation(s) in RCA: 18] [Impact Index Per Article: 18.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2024] [Accepted: 03/08/2024] [Indexed: 03/25/2024] Open
Abstract
Multi-omic studies of the human gut microbiome are crucial for understanding its role in disease across multiple functional layers. Nevertheless, integrating and analyzing such complex datasets poses significant challenges. Most notably, current analysis methods often yield extensive lists of disease-associated features (e.g., species, pathways, or metabolites), without capturing the multi-layered structure of the data. Here, we address this challenge by introducing "MintTea", an intermediate integration-based approach combining canonical correlation analysis extensions, consensus analysis, and an evaluation protocol. MintTea identifies "disease-associated multi-omic modules", comprising features from multiple omics that shift in concord and that collectively associate with the disease. Applied to diverse cohorts, MintTea captures modules with high predictive power, significant cross-omic correlations, and alignment with known microbiome-disease associations. For example, analyzing samples from a metabolic syndrome study, MintTea identifies a module with serum glutamate- and TCA cycle-related metabolites, along with bacterial species linked to insulin resistance. In another dataset, MintTea identifies a module associated with late-stage colorectal cancer, including Peptostreptococcus and Gemella species and fecal amino acids, in line with these species' metabolic activity and their coordinated gradual increase with cancer development. This work demonstrates the potential of advanced integration methods in generating systems-level, multifaceted hypotheses underlying microbiome-disease interactions.
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Affiliation(s)
- Efrat Muller
- Blavatnik School of Computer Science, Tel Aviv University, Tel Aviv, Israel
| | - Itamar Shiryan
- Blavatnik School of Computer Science, Tel Aviv University, Tel Aviv, Israel
| | - Elhanan Borenstein
- Blavatnik School of Computer Science, Tel Aviv University, Tel Aviv, Israel.
- Faculty of Medical and Health Sciences, Tel Aviv University, Tel Aviv, Israel.
- Santa Fe Institute, Santa Fe, NM, USA.
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45
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d'Humières C, Delavy M, Alla L, Ichou F, Gauliard E, Ghozlane A, Levenez F, Galleron N, Quinquis B, Pons N, Mullaert J, Bridier-Nahmias A, Condamine B, Touchon M, Rainteau D, Lamazière A, Lesnik P, Ponnaiah M, Lhomme M, Sertour N, Devente S, Docquier JD, Bougnoux ME, Tenaillon O, Magnan M, Ruppé E, Grall N, Duval X, Ehrlich D, Mentré F, Denamur E, Rocha EPC, Le Chatelier E, Burdet C. Perturbation and resilience of the gut microbiome up to 3 months after β-lactams exposure in healthy volunteers suggest an important role of microbial β-lactamases. MICROBIOME 2024; 12:50. [PMID: 38468305 DOI: 10.1186/s40168-023-01746-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/14/2023] [Accepted: 12/20/2023] [Indexed: 03/13/2024]
Abstract
BACKGROUND Antibiotics notoriously perturb the gut microbiota. We treated healthy volunteers either with cefotaxime or ceftriaxone for 3 days, and collected in each subject 12 faecal samples up to day 90. Using untargeted and targeted phenotypic and genotypic approaches, we studied the changes in the bacterial, phage and fungal components of the microbiota as well as the metabolome and the β-lactamase activity of the stools. This allowed assessing their degrees of perturbation and resilience. RESULTS While only two subjects had detectable concentrations of antibiotics in their faeces, suggesting important antibiotic degradation in the gut, the intravenous treatment perturbed very significantly the bacterial and phage microbiota, as well as the composition of the metabolome. In contrast, treatment impact was relatively low on the fungal microbiota. At the end of the surveillance period, we found evidence of resilience across the gut system since most components returned to a state like the initial one, even if the structure of the bacterial microbiota changed and the dynamics of the different components over time were rarely correlated. The observed richness of the antibiotic resistance genes repertoire was significantly reduced up to day 30, while a significant increase in the relative abundance of β-lactamase encoding genes was observed up to day 10, consistent with a concomitant increase in the β-lactamase activity of the microbiota. The level of β-lactamase activity at baseline was positively associated with the resilience of the metabolome content of the stools. CONCLUSIONS In healthy adults, antibiotics perturb many components of the microbiota, which return close to the baseline state within 30 days. These data suggest an important role of endogenous β-lactamase-producing anaerobes in protecting the functions of the microbiota by de-activating the antibiotics reaching the colon. Video Abstract.
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Affiliation(s)
- Camille d'Humières
- Université Paris Cité, IAME, INSERM, Paris, F-75018, France
- Institut Pasteur, Université Paris Cité, CNRS UMR3525, Microbial Evolutionary Genomics, Paris, 75015, France
| | - Margot Delavy
- Institut Pasteur, Université Paris Cité, INRAE, USC2019, Unité Biologie Et Pathogénicité Fongiques, Paris, F-75015, France
| | - Laurie Alla
- Université Paris-Saclay, INRAE, MetaGenoPolis, Jouy-en-Josas, F-78350, France
| | - Farid Ichou
- ICANomics, Foundation of Innovation in Cardiometabolism and Nutrition (IHU ICAN), Paris, F-75013, France
| | - Emilie Gauliard
- Sorbonne Université, INSERM U938, Centre de Recherche Saint-Antoine, Paris, F-75012, France
| | - Amine Ghozlane
- Institut Pasteur, Université Paris Cité, Bioinformatics and Biostatistics Hub, Paris, F-75015, France
| | - Florence Levenez
- Université Paris-Saclay, INRAE, MetaGenoPolis, Jouy-en-Josas, F-78350, France
| | - Nathalie Galleron
- Université Paris-Saclay, INRAE, MetaGenoPolis, Jouy-en-Josas, F-78350, France
| | - Benoit Quinquis
- Université Paris-Saclay, INRAE, MetaGenoPolis, Jouy-en-Josas, F-78350, France
| | - Nicolas Pons
- Université Paris-Saclay, INRAE, MetaGenoPolis, Jouy-en-Josas, F-78350, France
| | - Jimmy Mullaert
- Université Paris Cité, IAME, INSERM, Paris, F-75018, France
- AP-HP, Département d'Epidemiologie, Biostatistique and Recherche Clinique, Hôpital Bichat, Paris, F-75018, France
| | | | | | - Marie Touchon
- Institut Pasteur, Université Paris Cité, CNRS UMR3525, Microbial Evolutionary Genomics, Paris, 75015, France
| | - Dominique Rainteau
- Sorbonne Université, INSERM U938, Centre de Recherche Saint-Antoine, Paris, F-75012, France
| | - Antonin Lamazière
- Sorbonne Université, INSERM U938, Centre de Recherche Saint-Antoine, Paris, F-75012, France
| | - Philippe Lesnik
- INSERM UMR-S 1166, Institute of Cardiometabolism and Nutrition, Sorbonne Université, Hôpital Pitié-Salpêtrière, Paris, F-75013, France
- ICANomics, Foundation of Innovation in Cardiometabolism and Nutrition (IHU ICAN), Paris, F-75013, France
| | - Maharajah Ponnaiah
- ICANomics, Foundation of Innovation in Cardiometabolism and Nutrition (IHU ICAN), Paris, F-75013, France
| | - Marie Lhomme
- ICANomics, Foundation of Innovation in Cardiometabolism and Nutrition (IHU ICAN), Paris, F-75013, France
| | - Natacha Sertour
- Institut Pasteur, Université Paris Cité, INRAE, USC2019, Unité Biologie Et Pathogénicité Fongiques, Paris, F-75015, France
| | - Savannah Devente
- Dipartimento di Biotecnologie Mediche, Università di Siena, Siena, I-53100, Italy
| | - Jean-Denis Docquier
- Dipartimento di Biotecnologie Mediche, Università di Siena, Siena, I-53100, Italy
| | - Marie-Elisabeth Bougnoux
- Institut Pasteur, Université Paris Cité, INRAE, USC2019, Unité Biologie Et Pathogénicité Fongiques, Paris, F-75015, France
- AP-HP, Unité de Parasitologie-Mycologie, Service de Microbiologie Clinique, Hôpital Necker-Enfants-Malades, Paris, F-75015, France
| | | | - Mélanie Magnan
- Université Paris Cité, IAME, INSERM, Paris, F-75018, France
| | - Etienne Ruppé
- Université Paris Cité, IAME, INSERM, Paris, F-75018, France
- AP-HP, Laboratoire de Bactériologie, Hôpital Bichat, Paris, F-75018, France
| | - Nathalie Grall
- Université Paris Cité, IAME, INSERM, Paris, F-75018, France
- AP-HP, Laboratoire de Bactériologie, Hôpital Bichat, Paris, F-75018, France
| | - Xavier Duval
- Université Paris Cité, IAME, INSERM, Paris, F-75018, France
- AP-HP, Centre d'Investigation Clinique, INSERM CIC 1425, Hôpital Bichat, Paris, F-75018, France
| | - Dusko Ehrlich
- Université Paris-Saclay, INRAE, MetaGenoPolis, Jouy-en-Josas, F-78350, France
- University College London, Institute for Neurology, London, UK
| | - France Mentré
- Université Paris Cité, IAME, INSERM, Paris, F-75018, France
- AP-HP, Département d'Epidemiologie, Biostatistique and Recherche Clinique, Hôpital Bichat, Paris, F-75018, France
| | - Erick Denamur
- Université Paris Cité, IAME, INSERM, Paris, F-75018, France
- AP-HP, Laboratoire de Génétique Moléculaire, Hôpital Bichat, Paris, F-75018, France
| | - Eduardo P C Rocha
- Institut Pasteur, Université Paris Cité, CNRS UMR3525, Microbial Evolutionary Genomics, Paris, 75015, France
| | | | - Charles Burdet
- Université Paris Cité, IAME, INSERM, Paris, F-75018, France.
- AP-HP, Département d'Epidemiologie, Biostatistique and Recherche Clinique, Hôpital Bichat, Paris, F-75018, France.
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Charitos IA, Aliani M, Tondo P, Venneri M, Castellana G, Scioscia G, Castellaneta F, Lacedonia D, Carone M. Biomolecular Actions by Intestinal Endotoxemia in Metabolic Syndrome. Int J Mol Sci 2024; 25:2841. [PMID: 38474087 DOI: 10.3390/ijms25052841] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2024] [Revised: 02/19/2024] [Accepted: 02/27/2024] [Indexed: 03/14/2024] Open
Abstract
Metabolic syndrome (MetS) is a combination of metabolic disorders that concurrently act as factors promoting systemic pathologies such as atherosclerosis or diabetes mellitus. It is now believed to encompass six main interacting conditions: visceral fat, imbalance of lipids (dyslipidemia), hypertension, insulin resistance (with or without impairing both glucose tolerance and fasting blood sugar), and inflammation. In the last 10 years, there has been a progressive interest through scientific research investigations conducted in the field of metabolomics, confirming a trend to evaluate the role of the metabolome, particularly the intestinal one. The intestinal microbiota (IM) is crucial due to the diversity of microorganisms and their abundance. Consequently, IM dysbiosis and its derivate toxic metabolites have been correlated with MetS. By intervening in these two factors (dysbiosis and consequently the metabolome), we can potentially prevent or slow down the clinical effects of the MetS process. This, in turn, may mitigate dysregulations of intestinal microbiota axes, such as the lung axis, thereby potentially alleviating the negative impact on respiratory pathology, such as the chronic obstructive pulmonary disease. However, the biomolecular mechanisms through which the IM influences the host's metabolism via a dysbiosis metabolome in both normal and pathological conditions are still unclear. In this study, we seek to provide a description of the knowledge to date of the IM and its metabolome and the factors that influence it. Furthermore, we analyze the interactions between the functions of the IM and the pathophysiology of major metabolic diseases via local and systemic metabolome's relate endotoxemia.
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Affiliation(s)
- Ioannis Alexandros Charitos
- Istituti Clinici Scientifici Maugeri IRCCS, Pneumology and Respiratory Rehabilitation Unit, "Istitute" of Bari, 70124 Bari, Italy
| | - Maria Aliani
- Istituti Clinici Scientifici Maugeri IRCCS, Pneumology and Respiratory Rehabilitation Unit, "Istitute" of Bari, 70124 Bari, Italy
| | - Pasquale Tondo
- Department of Medical and Surgical Sciences, University of Foggia, 71122 Foggia, Italy
- Institute of Respiratory Diseases, Policlinico Riuniti of Foggia, 71122 Foggia, Italy
| | - Maria Venneri
- Istituti Clinici Scientifici Maugeri IRCCS, Genomics and Proteomics Laboratory, "Istitute" of Bari, 70124 Bari, Italy
| | - Giorgio Castellana
- Istituti Clinici Scientifici Maugeri IRCCS, Pneumology and Respiratory Rehabilitation Unit, "Istitute" of Bari, 70124 Bari, Italy
| | - Giulia Scioscia
- Department of Medical and Surgical Sciences, University of Foggia, 71122 Foggia, Italy
- Institute of Respiratory Diseases, Policlinico Riuniti of Foggia, 71122 Foggia, Italy
| | - Francesca Castellaneta
- School of Clinical Biochemistry and Pathology, University of Bari (Aldo Moro), 70124 Bari, Italy
| | - Donato Lacedonia
- Department of Medical and Surgical Sciences, University of Foggia, 71122 Foggia, Italy
- Institute of Respiratory Diseases, Policlinico Riuniti of Foggia, 71122 Foggia, Italy
| | - Mauro Carone
- Istituti Clinici Scientifici Maugeri IRCCS, Pneumology and Respiratory Rehabilitation Unit, "Istitute" of Bari, 70124 Bari, Italy
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Li T, Ding N, Guo H, Hua R, Lin Z, Tian H, Yu Y, Fan D, Yuan Z, Gonzalez FJ, Wu Y. A gut microbiota-bile acid axis promotes intestinal homeostasis upon aspirin-mediated damage. Cell Host Microbe 2024; 32:191-208.e9. [PMID: 38237593 PMCID: PMC10922796 DOI: 10.1016/j.chom.2023.12.015] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2023] [Revised: 11/18/2023] [Accepted: 12/21/2023] [Indexed: 02/17/2024]
Abstract
Aspirin-related gastrointestinal damage is of growing concern. Aspirin use modulates the gut microbiota and associated metabolites, such as bile acids (BAs), but how this impacts intestinal homeostasis remains unclear. Herein, using clinical cohorts and aspirin-treated mice, we identified an intestinal microbe, Parabacteroides goldsteinii, whose growth is suppressed by aspirin. Mice supplemented with P. goldsteinii or its BA metabolite, 7-keto-lithocholic acid (7-keto-LCA), showed reduced aspirin-mediated damage of the intestinal niche and gut barrier, effects that were lost with a P. goldsteinii hdhA mutant unable to generate 7-keto-LCA. Specifically, 7-keto-LCA promotes repair of the intestinal epithelium by suppressing signaling by the intestinal BA receptor, farnesoid X receptor (FXR). 7-Keto-LCA was confirmed to be an FXR antagonist that facilitates Wnt signaling and thus self-renewal of intestinal stem cells. These results reveal the impact of oral aspirin on the gut microbiota and intestinal BA metabolism that in turn modulates gastrointestinal homeostasis.
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Affiliation(s)
- Ting Li
- Department of Cardiovascular Medicine, First Affiliated Hospital, Xi'an Jiaotong University, Xi'an, Shaanxi, China; Key Laboratory of Molecular Cardiology, Xi'an, Shaanxi, China; Key Laboratory of Environment and Genes Related to Diseases, Ministry of Education, Xi'an, Shaanxi, China
| | - Ning Ding
- Department of Cardiovascular Medicine, First Affiliated Hospital, Xi'an Jiaotong University, Xi'an, Shaanxi, China; Key Laboratory of Molecular Cardiology, Xi'an, Shaanxi, China; Key Laboratory of Environment and Genes Related to Diseases, Ministry of Education, Xi'an, Shaanxi, China
| | - Hanqing Guo
- Department of Gastroenterology, Xi'an Central Hospital, Xi'an Jiaotong University, Xi'an, Shaanxi, China
| | - Rui Hua
- Department of Cardiovascular Medicine, First Affiliated Hospital, Xi'an Jiaotong University, Xi'an, Shaanxi, China
| | - Zehao Lin
- Department of Cardiovascular Medicine, First Affiliated Hospital, Xi'an Jiaotong University, Xi'an, Shaanxi, China
| | - Huohuan Tian
- Department of Cardiovascular Medicine, First Affiliated Hospital, Xi'an Jiaotong University, Xi'an, Shaanxi, China
| | - Yue Yu
- Department of Cardiovascular Medicine, First Affiliated Hospital, Xi'an Jiaotong University, Xi'an, Shaanxi, China
| | - Daiming Fan
- Xijing Hospital of Digestive Diseases, Fourth Military Medical University, Xi'an, Shaanxi, China
| | - Zuyi Yuan
- Department of Cardiovascular Medicine, First Affiliated Hospital, Xi'an Jiaotong University, Xi'an, Shaanxi, China; Key Laboratory of Molecular Cardiology, Xi'an, Shaanxi, China; Key Laboratory of Environment and Genes Related to Diseases, Ministry of Education, Xi'an, Shaanxi, China.
| | - Frank J Gonzalez
- Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
| | - Yue Wu
- Department of Cardiovascular Medicine, First Affiliated Hospital, Xi'an Jiaotong University, Xi'an, Shaanxi, China; Key Laboratory of Molecular Cardiology, Xi'an, Shaanxi, China; Key Laboratory of Environment and Genes Related to Diseases, Ministry of Education, Xi'an, Shaanxi, China.
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48
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Cuthbertson L, Löber U, Ish-Horowicz JS, McBrien CN, Churchward C, Parker JC, Olanipekun MT, Burke C, McGowan A, Davies GA, Lewis KE, Hopkin JM, Chung KF, O'Carroll O, Faul J, Creaser-Thomas J, Andrews M, Ghosal R, Piatek S, Willis-Owen SAG, Bartolomaeus TUP, Birkner T, Dwyer S, Kumar N, Turek EM, William Musk A, Hui J, Hunter M, James A, Dumas ME, Filippi S, Cox MJ, Lawley TD, Forslund SK, Moffatt MF, Cookson WOC. Genomic attributes of airway commensal bacteria and mucosa. Commun Biol 2024; 7:171. [PMID: 38347162 PMCID: PMC10861553 DOI: 10.1038/s42003-024-05840-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2023] [Accepted: 01/22/2024] [Indexed: 02/15/2024] Open
Abstract
Microbial communities at the airway mucosal barrier are conserved and highly ordered, in likelihood reflecting co-evolution with human host factors. Freed of selection to digest nutrients, the airway microbiome underpins cognate management of mucosal immunity and pathogen resistance. We show here the initial results of systematic culture and whole-genome sequencing of the thoracic airway bacteria, identifying 52 novel species amongst 126 organisms that constitute 75% of commensals typically present in heathy individuals. Clinically relevant genes encode antimicrobial synthesis, adhesion and biofilm formation, immune modulation, iron utilisation, nitrous oxide (NO) metabolism and sphingolipid signalling. Using whole-genome content we identify dysbiotic features that may influence asthma and chronic obstructive pulmonary disease. We match isolate gene content to transcripts and metabolites expressed late in airway epithelial differentiation, identifying pathways to sustain host interactions with microbiota. Our results provide a systematic basis for decrypting interactions between commensals, pathogens, and mucosa in lung diseases of global significance.
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Affiliation(s)
- Leah Cuthbertson
- National Heart and Lung Institute, Imperial College London, London, UK
| | - Ulrike Löber
- Max Delbrück Center for Molecular Medicine (MDC), 13125, Berlin, Germany
- Experimental and Clinical Research Center, A Cooperation of Charité-Universitätsmedizin Berlin and Max Delbrück Center for Molecular Medicine, Lindenberger Weg 80, 13125, Berlin, Germany
- DZHK (German Centre for Cardiovascular Research), Partner Site, 10785, Berlin, Germany
- Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, 10117, Berlin, Germany
| | - Jonathan S Ish-Horowicz
- National Heart and Lung Institute, Imperial College London, London, UK
- Department of Mathematics, Imperial College London, London, UK
| | - Claire N McBrien
- National Heart and Lung Institute, Imperial College London, London, UK
| | - Colin Churchward
- National Heart and Lung Institute, Imperial College London, London, UK
| | - Jeremy C Parker
- National Heart and Lung Institute, Imperial College London, London, UK
| | | | - Conor Burke
- Department of Respiratory Medicine, Connolly Hospital, Dublin, Ireland
| | - Aisling McGowan
- Department of Respiratory Medicine, Connolly Hospital, Dublin, Ireland
| | - Gwyneth A Davies
- Population Data Science and Health Data Research UK BREATHE Hub, Swansea University Medical School, Swansea University, Swansea, UK
- College of Medicine, Institute of Life Science, Swansea University, Swansea, UK
| | - Keir E Lewis
- College of Medicine, Institute of Life Science, Swansea University, Swansea, UK
- Respiratory Medicine, Hywel Dda University Health Board, Llanelli, UK
| | - Julian M Hopkin
- College of Medicine, Institute of Life Science, Swansea University, Swansea, UK
| | - Kian Fan Chung
- National Heart and Lung Institute, Imperial College London, London, UK
| | - Orla O'Carroll
- Department of Respiratory Medicine, Connolly Hospital, Dublin, Ireland
| | - John Faul
- Department of Respiratory Medicine, Connolly Hospital, Dublin, Ireland
| | - Joy Creaser-Thomas
- College of Medicine, Institute of Life Science, Swansea University, Swansea, UK
| | - Mark Andrews
- Respiratory Medicine, Hywel Dda University Health Board, Llanelli, UK
| | - Robin Ghosal
- Respiratory Medicine, Hywel Dda University Health Board, Llanelli, UK
| | - Stefan Piatek
- National Heart and Lung Institute, Imperial College London, London, UK
| | | | - Theda U P Bartolomaeus
- Max Delbrück Center for Molecular Medicine (MDC), 13125, Berlin, Germany
- Experimental and Clinical Research Center, A Cooperation of Charité-Universitätsmedizin Berlin and Max Delbrück Center for Molecular Medicine, Lindenberger Weg 80, 13125, Berlin, Germany
- DZHK (German Centre for Cardiovascular Research), Partner Site, 10785, Berlin, Germany
- Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, 10117, Berlin, Germany
| | - Till Birkner
- Max Delbrück Center for Molecular Medicine (MDC), 13125, Berlin, Germany
- Experimental and Clinical Research Center, A Cooperation of Charité-Universitätsmedizin Berlin and Max Delbrück Center for Molecular Medicine, Lindenberger Weg 80, 13125, Berlin, Germany
- Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, 10117, Berlin, Germany
| | - Sarah Dwyer
- National Heart and Lung Institute, Imperial College London, London, UK
| | - Nitin Kumar
- Host-Microbiota Interactions Laboratory, Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, UK
| | - Elena M Turek
- National Heart and Lung Institute, Imperial College London, London, UK
| | - A William Musk
- School of Population and Global Health, The University of Western Australia, Perth, WA, Australia
- Busselton Population Medical Research Institute, Sir Charles Gairdner Hospital, Perth, WA, Australia
- Department of Respiratory Medicine Sir Charles Gairdner Hospital, Perth, WA, Australia
| | - Jennie Hui
- School of Population and Global Health, The University of Western Australia, Perth, WA, Australia
- Busselton Population Medical Research Institute, Sir Charles Gairdner Hospital, Perth, WA, Australia
| | - Michael Hunter
- School of Population and Global Health, The University of Western Australia, Perth, WA, Australia
- Busselton Population Medical Research Institute, Sir Charles Gairdner Hospital, Perth, WA, Australia
| | - Alan James
- School of Population and Global Health, The University of Western Australia, Perth, WA, Australia
- Department of Respiratory Medicine Sir Charles Gairdner Hospital, Perth, WA, Australia
- Department of Pulmonary Physiology and Sleep Medicine, Sir Charles Gairdner Hospital, Perth, WA, Australia
| | - Marc-Emmanuel Dumas
- National Heart and Lung Institute, Imperial College London, London, UK
- Department of Metabolism, Digestion and Reproduction, Imperial College London, London, UK
- U1283 INSERM / UMR8199 CNRS, Institut Pasteur de Lille, Lille University Hospital, European Genomic Institute for Diabetes, University of Lille, Lille, France
- McGill Genome Centre, McGill University, Montréal, QC, Canada
| | - Sarah Filippi
- Department of Mathematics, Imperial College London, London, UK
| | - Michael J Cox
- University of Birmingham College of Medical and Dental Sciences, 150183, Institute of Microbiology and Infection, Birmingham, UK
| | - Trevor D Lawley
- Host-Microbiota Interactions Laboratory, Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, UK
| | - Sofia K Forslund
- Max Delbrück Center for Molecular Medicine (MDC), 13125, Berlin, Germany.
- Experimental and Clinical Research Center, A Cooperation of Charité-Universitätsmedizin Berlin and Max Delbrück Center for Molecular Medicine, Lindenberger Weg 80, 13125, Berlin, Germany.
- DZHK (German Centre for Cardiovascular Research), Partner Site, 10785, Berlin, Germany.
- Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, 10117, Berlin, Germany.
- Structural and Computational Biology Unit, European Molecular Biology Laboratory, Structural and Computational Biology Unit, 69117, Heidelberg, Germany.
| | - Miriam F Moffatt
- National Heart and Lung Institute, Imperial College London, London, UK.
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49
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She J, Tuerhongjiang G, Guo M, Liu J, Hao X, Guo L, Liu N, Xi W, Zheng T, Du B, Lou B, Gao X, Yuan X, Yu Y, Zhang Y, Gao F, Zhuo X, Xiong Y, Zhang X, Yu J, Yuan Z, Wu Y. Statins aggravate insulin resistance through reduced blood glucagon-like peptide-1 levels in a microbiota-dependent manner. Cell Metab 2024; 36:408-421.e5. [PMID: 38325336 DOI: 10.1016/j.cmet.2023.12.027] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/04/2023] [Revised: 10/23/2023] [Accepted: 12/28/2023] [Indexed: 02/09/2024]
Abstract
Statins are currently the most common cholesterol-lowering drug, but the underlying mechanism of statin-induced hyperglycemia is unclear. To investigate whether the gut microbiome and its metabolites contribute to statin-associated glucose intolerance, we recruited 30 patients with atorvastatin and 10 controls, followed up for 16 weeks, and found a decreased abundance of the genus Clostridium in feces and altered serum and fecal bile acid profiles among patients with atorvastatin therapy. Animal experiments validated that statin could induce glucose intolerance, and transplantation of Clostridium sp. and supplementation of ursodeoxycholic acid (UDCA) could ameliorate statin-induced glucose intolerance. Furthermore, oral UDCA administration in humans alleviated the glucose intolerance without impairing the lipid-lowering effect. Our study demonstrated that the statin-induced hyperglycemic effect was attributed to the Clostridium sp.-bile acids axis and provided important insights into adjuvant therapy of UDCA to lower the adverse risk of statin therapy.
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Affiliation(s)
- Jianqing She
- Cardiovascular Department, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, China; Key Laboratory of Environment and Genes Related to Diseases, Ministry of Education, Xi'an, Shaanxi, China; Cardiometabolic Innovation Center, Ministry of Education, Xi'an, Shaanxi, China; MED-X Institute, Center for Immunological and Metabolic Diseases (CIMD), First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, China
| | - Gulinigaer Tuerhongjiang
- Cardiovascular Department, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, China; Key Laboratory of Environment and Genes Related to Diseases, Ministry of Education, Xi'an, Shaanxi, China
| | - Manyun Guo
- Cardiovascular Department, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, China; Key Laboratory of Environment and Genes Related to Diseases, Ministry of Education, Xi'an, Shaanxi, China
| | - Junhui Liu
- Clinical Laboratory, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, China
| | - Xiang Hao
- Cardiovascular Department, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, China; Key Laboratory of Environment and Genes Related to Diseases, Ministry of Education, Xi'an, Shaanxi, China
| | - Liangan Guo
- Cardiovascular Department, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, China; Key Laboratory of Environment and Genes Related to Diseases, Ministry of Education, Xi'an, Shaanxi, China
| | - Nairong Liu
- Cardiovascular Department, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, China; Key Laboratory of Environment and Genes Related to Diseases, Ministry of Education, Xi'an, Shaanxi, China
| | - Wen Xi
- Clinical Laboratory, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, China
| | - Tao Zheng
- Cardiovascular Department, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, China; Key Laboratory of Environment and Genes Related to Diseases, Ministry of Education, Xi'an, Shaanxi, China
| | - Bin Du
- Cardiovascular Department, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, China; Key Laboratory of Environment and Genes Related to Diseases, Ministry of Education, Xi'an, Shaanxi, China
| | - Bowen Lou
- Cardiovascular Department, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, China; Key Laboratory of Environment and Genes Related to Diseases, Ministry of Education, Xi'an, Shaanxi, China
| | - Xiyu Gao
- Cardiovascular Department, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, China; Key Laboratory of Environment and Genes Related to Diseases, Ministry of Education, Xi'an, Shaanxi, China
| | - Xiao Yuan
- Cardiovascular Department, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, China; Key Laboratory of Environment and Genes Related to Diseases, Ministry of Education, Xi'an, Shaanxi, China
| | - Yue Yu
- Cardiovascular Department, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, China; Key Laboratory of Environment and Genes Related to Diseases, Ministry of Education, Xi'an, Shaanxi, China
| | - Yi Zhang
- MED-X Institute, Center for Immunological and Metabolic Diseases (CIMD), First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, China
| | - Fan Gao
- Clinical Research Center, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, China
| | - Xiaozhen Zhuo
- Cardiovascular Department, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, China; Key Laboratory of Environment and Genes Related to Diseases, Ministry of Education, Xi'an, Shaanxi, China; Cardiometabolic Innovation Center, Ministry of Education, Xi'an, Shaanxi, China
| | - Ying Xiong
- Cardiovascular Department, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, China; Key Laboratory of Environment and Genes Related to Diseases, Ministry of Education, Xi'an, Shaanxi, China; Cardiometabolic Innovation Center, Ministry of Education, Xi'an, Shaanxi, China
| | - Xiang Zhang
- Department of Medicine and Therapeutics and Institute of Digestive Disease, The State Key Laboratory of Digestive Disease, The Chinese University of Hong Kong, Hong Kong SAR, China
| | - Jun Yu
- Department of Medicine and Therapeutics and Institute of Digestive Disease, The State Key Laboratory of Digestive Disease, The Chinese University of Hong Kong, Hong Kong SAR, China.
| | - Zuyi Yuan
- Cardiovascular Department, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, China; Key Laboratory of Environment and Genes Related to Diseases, Ministry of Education, Xi'an, Shaanxi, China; Cardiometabolic Innovation Center, Ministry of Education, Xi'an, Shaanxi, China.
| | - Yue Wu
- Cardiovascular Department, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, China; Key Laboratory of Environment and Genes Related to Diseases, Ministry of Education, Xi'an, Shaanxi, China; Cardiometabolic Innovation Center, Ministry of Education, Xi'an, Shaanxi, China.
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50
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You Z, Wang C, Lan X, Li W, Shang D, Zhang F, Ye Y, Liu H, Zhou Y, Ning Y. The contribution of polyamine pathway to determinations of diagnosis for treatment-resistant depression: A metabolomic analysis. Prog Neuropsychopharmacol Biol Psychiatry 2024; 128:110849. [PMID: 37659714 DOI: 10.1016/j.pnpbp.2023.110849] [Citation(s) in RCA: 3] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/07/2023] [Revised: 08/26/2023] [Accepted: 08/28/2023] [Indexed: 09/04/2023]
Abstract
OBJECTIVES Approximately one-third of major depressive disorder (MDD) patients do not respond to standard antidepressants and develop treatment-resistant depression (TRD). We aimed to reveal metabolic differences and discover promising potential biomarkers in TRD. METHODS Our study recruited 108 participants including healthy controls (n = 40) and patients with TRD (n = 35) and first-episode drug-naive MDD (DN-MDD) (n = 33). Plasma samples were presented to ultra performance liquid chromatography-tandem mass spectrometry. Then, a machine-learning algorithm was conducted to facilitate the selection of potential biomarkers. RESULTS TRD appeared to be a distinct metabolic disorder from DN-MDD and healthy controls (HCs). Compared to HCs, 199 and 176 differentially expressed metabolites were identified in TRD and DN-MDD, respectively. Of all the metabolites that were identified, spermine, spermidine, and carnosine were considered the most promising biomarkers for diagnosing TRD and DN-MDD patients, with the resulting area under the ROC curve of 0.99, 0.99, and 0.93, respectively. Metabolic pathway analysis yielded compelling evidence of marked changes or imbalances in both polyamine metabolism and energy metabolism, which could potentially represent the primary altered pathways associated with MDD. Additionally, L-glutamine, Beta-alanine, and spermine were correlated with HAMD score. CONCLUSIONS A more disordered metabolism structure is found in TRD than in DN-MDD and HCs. Future investigations should prioritize the comprehensive analysis of potential roles played by these differential metabolites and disturbances in polyamine pathways in the pathophysiology of TRD and depression.
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Affiliation(s)
- Zerui You
- The First School of Clinical Medicine, Southern Medical University, Guangzhou, China; Department of Child and Adolescent Psychiatry, The Affiliated Brain Hospital of Guangzhou Medical University, Guangzhou, China; Key Laboratory of Neurogenetics and Channelopathies of Guangdong Province and the Ministry of Education of China, Guangzhou Medical University, Guangzhou, China; Guangdong Engineering Technology Research Center for Translational Medicine of Mental Disorders, Guangzhou, China
| | - Chengyu Wang
- Department of Child and Adolescent Psychiatry, The Affiliated Brain Hospital of Guangzhou Medical University, Guangzhou, China; Key Laboratory of Neurogenetics and Channelopathies of Guangdong Province and the Ministry of Education of China, Guangzhou Medical University, Guangzhou, China; Guangdong Engineering Technology Research Center for Translational Medicine of Mental Disorders, Guangzhou, China
| | - Xiaofeng Lan
- Department of Child and Adolescent Psychiatry, The Affiliated Brain Hospital of Guangzhou Medical University, Guangzhou, China; Key Laboratory of Neurogenetics and Channelopathies of Guangdong Province and the Ministry of Education of China, Guangzhou Medical University, Guangzhou, China; Guangdong Engineering Technology Research Center for Translational Medicine of Mental Disorders, Guangzhou, China
| | - Weicheng Li
- The First School of Clinical Medicine, Southern Medical University, Guangzhou, China; Department of Child and Adolescent Psychiatry, The Affiliated Brain Hospital of Guangzhou Medical University, Guangzhou, China; Key Laboratory of Neurogenetics and Channelopathies of Guangdong Province and the Ministry of Education of China, Guangzhou Medical University, Guangzhou, China; Guangdong Engineering Technology Research Center for Translational Medicine of Mental Disorders, Guangzhou, China
| | - Dewei Shang
- Department of Child and Adolescent Psychiatry, The Affiliated Brain Hospital of Guangzhou Medical University, Guangzhou, China; Key Laboratory of Neurogenetics and Channelopathies of Guangdong Province and the Ministry of Education of China, Guangzhou Medical University, Guangzhou, China; Guangdong Engineering Technology Research Center for Translational Medicine of Mental Disorders, Guangzhou, China
| | - Fan Zhang
- The First School of Clinical Medicine, Southern Medical University, Guangzhou, China; Department of Child and Adolescent Psychiatry, The Affiliated Brain Hospital of Guangzhou Medical University, Guangzhou, China; Key Laboratory of Neurogenetics and Channelopathies of Guangdong Province and the Ministry of Education of China, Guangzhou Medical University, Guangzhou, China; Guangdong Engineering Technology Research Center for Translational Medicine of Mental Disorders, Guangzhou, China
| | - Yanxiang Ye
- Department of Child and Adolescent Psychiatry, The Affiliated Brain Hospital of Guangzhou Medical University, Guangzhou, China; Key Laboratory of Neurogenetics and Channelopathies of Guangdong Province and the Ministry of Education of China, Guangzhou Medical University, Guangzhou, China; Guangdong Engineering Technology Research Center for Translational Medicine of Mental Disorders, Guangzhou, China
| | - Haiyan Liu
- Department of Child and Adolescent Psychiatry, The Affiliated Brain Hospital of Guangzhou Medical University, Guangzhou, China; Key Laboratory of Neurogenetics and Channelopathies of Guangdong Province and the Ministry of Education of China, Guangzhou Medical University, Guangzhou, China; Guangdong Engineering Technology Research Center for Translational Medicine of Mental Disorders, Guangzhou, China
| | - Yanling Zhou
- Department of Child and Adolescent Psychiatry, The Affiliated Brain Hospital of Guangzhou Medical University, Guangzhou, China; Key Laboratory of Neurogenetics and Channelopathies of Guangdong Province and the Ministry of Education of China, Guangzhou Medical University, Guangzhou, China; Guangdong Engineering Technology Research Center for Translational Medicine of Mental Disorders, Guangzhou, China.
| | - Yuping Ning
- The First School of Clinical Medicine, Southern Medical University, Guangzhou, China; Department of Child and Adolescent Psychiatry, The Affiliated Brain Hospital of Guangzhou Medical University, Guangzhou, China; Key Laboratory of Neurogenetics and Channelopathies of Guangdong Province and the Ministry of Education of China, Guangzhou Medical University, Guangzhou, China; Guangdong Engineering Technology Research Center for Translational Medicine of Mental Disorders, Guangzhou, China.
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