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Su F, Su M, Wei W, Wu J, Chen L, Sun X, Liu M, Sun S, Mao R, Bourgonje AR, Hu S. Integrating multi-omics data to reveal the host-microbiota interactome in inflammatory bowel disease. Gut Microbes 2025; 17:2476570. [PMID: 40063366 PMCID: PMC11901428 DOI: 10.1080/19490976.2025.2476570] [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: 12/17/2024] [Revised: 02/14/2025] [Accepted: 03/03/2025] [Indexed: 03/14/2025] Open
Abstract
Numerous studies have accelerated the knowledge expansion on the role of gut microbiota in inflammatory bowel disease (IBD). However, the precise mechanisms behind host-microbe cross-talk remain largely undefined, due to the complexity of the human intestinal ecosystem and multiple external factors. In this review, we introduce the interactome concept to systematically summarize how intestinal dysbiosis is involved in IBD pathogenesis in terms of microbial composition, functionality, genomic structure, transcriptional activity, and downstream proteins and metabolites. Meanwhile, this review also aims to present an updated overview of the relevant mechanisms, high-throughput multi-omics methodologies, different types of multi-omics cohort resources, and computational methods used to understand host-microbiota interactions in the context of IBD. Finally, we discuss the challenges pertaining to the integration of multi-omics data in order to reveal host-microbiota cross-talk and offer insights into relevant future research directions.
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Affiliation(s)
- Fengyuan Su
- Institute of Precision Medicine, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China
- Department of Gastroenterology, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China
| | - Meng Su
- The First Clinical Medical School, Nanfang Hospital of Southern Medical University, Guangzhou, China
| | - Wenting Wei
- Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, China
| | - Jiayun Wu
- Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, China
| | - Leyan Chen
- Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, China
| | - Xiqiao Sun
- Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, China
| | - Moyan Liu
- Amsterdam UMC location Academic Medical Center, Department of Experimental Vascular Medicine, Amsterdam, The Netherlands
| | - Shiqiang Sun
- Department of Gastroenterology and Hepatology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
| | - Ren Mao
- Department of Gastroenterology, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China
| | - Arno R. Bourgonje
- Department of Gastroenterology and Hepatology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
- The Henry D. Janowitz Division of Gastroenterology, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Shixian Hu
- Institute of Precision Medicine, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China
- Department of Gastroenterology, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China
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Slager J, Simpson HL, Gacesa R, Chen L, Tan IL, Gelderloos J, Maatman A, Wijmenga C, Zhernakova A, Fu J, Weersma RK, Gonera G, Jonkers IH, Withoff S. High-resolution analysis of the treated coeliac disease microbiome reveals strain-level variation. Gut Microbes 2025; 17:2489071. [PMID: 40289251 PMCID: PMC12036492 DOI: 10.1080/19490976.2025.2489071] [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: 12/23/2024] [Revised: 03/05/2025] [Accepted: 03/31/2025] [Indexed: 04/30/2025] Open
Abstract
BACKGROUND Coeliac disease (CeD) is an immune-mediated disorder primarily affecting the small intestine, characterized by an inflammatory immune reaction to dietary gluten. CeD onset results from a multifaceted interplay of genetic and environmental factors. While recent data show that alterations in gut microbiome composition could play an important role, many current studies are constrained by small sample sizes and limited resolution. METHODS To address these limitations, we analyzed fecal gut microbiota from two Dutch cohorts, CeDNN (128 treated CeD patients (tCeD), 106 controls) and the Lifelines Dutch Microbiome Project (24 self-reported tCeD, 654 controls), using shotgun metagenomic sequencing. Self-reported IBS (570 cases, 1710 controls) and IBD (93 cases, 465 controls) were used as comparative conditions of the gastrointestinal tract. Interindividual variation within the case and control groups was calculated at whole microbiome and strain level. Finally, species-specific gene repertoires were analyzed in tCeD patients and controls. RESULTS Within-individual microbiome diversity was decreased in patients with self-reported IBS and IBD but not in tCeD patients. Each condition displayed a unique microbial pattern and, in addition to confirming previously reported microbiome associations, we identify an increase in the levels of Clostridium sp. CAG:253, Roseburia hominis, and Eggerthella lenta, amongst others. We further show that the observed changes can partially be explained by gluten-free diet adherence. We also observe increased interindividual variation of gut microbiome composition among tCeD patients and a higher bacterial mutation frequency in tCeD that contributes to higher interindividual variation at strain level. In addition, the immotile European subspecies of Eubacterium rectale, which has a distinct carbohydrate metabolism potential, was nearly absent in tCeD patients. CONCLUSION Our study sheds light on the complex interplay between the gut microbiome and CeD, revealing increased interindividual variation and strain-level variation in tCeD patients. These findings expand our understanding of the microbiome's role in intestinal health and disease.
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Affiliation(s)
- Jelle Slager
- Department of Genetics, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
| | - Hanna L. Simpson
- Department of Genetics, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
| | - Ranko Gacesa
- Department of Genetics, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
- Department of Gastroenterology and Hepatology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
| | - Lianmin Chen
- Department of Genetics, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
- Department of Pediatrics, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
- Department of Cardiology, Nanjing Medical University, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
- Cardiovascular Research Center, The Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou Municipal Hospital, Gusu School, Nanjing Medical University, Suzhou, China
| | - Ineke L. Tan
- Department of Genetics, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
- Department of Gastroenterology and Hepatology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
| | - Jody Gelderloos
- Department of Genetics, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
| | - Astrid Maatman
- Department of Genetics, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
| | - Cisca Wijmenga
- Department of Genetics, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
| | - Alexandra Zhernakova
- Department of Genetics, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
| | - Jingyuan Fu
- Department of Genetics, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
- Department of Pediatrics, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
| | - Rinse K. Weersma
- Department of Gastroenterology and Hepatology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
| | - Gieneke Gonera
- Department of Pediatrics, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
- Department of Pediatrics, Wilhelmina Hospital Assen, Assen, The Netherlands
| | - Iris H. Jonkers
- Department of Genetics, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
| | - Sebo Withoff
- Department of Genetics, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
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DeSantis AH, Buss K, Coker KM, Pasternak BA, Chi J, Patterson JS, Gu H, Jurutka PW, Sandrin TR. Multiomics-Based Profiling of the Fecal Microbiome Reveals Potential Disease-Specific Signatures in Pediatric IBD (PIBD). Biomolecules 2025; 15:746. [PMID: 40427639 PMCID: PMC12109367 DOI: 10.3390/biom15050746] [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: 04/01/2025] [Revised: 05/16/2025] [Accepted: 05/17/2025] [Indexed: 05/29/2025] Open
Abstract
Inflammatory bowel disease (IBD), which includes Crohn's Disease (CD) and Ulcerative Colitis (UC), is a chronic gastrointestinal (GI) disorder affecting 1 in 100 people in the United States. Pediatric IBD (PIBD) is estimated to impact 15 per 100,000 children in North America. Factors such as the gut microbiome (GM), genetic predisposition to the disease, and certain environmental factors are thought to be involved in pathogenesis. However, the pathophysiology of IBD is incompletely understood, and diagnostic biomarkers and effective treatments, particularly for PIBD, are limited. Recent work suggests that these factors may interact to influence disease development, and multiomic approaches have emerged as promising tools to elucidate the pathophysiology. We employed metagenomics, metabolomics- and metatranscriptomics-based approaches to examine the microbiome, its genetic potential, and its activity to identify factors associated with PIBD. Metagenomics-based analyses revealed pathways such as octane oxidation and glycolysis that were differentially expressed in UC patients. Additionally, metatranscriptomics-based analyses suggested enrichment of glycan degradation and two component systems in UC samples as well as protein processing in the endoplasmic reticulum, ribosome, and protein export in CD and UC samples. In addition, metabolomics-based approaches revealed patterns of differentially abundant metabolites between healthy and PIBD individuals. Interestingly, overall microbiome community composition (as measured by alpha and beta diversity indices) did not appear to be associated with PIBD. However, we observed a small number of differentially abundant taxa in UC versus healthy controls, including members of the Classes Gammaproteobacteria and Clostridia as well as members of the Family Rikenellaceae. Accordingly, when identifying potential biomarkers for PIBD, our results suggest that multiomics-based approaches afford enhanced potential to detect putative biomarkers for PIBD compared to microbiome community composition sequence data alone.
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Affiliation(s)
- Anita H. DeSantis
- School of Mathematical and Natural Sciences, Arizona State University, 4701 W. Thunderbird Rd, Glendale, AZ 85306, USA; (A.H.D.); (K.M.C.); (P.W.J.)
| | - Kristina Buss
- Biosciences Core, Arizona State University, 1001 S. McAllister Ave, Tempe, AZ 85281, USA;
| | - Keaton M. Coker
- School of Mathematical and Natural Sciences, Arizona State University, 4701 W. Thunderbird Rd, Glendale, AZ 85306, USA; (A.H.D.); (K.M.C.); (P.W.J.)
| | - Brad A. Pasternak
- Phoenix Children’s Hospital, 1919 E. Thomas Rd, Phoenix, AZ 85016, USA;
| | - Jinhua Chi
- College of Health Solutions, Health North Building, Arizona State University, 550 N. 3rd St, Suite 501, Phoenix, AZ 85004, USA; (J.C.); (J.S.P.); (H.G.)
| | - Jeffrey S. Patterson
- College of Health Solutions, Health North Building, Arizona State University, 550 N. 3rd St, Suite 501, Phoenix, AZ 85004, USA; (J.C.); (J.S.P.); (H.G.)
| | - Haiwei Gu
- College of Health Solutions, Health North Building, Arizona State University, 550 N. 3rd St, Suite 501, Phoenix, AZ 85004, USA; (J.C.); (J.S.P.); (H.G.)
| | - Peter W. Jurutka
- School of Mathematical and Natural Sciences, Arizona State University, 4701 W. Thunderbird Rd, Glendale, AZ 85306, USA; (A.H.D.); (K.M.C.); (P.W.J.)
- College of Medicine, University of Arizona, 475 N. 5th St, Phoenix, AZ 85004, USA
| | - Todd R. Sandrin
- School of Mathematical and Natural Sciences, Arizona State University, 4701 W. Thunderbird Rd, Glendale, AZ 85306, USA; (A.H.D.); (K.M.C.); (P.W.J.)
- Center for Health through Microbiomes, Arizona State University, 1001 S. McAllister Ave, Tempe, AZ 85281, USA
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Stevens CL, Adriaans GMC, Spooren CEGM, Peters V, Pierik MJ, Weersma RK, van Dullemen HM, Festen EAM, Visschedijk MC, Hendrix EMB, Perenboom CWM, Feskens EJM, Dijkstra G, Almeida RJ, Jonkers DMAE, Campmans-Kuijpers MJE. Exploring diet categorizations and their influence on flare prediction in inflammatory bowel disease, using the Sparse Grouped Least Absolute Shrinkage and Selection Operator method. Clin Nutr 2025; 47:212-226. [PMID: 40048994 DOI: 10.1016/j.clnu.2025.02.027] [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: 11/25/2024] [Revised: 02/11/2025] [Accepted: 02/20/2025] [Indexed: 03/23/2025]
Abstract
BACKGROUND & AIMS Diet is an important environmental factor in inflammatory bowel disease (IBD) onset and disease course, but analyses are hindered by its complexity. We aim to explore the Sparse Grouped Least Absolute Shrinkage and Selection Operator (Sparse Grouped LASSO or SGL) method to study whether different food categorizations, representing different dietary patterns, can predict flares in IBD. METHODS Baseline data on habitual dietary intake and longitudinal data on disease course were collected over a 24 month-period in two distinct cohorts. Food items were classified into 22 food groups. These were further classified into three diet categorizations: 1. Plant vs animal vs mixed; 2. Potentially healthy vs potentially unhealthy vs neutral; 3. Ultra-processed vs not ultra-processed. The SGL parameter 'lambda' identifies important groups using a-priori group information, while allowing for only a subset of variables within a group to be important predictors. RESULTS Of 724 eligible patients, 427 were in remission at baseline and were included in the SGL analyses. 106 (24.8 %) included patients developed a flare within 11.2 ± 6.6 months (65.1 % female, 34 % ulcerative colitis, mean age 43.3 ± 14.7 years). They had a higher crude food intake of red meat (p = 0.028) and vegetables (p = 0.027) than those who stayed in remission. Prediction models for flare development were moderate with AUC varying between 0.425 and 0.542 for model 1, 0.512 and 0.562 for model 2 and 0.451 and 0.612 for model 3. All models showed red meat, legumes and vegetables as the first selected predicting variables. However, female sex and energy intake had the highest predictive values in all 3 models. CONCLUSION Categorization of the same food groups in different ways influences the predictive value of the SGL method. The current exploration of the SGL method shows that food might not be the most important predictor of flares in IBD.
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Affiliation(s)
- Corien L Stevens
- Department of Gastroenterology and Hepatology, University Medical Centre Groningen, University of Groningen, Groningen, the Netherlands.
| | - Greetje M C Adriaans
- Department Gastroenterology-Hepatology, Maastricht University Medical Centre+, Maastricht, the Netherlands; Research Institute for Nutrition and Translational Research in Metabolism (NUTRIM), Maastricht University, Maastricht, the Netherlands
| | - Corinne E G M Spooren
- Department Gastroenterology-Hepatology, Maastricht University Medical Centre+, Maastricht, the Netherlands; Research Institute for Nutrition and Translational Research in Metabolism (NUTRIM), Maastricht University, Maastricht, the Netherlands
| | - Vera Peters
- Department of Gastroenterology and Hepatology, University Medical Centre Groningen, University of Groningen, Groningen, the Netherlands
| | - Marie J Pierik
- Department Gastroenterology-Hepatology, Maastricht University Medical Centre+, Maastricht, the Netherlands; Research Institute for Nutrition and Translational Research in Metabolism (NUTRIM), Maastricht University, Maastricht, the Netherlands
| | - Rinse K Weersma
- Department of Gastroenterology and Hepatology, University Medical Centre Groningen, University of Groningen, Groningen, the Netherlands
| | - Hendrik M van Dullemen
- Department of Gastroenterology and Hepatology, University Medical Centre Groningen, University of Groningen, Groningen, the Netherlands
| | - Eleonora A M Festen
- Department of Gastroenterology and Hepatology, University Medical Centre Groningen, University of Groningen, Groningen, the Netherlands
| | - Marijn C Visschedijk
- Department of Gastroenterology and Hepatology, University Medical Centre Groningen, University of Groningen, Groningen, the Netherlands
| | - Evelien M B Hendrix
- Department Gastroenterology-Hepatology, Maastricht University Medical Centre+, Maastricht, the Netherlands; Research Institute for Nutrition and Translational Research in Metabolism (NUTRIM), Maastricht University, Maastricht, the Netherlands
| | - Corine W M Perenboom
- Division of Human Nutrition and Health, Wageningen University & Research, Wageningen, the Netherlands
| | - Edith J M Feskens
- Division of Human Nutrition and Health, Wageningen University & Research, Wageningen, the Netherlands
| | - Gerard Dijkstra
- Department of Gastroenterology and Hepatology, University Medical Centre Groningen, University of Groningen, Groningen, the Netherlands
| | - Rui J Almeida
- Department of Quantitative Economics, School of Business and Economics, Maastricht University, Maastricht, the Netherlands; Department of Data Analytics and Digitalization, Maastricht University, Maastricht, the Netherlands
| | - Daisy M A E Jonkers
- Department Gastroenterology-Hepatology, Maastricht University Medical Centre+, Maastricht, the Netherlands; Research Institute for Nutrition and Translational Research in Metabolism (NUTRIM), Maastricht University, Maastricht, the Netherlands
| | - Marjo J E Campmans-Kuijpers
- Department of Gastroenterology and Hepatology, University Medical Centre Groningen, University of Groningen, Groningen, the Netherlands
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Leo S, Leonard MM, Valitutti F, Fasano A. Gut dysbiosis: cause or consequence of intestinal inflammation in celiac disease? Expert Rev Gastroenterol Hepatol 2025; 19:505-513. [PMID: 40133841 DOI: 10.1080/17474124.2025.2483406] [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: 11/19/2024] [Accepted: 03/19/2025] [Indexed: 03/27/2025]
Abstract
INTRODUCTION Celiac disease (CeD) is an immune-mediated condition that occurs in genetically predisposed individuals ingesting gluten. It is characterized by enteropathy leading to both gastrointestinal and extra-intestinal symptoms. The prevalence of CeD has increased world-wide. Evidence suggests that genetic predisposition and exposure to gluten are necessary but not sufficient for CeD onset, implying that other unknown factors are at play in its pathogenesis. AREAS COVERED This review summarizes the current knowledge on the contribution of the gut microbiota to CeD pathogenesis, aiming to address the question of whether it is the cause or consequence of the celiac enteropathy. We reviewed the current literature (studies published in PubMed database between 2007 and 2023), linking gut microbiota dysbiosis and CeD, focusing specifically on prospective birth cohorts' studies and discussing how multi-omics and artificial intelligence (AI) could transform the diagnosis of CeD in a personalized medicine approach. EXPERT OPINION A multi-omic approach will allow for better clarification of the pivotal role of the microbiome in epigenetically triggering CeD pathogenesis. Further, the combination of multi-omics results with AI would pave the way to an improved CeD diagnosis and to the identification of new personalized therapeutic interventions.
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Affiliation(s)
- Stefano Leo
- European Biomedical Research Institute of Salerno, Salerno, Italy
| | - Maureen M Leonard
- Division of Pediatric Gastroenterology and Nutrition, MassGeneral Hospital for Children, Harvard Medical School, Boston, MA, USA
- Mucosal Immunology and Biology Research Center, MassGeneral Hospital for Children, Harvard Medical School, Boston, MA, USA
- Celiac Research Program, Harvard Medical School, Boston, MA, USA
| | - Francesco Valitutti
- Pediatrics Section, Department of Medicine and Surgery, University of Perugia, Perugia, Italy
| | - Alessio Fasano
- European Biomedical Research Institute of Salerno, Salerno, Italy
- Division of Pediatric Gastroenterology and Nutrition, MassGeneral Hospital for Children, Harvard Medical School, Boston, MA, USA
- Mucosal Immunology and Biology Research Center, MassGeneral Hospital for Children, Harvard Medical School, Boston, MA, USA
- Celiac Research Program, Harvard Medical School, Boston, MA, USA
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Gulyaeva A, Liu L, Garmaeva S, Kruk M, Weersma RK, Harmsen HJM, Zhernakova A. Identification and characterization of Faecalibacterium prophages rich in diversity-generating retroelements. Microbiol Spectr 2025; 13:e0106624. [PMID: 39745426 PMCID: PMC11792537 DOI: 10.1128/spectrum.01066-24] [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: 04/28/2024] [Accepted: 11/25/2024] [Indexed: 02/05/2025] Open
Abstract
Metagenomics has revealed the incredible diversity of phages within the human gut. However, very few of these phages have been subjected to in-depth experimental characterization. One promising method of obtaining novel phages for experimental characterization is through induction of the prophages integrated into the genomes of cultured gut bacteria. Here, we developed a bioinformatic approach to prophage identification that builds on prophage genomic properties, existing prophage-detecting software, and publicly available virome sequencing data. We applied our approach to 22 strains of bacteria belonging to the genus Faecalibacterium, resulting in identification of 15 candidate prophages, and validated the approach by demonstrating the activity of five prophages from four of the strains. The genomes of three active phages were identical or similar to those of known phages, while the other two active phages were not represented in the Viral RefSeq database. Four of the active phages possessed a diversity-generating retroelement (DGR), and one retroelement had two variable regions. DGRs of two phages were active at the time of the induction experiments, as evidenced by nucleotide variation in sequencing reads. We also predicted that the host range of two active phages may include multiple bacterial species. Finally, we noted that four phages were less prevalent in the metagenomes of inflammatory bowel disease patients compared to a general population cohort, a difference mainly explained by differences in the abundance of the host bacteria. Our study highlights the utility of prophage identification and induction for unraveling phage molecular mechanisms and ecological interactions.IMPORTANCEWhile hundreds of thousands of phage genomes have been discovered in metagenomics studies, only a few of these phages have been characterized experimentally. Here, we explore phage characterization through bioinformatic identification of prophages in genomes of cultured bacteria, followed by prophage induction. Using this approach, we detect the activity of five prophages in four strains of commensal gut bacteria Faecalibacterium. We further note that four of the prophages possess diversity-generating retroelements implicated in rapid mutation of phage genome loci associated with phage-host and phage-environment interactions and analyze the intricate patterns of retroelement activity. Our study highlights the potential of prophage characterization for elucidating complex molecular mechanisms employed by the phages.
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Affiliation(s)
- Anastasia Gulyaeva
- Department of Genetics, University Medical Center Groningen, Groningen, the Netherlands
| | - Lei Liu
- Department of Medical Microbiology, University Medical Center Groningen, Groningen, the Netherlands
| | - Sanzhima Garmaeva
- Department of Genetics, University Medical Center Groningen, Groningen, the Netherlands
| | - Marloes Kruk
- Department of Genetics, University Medical Center Groningen, Groningen, the Netherlands
| | - Rinse K. Weersma
- Department of Genetics, University Medical Center Groningen, Groningen, the Netherlands
- Department of Gastroenterology and Hepatology, University Medical Center Groningen, Groningen, the Netherlands
| | - Hermie J. M. Harmsen
- Department of Medical Microbiology, University Medical Center Groningen, Groningen, the Netherlands
| | - Alexandra Zhernakova
- Department of Genetics, University Medical Center Groningen, Groningen, the Netherlands
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Silverman AL, Shung D, Stidham RW, Kochhar GS, Iacucci M. How Artificial Intelligence Will Transform Clinical Care, Research, and Trials for Inflammatory Bowel Disease. Clin Gastroenterol Hepatol 2025; 23:428-439.e4. [PMID: 38992406 PMCID: PMC11719376 DOI: 10.1016/j.cgh.2024.05.048] [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: 03/08/2024] [Revised: 04/30/2024] [Accepted: 05/02/2024] [Indexed: 07/13/2024]
Abstract
Artificial intelligence (AI) refers to computer-based methodologies that use data to teach a computer to solve pre-defined tasks; these methods can be applied to identify patterns in large multi-modal data sources. AI applications in inflammatory bowel disease (IBD) includes predicting response to therapy, disease activity scoring of endoscopy, drug discovery, and identifying bowel damage in images. As a complex disease with entangled relationships between genomics, metabolomics, microbiome, and the environment, IBD stands to benefit greatly from methodologies that can handle this complexity. We describe current applications, critical challenges, and propose future directions of AI in IBD.
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Affiliation(s)
- Anna L Silverman
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Mayo Clinic, Scottsdale, Arizona.
| | - Dennis Shung
- Section of Digestive Diseases, Department of Medicine, Yale School of Medicine, Yale University, New Haven, Connecticut
| | - Ryan W Stidham
- Division of Gastroenterology, Department of Internal Medicine, Michigan Medicine, Ann Arbor, Michigan; Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, Michigan; Michigan Institute for Data Science, University of Michigan, Ann Arbor, Michigan
| | - Gursimran S Kochhar
- Division of Gastroenterology, Hepatology, and Nutrition, Allegheny Health Network, Pittsburgh, Pennsylvania
| | - Marietta Iacucci
- University of Birmingham, Institute of Immunology and Immunotherapy, Birmingham, United Kingdom; College of Medicine and Health, University College Cork, and APC Microbiome Ireland, Cork, Ireland
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Barth I, Stevens CL, Peters V, Lucassen DA, Feskens EJM, Dijkstra G, Campmans-Kuijpers MJE. Relative Validity of the Groningen IBD Nutritional Questionnaire (GINQ-FFQ): A Food Frequency Questionnaire Designed to Assess Nutritional Intake in Patients with Inflammatory Bowel Disease. Nutrients 2025; 17:239. [PMID: 39861369 PMCID: PMC11768067 DOI: 10.3390/nu17020239] [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: 12/23/2024] [Revised: 01/06/2025] [Accepted: 01/08/2025] [Indexed: 01/27/2025] Open
Abstract
Background and Objective: To assess nutritional intake of patients with inflammatory bowel disease (IBD), a disease-specific food frequency questionnaire (FFQ) was developed: the Groningen IBD Nutritional Questionnaire (GINQ-FFQ). Aim of this study was to assess the relative validity of the GINQ-FFQ. Methods: Between 2019 and 2022, participants of the 1000IBD cohort were included and filled out a 3-day food diary and the GINQ-FFQ. Nutritional intake of nutrients and food groups was calculated. Bland-Altman analysis was conducted for energy intake, while paired t-tests and Wilcoxon signed rank tests were used for nutrient and food group intake. Additionally, group-level bias, cross-classification, and correlation analysis were performed. Results: 142 patients (59.2% females, mean age of 49 ± 14 years) were included. Bland-Altman analysis showed a mean difference between the GINQ-FFQ and 3FD of -63.6 kcal (±638.4), with limits of agreement ranging from -1315 to 1188 kcal. Differences in energy intake was significantly associated with higher mean total energy intake (p < 0.001). When stratifying for sex, this association only was significant for males. Group-level bias showed that the GINQ-FFQ tends to result in lower intake reports for macro- and micronutrients. Ranking ability (cross-classification) of macro-, micronutrients and food groups was good. Correlation coefficients for nutrients and food groups were considered acceptable or good. Conclusions: Overall, the GINQ-FFQ is a valid food frequency questionnaire to assess nutritional intake specifically for patients with IBD. However, for males with high total energy intakes, dietary assessment could be less accurate.
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Affiliation(s)
- Iris Barth
- Department of Gastroenterology and Hepatology, University Medical Centre Groningen (UMCG), 9713 GZ Groningen, The Netherlands (G.D.); (M.J.E.C.-K.)
- Graduate School of Medical Sciences (GSMS), University of Groningen (RUG), 9700 AB Groningen, The Netherlands
| | - Corien L. Stevens
- Department of Gastroenterology and Hepatology, University Medical Centre Groningen (UMCG), 9713 GZ Groningen, The Netherlands (G.D.); (M.J.E.C.-K.)
- Graduate School of Medical Sciences (GSMS), University of Groningen (RUG), 9700 AB Groningen, The Netherlands
| | - Vera Peters
- Department of Gastroenterology and Hepatology, University Medical Centre Groningen (UMCG), 9713 GZ Groningen, The Netherlands (G.D.); (M.J.E.C.-K.)
- Graduate School of Medical Sciences (GSMS), University of Groningen (RUG), 9700 AB Groningen, The Netherlands
| | - Desiree A. Lucassen
- Division of Human Nutrition and Health, Wageningen University & Research, 6700 AB Wageningen, The Netherlands; (D.A.L.); (E.J.M.F.)
| | - Edith J. M. Feskens
- Division of Human Nutrition and Health, Wageningen University & Research, 6700 AB Wageningen, The Netherlands; (D.A.L.); (E.J.M.F.)
| | - Gerard Dijkstra
- Department of Gastroenterology and Hepatology, University Medical Centre Groningen (UMCG), 9713 GZ Groningen, The Netherlands (G.D.); (M.J.E.C.-K.)
- Graduate School of Medical Sciences (GSMS), University of Groningen (RUG), 9700 AB Groningen, The Netherlands
| | - Marjo J. E. Campmans-Kuijpers
- Department of Gastroenterology and Hepatology, University Medical Centre Groningen (UMCG), 9713 GZ Groningen, The Netherlands (G.D.); (M.J.E.C.-K.)
- Graduate School of Medical Sciences (GSMS), University of Groningen (RUG), 9700 AB Groningen, The Netherlands
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9
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Karmi N, Sun S, Festen EAM, Vich Vila A, Gacesa R, Weersma RK. Gut microbial metabolism of 5-aminosalicylic acid in inflammatory bowel disease. Gut 2024; 73:e41. [PMID: 38569847 DOI: 10.1136/gutjnl-2024-332205] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/13/2024] [Accepted: 02/27/2024] [Indexed: 04/05/2024]
Affiliation(s)
- Naomi Karmi
- Department of Gastroenterology and Hepatology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
| | - Shiqiang Sun
- Department of Gastroenterology and Hepatology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
| | - Eleonora A M Festen
- Department of Gastroenterology and Hepatology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
| | - Arnau Vich Vila
- Department of Gastroenterology and Hepatology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
- Department of Microbiology and Immunology, Rega Institute for Medical Research, Leuven, Belgium
- Center for Microbiology, VIB-KU Leuven, Leuven, Belgium
| | - Ranko Gacesa
- Department of Gastroenterology and Hepatology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
- Department of Genetics, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
| | - Rinse K Weersma
- Department of Gastroenterology and Hepatology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
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10
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Vich Vila A, Zhang J, Liu M, Faber KN, Weersma RK. Untargeted faecal metabolomics for the discovery of biomarkers and treatment targets for inflammatory bowel diseases. Gut 2024; 73:1909-1920. [PMID: 39002973 PMCID: PMC11503092 DOI: 10.1136/gutjnl-2023-329969] [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] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/11/2024] [Accepted: 06/23/2024] [Indexed: 07/15/2024]
Abstract
The gut microbiome has been recognised as a key component in the pathogenesis of inflammatory bowel diseases (IBD), and the wide range of metabolites produced by gut bacteria are an important mechanism by which the human microbiome interacts with host immunity or host metabolism. High-throughput metabolomic profiling and novel computational approaches now allow for comprehensive assessment of thousands of metabolites in diverse biomaterials, including faecal samples. Several groups of metabolites, including short-chain fatty acids, tryptophan metabolites and bile acids, have been associated with IBD. In this Recent Advances article, we describe the contribution of metabolomics research to the field of IBD, with a focus on faecal metabolomics. We discuss the latest findings on the significance of these metabolites for IBD prognosis and therapeutic interventions and offer insights into the future directions of metabolomics research.
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Affiliation(s)
- Arnau Vich Vila
- Department of Gastroenterology and Hepatology, University of Groningen and University Medical Center Groningen, Groningen, The Netherlands
- Department of Genetics, University of Groningen and University Medical Center Groningen, Groningen, The Netherlands
| | - Jingwan Zhang
- Department of Medicine & Therapeutics, The Chinese University of Hong Kong, Hong Kong (SAR), People's Republic of China
- Microbiota I-Center (MagIC), Hong Kong (SAR), People's Republic of China
| | - Moting Liu
- Department of Gastroenterology and Hepatology, University of Groningen and University Medical Center Groningen, Groningen, The Netherlands
| | - Klaas Nico Faber
- Department of Gastroenterology and Hepatology, University of Groningen and University Medical Center Groningen, Groningen, The Netherlands
| | - Rinse K Weersma
- Department of Gastroenterology and Hepatology, University of Groningen and University Medical Center Groningen, Groningen, The Netherlands
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11
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Briggs K, Tomar V, Ollberding N, Haberman Y, Bourgonje AR, Hu S, Chaaban L, Sunuwar L, Weersma RK, Denson LA, Melia JMP. Crohn's Disease-Associated Pathogenic Mutation in the Manganese Transporter ZIP8 Shifts the Ileal and Rectal Mucosal Microbiota Implicating Aberrant Bile Acid Metabolism. Inflamm Bowel Dis 2024; 30:1379-1388. [PMID: 38289995 PMCID: PMC11291615 DOI: 10.1093/ibd/izae003] [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: 09/27/2023] [Indexed: 02/01/2024]
Abstract
BACKGROUND A pathogenic mutation in the manganese transporter ZIP8 (A391T; rs13107325) increases the risk of Crohn's disease. ZIP8 regulates manganese homeostasis and given the shared need for metals between the host and resident microbes, there has been significant interest in alterations of the microbiome in carriers of ZIP8 A391T. Prior studies have not examined the ileal microbiome despite associations between ileal disease and ZIP8 A391T. METHODS Here, we used the Pediatric Risk Stratification Study (RISK) cohort to perform a secondary analysis of 16S ribosomal RNA gene sequencing data obtained from ileal and rectal mucosa to study associations between ZIP8 A391T carrier status and microbiota composition. RESULTS We found sequence variants mapping to Veillonella were decreased in the ileal mucosa of ZIP8 A391T carriers. Prior human studies have demonstrated the sensitivity of Veillonella to bile acid abundance. We therefore hypothesized that bile acid homeostasis is differentially regulated in carriers of ZIP8 A391T. Using a mouse model of ZIP8 A391T, we demonstrate an increase in total bile acids in the liver and stool and decreased fibroblast growth factor 15 (Fgf15) signaling, consistent with our hypothesis. We confirmed dysregulation of FGF19 in the 1000IBD cohort, finding that plasma FGF19 levels are lower in ZIP8 A391T carriers with ileocolonic Crohn's disease. CONCLUSIONS In the search for genotype-specific therapeutic paradigms for patients with Crohn's disease, these data suggest targeting the FGF19 pathway in ZIP8 A391T carriers. Aberrant bile acid metabolism may precede development of Crohn's disease and prioritize study of the interactions between manganese homeostasis, bile acid metabolism and signaling, and complicated ileal Crohn's disease.
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Affiliation(s)
- Kristi Briggs
- Division of Gastroenterology and Hepatology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Vartika Tomar
- Division of Gastroenterology and Hepatology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Nicholas Ollberding
- Department of Pediatrics, Cincinnati Children’s Hospital Medical Center, University of Cincinnati College of Medicine, Cincinnati, OH, USA
| | - Yael Haberman
- Department of Pediatrics, Cincinnati Children’s Hospital Medical Center, University of Cincinnati College of Medicine, Cincinnati, OH, USA
- Department of Pediatrics, Sheba Medical Center, Tel-Hashomer, affiliated with Tel Aviv University, Tel Aviv, Israel
| | - Arno R Bourgonje
- Department of Gastroenterology and Hepatology, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands
- Henry D. Janowitz Division of Gastroenterology, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Shixian Hu
- Department of Gastroenterology and Hepatology, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands
- Department of Gastroenterology, First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, Guangdong, China
- Institute of Precision Medicine, First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, Guangdong, China
| | - Lara Chaaban
- Division of Gastroenterology and Hepatology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Laxmi Sunuwar
- Division of Gastroenterology and Hepatology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Rinse K Weersma
- Department of Gastroenterology and Hepatology, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands
| | - Lee A Denson
- Department of Pediatrics, Cincinnati Children’s Hospital Medical Center, University of Cincinnati College of Medicine, Cincinnati, OH, USA
| | - Joanna M P Melia
- Division of Gastroenterology and Hepatology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA
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12
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Bourgonje AR, Hörstke NV, Fehringer M, Innocenti G, Vogl T. Systemic antibody responses against gut microbiota flagellins implicate shared and divergent immune reactivity in Crohn's disease and chronic fatigue syndrome. MICROBIOME 2024; 12:141. [PMID: 39075559 DOI: 10.1186/s40168-024-01858-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/24/2023] [Accepted: 06/12/2024] [Indexed: 07/31/2024]
Abstract
BACKGROUND Elevated systemic antibody responses against gut microbiota flagellins are observed in both Crohn's disease (CD) and myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), suggesting potential serological biomarkers for diagnosis. However, flagellin-specific antibody repertoires and functional roles in the diseases remain incompletely understood. Bacterial flagellins can be categorized into three types depending on their interaction with toll-like receptor 5 (TLR5): (1) "stimulator" and (2) "silent" flagellins, which bind TLR5 through a conserved N-terminal motif, with only stimulators activating TLR5 (involving a C-terminal domain); (3) "evader" flagellins of pathogens, which entirely circumvent TLR5 activation via mutations in the N-terminal TLR5 binding motif. RESULTS Here, we show that both CD and ME/CFS patients exhibit elevated antibody responses against distinct regions of flagellins compared to healthy individuals. N-terminal binding to Lachnospiraceae flagellins was comparable in both diseases, while C-terminal binding was more prevalent in CD. N-terminal antibody-bound flagellin sequences were similar across CD and ME/CFS, resembling "stimulator" and "silent" flagellins more than evaders. However, C-terminal antibody-bound flagellins showed a higher resemblance to the stimulator than to silent flagellins in CD, which was not observed in ME/CFS. CONCLUSIONS These findings suggest that antibody binding to the N-terminal domain of stimulator and silent flagellins may impact TLR5 activation in both CD and ME/CFS patients. Blocking this interaction could lead commensal bacteria to be recognized as pathogenic evaders, potentially contributing to dysregulation in both diseases. Furthermore, elevated antibody binding to the C-terminal domain of stimulator flagellins in CD may explain pathophysiological differences between the diseases. Overall, these results highlight the diagnostic potential of these antibody responses and lay a foundation for deeper mechanistic studies of flagellin/TLR5 interactions and their impact on innate/adaptive immunity balance.
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Affiliation(s)
- Arno R Bourgonje
- The Henry D. Janowitz Division of Gastroenterology, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA
- Department of Gastroenterology and Hepatology, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands
| | - Nicolai V Hörstke
- Center for Cancer Research, Medical University of Vienna, Vienna, Austria
| | - Michaela Fehringer
- Center for Cancer Research, Medical University of Vienna, Vienna, Austria
| | - Gabriel Innocenti
- Center for Cancer Research, Medical University of Vienna, Vienna, Austria
| | - Thomas Vogl
- Center for Cancer Research, Medical University of Vienna, Vienna, Austria.
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13
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Carasso S, Zaatry R, Hajjo H, Kadosh-Kariti D, Ben-Assa N, Naddaf R, Mandelbaum N, Pressman S, Chowers Y, Gefen T, Jeffrey KL, Jofre J, Coyne MJ, Comstock LE, Sharon I, Geva-Zatorsky N. Inflammation and bacteriophages affect DNA inversion states and functionality of the gut microbiota. Cell Host Microbe 2024; 32:322-334.e9. [PMID: 38423015 PMCID: PMC10939037 DOI: 10.1016/j.chom.2024.02.003] [Citation(s) in RCA: 24] [Impact Index Per Article: 24.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2023] [Revised: 12/11/2023] [Accepted: 02/06/2024] [Indexed: 03/02/2024]
Abstract
Reversible genomic DNA inversions control the expression of numerous gut bacterial molecules, but how this impacts disease remains uncertain. By analyzing metagenomic samples from inflammatory bowel disease (IBD) cohorts, we identified multiple invertible regions where a particular orientation correlated with disease. These include the promoter of polysaccharide A (PSA) of Bacteroides fragilis, which induces regulatory T cells (Tregs) and ameliorates experimental colitis. The PSA promoter was mostly oriented "OFF" in IBD patients, which correlated with increased B. fragilis-associated bacteriophages. Similarly, in mice colonized with a healthy human microbiota and B. fragilis, induction of colitis caused a decline of PSA in the "ON" orientation that reversed as inflammation resolved. Monocolonization of mice with B. fragilis revealed that bacteriophage infection increased the frequency of PSA in the "OFF" orientation, causing reduced PSA expression and decreased Treg cells. Altogether, we reveal dynamic bacterial phase variations driven by bacteriophages and host inflammation, signifying bacterial functional plasticity during disease.
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Affiliation(s)
- Shaqed Carasso
- Department of Cell Biology and Cancer Science, Rappaport Faculty of Medicine, Technion - Israel Institute of Technology, Rappaport Technion Integrated Cancer Center (RTICC), Haifa 32000, Israel
| | - Rawan Zaatry
- Department of Cell Biology and Cancer Science, Rappaport Faculty of Medicine, Technion - Israel Institute of Technology, Rappaport Technion Integrated Cancer Center (RTICC), Haifa 32000, Israel
| | - Haitham Hajjo
- Department of Cell Biology and Cancer Science, Rappaport Faculty of Medicine, Technion - Israel Institute of Technology, Rappaport Technion Integrated Cancer Center (RTICC), Haifa 32000, Israel
| | - Dana Kadosh-Kariti
- Department of Cell Biology and Cancer Science, Rappaport Faculty of Medicine, Technion - Israel Institute of Technology, Rappaport Technion Integrated Cancer Center (RTICC), Haifa 32000, Israel
| | - Nadav Ben-Assa
- Department of Cell Biology and Cancer Science, Rappaport Faculty of Medicine, Technion - Israel Institute of Technology, Rappaport Technion Integrated Cancer Center (RTICC), Haifa 32000, Israel
| | - Rawi Naddaf
- Department of Cell Biology and Cancer Science, Rappaport Faculty of Medicine, Technion - Israel Institute of Technology, Rappaport Technion Integrated Cancer Center (RTICC), Haifa 32000, Israel
| | - Noa Mandelbaum
- Department of Cell Biology and Cancer Science, Rappaport Faculty of Medicine, Technion - Israel Institute of Technology, Rappaport Technion Integrated Cancer Center (RTICC), Haifa 32000, Israel
| | - Sigal Pressman
- Department of Gastroenterology, Rambam Health Care Campus, Haifa 3109601, Israel; Clinical Research Institute, Rambam Health Care Campus, Haifa 3109601, Israel
| | - Yehuda Chowers
- Department of Gastroenterology, Rambam Health Care Campus, Haifa 3109601, Israel; Clinical Research Institute, Rambam Health Care Campus, Haifa 3109601, Israel; Rappaport Faculty of Medicine, Technion - Israel Institute of Technology, Haifa 32000, Israel
| | - Tal Gefen
- Department of Cell Biology and Cancer Science, Rappaport Faculty of Medicine, Technion - Israel Institute of Technology, Rappaport Technion Integrated Cancer Center (RTICC), Haifa 32000, Israel
| | - Kate L Jeffrey
- Moderna, Inc., Cambridge, MA 02139, USA; Center for the Study of Inflammatory Bowel Disease, Division of Gastroenterology, Department of Medicine, Massachusetts General Hospital Research Institute, Boston, MA 02114, USA; Harvard Medical School, Boston, MA 02115, USA; Program in Immunology, Harvard Medical School, Boston, MA 02115, USA
| | - Juan Jofre
- Department of Genetics, Microbiology and Statistics, School of Biology, University of Barcelona, Avda. Diagonal 643 08028, Barcelona, Spain
| | - Michael J Coyne
- Duchossois Family Institute and Department of Microbiology, University of Chicago, Chicago, IL, USA
| | - Laurie E Comstock
- Duchossois Family Institute and Department of Microbiology, University of Chicago, Chicago, IL, USA
| | - Itai Sharon
- Migal-Galilee Research Institute, P.O. Box 831, Kiryat Shmona 11016, Israel; Faculty of Sciences and Technology, Tel-Hai Academic College, Upper Galilee 1220800, Israel
| | - Naama Geva-Zatorsky
- Department of Cell Biology and Cancer Science, Rappaport Faculty of Medicine, Technion - Israel Institute of Technology, Rappaport Technion Integrated Cancer Center (RTICC), Haifa 32000, Israel; CIFAR, MaRS Centre, West Tower 661, Suite 505, Toronto, ON M5G 1M1, Canada.
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14
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Busonero F, Lenarduzzi S, Crobu F, Gentile RM, Carta A, Cracco F, Maschio A, Camarda S, Marongiu M, Zanetti D, Conversano C, Di Lorenzo G, Mazzà D, De Seta F, Girotto G, Sanna S. The Women4Health cohort: a unique cohort to study women-specific mechanisms of cardio-metabolic regulation. EUROPEAN HEART JOURNAL OPEN 2024; 4:oeae012. [PMID: 38532851 PMCID: PMC10964981 DOI: 10.1093/ehjopen/oeae012] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 12/06/2023] [Revised: 02/22/2024] [Accepted: 02/26/2024] [Indexed: 03/28/2024]
Abstract
Aims Epidemiological research has shown relevant differences between sexes in clinical manifestations, severity, and progression of cardiovascular and metabolic disorders. To date, the mechanisms underlying these differences remain unknown. Given the rising incidence of such diseases, gender-specific research on established and emerging risk factors, such as dysfunction of glycaemic and/or lipid metabolism, of sex hormones and of gut microbiome, is of paramount importance. The relationships between sex hormones, gut microbiome, and host glycaemic and/or lipid metabolism are largely unknown even in the homoeostasis status. Yet this knowledge gap would be pivotal to pinpoint to key mechanisms that are likely to be disrupted in disease context. Methods and results Here we present the Women4Health (W4H) cohort, a unique cohort comprising up to 300 healthy women followed up during a natural menstrual cycle, set up with the primary goal to investigate the combined role of sex hormones and gut microbiota variations in regulating host lipid and glucose metabolism during homoeostasis, using a multi-omics strategy. Additionally, the W4H cohort will take into consideration another ecosystem that is unique to women, the vaginal microbiome, investigating its interaction with gut microbiome and exploring-for the first time-its role in cardiometabolic disorders. Conclusion The W4H cohort study lays a foundation for improving current knowledge of women-specific mechanisms in cardiometabolic regulation. It aspires to transform insights on host-microbiota interactions into prevention and therapeutic approaches for personalized health care.
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Affiliation(s)
- Fabio Busonero
- Institute of Genetic and Biomedical Research (IRGB), National Research Council (CNR), c/o Cittadella Universitaria di Monserrato, SS554 Km 4500, Monserrato, 09042, CA, Italy
| | - Stefania Lenarduzzi
- Institute for Maternal and Child Health—IRCCS ‘Burlo Garofolo’, Via dell'Istria 65/1, Trieste, 34137, TS, Italy
| | - Francesca Crobu
- Institute of Genetic and Biomedical Research (IRGB), National Research Council (CNR), c/o Cittadella Universitaria di Monserrato, SS554 Km 4500, Monserrato, 09042, CA, Italy
| | - Roberta Marie Gentile
- Department of Medicine, Surgery and Health Sciences, University of Trieste, Piazzale Europa 1, Trieste, 34137, TS, Italy
| | - Andrea Carta
- Department of Business and Economics, University of Cagliari, via Università 40, 09124, Cagliari, CA, Italy
| | - Francesco Cracco
- Department of Medicine, Surgery and Health Sciences, University of Trieste, Piazzale Europa 1, Trieste, 34137, TS, Italy
| | - Andrea Maschio
- Institute of Genetic and Biomedical Research (IRGB), National Research Council (CNR), c/o Cittadella Universitaria di Monserrato, SS554 Km 4500, Monserrato, 09042, CA, Italy
| | - Silvia Camarda
- Department of Medicine, Surgery and Health Sciences, University of Trieste, Piazzale Europa 1, Trieste, 34137, TS, Italy
| | - Michele Marongiu
- Institute of Genetic and Biomedical Research (IRGB), National Research Council (CNR), c/o Cittadella Universitaria di Monserrato, SS554 Km 4500, Monserrato, 09042, CA, Italy
| | - Daniela Zanetti
- Institute of Genetic and Biomedical Research (IRGB), National Research Council (CNR), c/o Cittadella Universitaria di Monserrato, SS554 Km 4500, Monserrato, 09042, CA, Italy
| | - Claudio Conversano
- Institute of Genetic and Biomedical Research (IRGB), National Research Council (CNR), c/o Cittadella Universitaria di Monserrato, SS554 Km 4500, Monserrato, 09042, CA, Italy
- Department of Business and Economics, University of Cagliari, via Università 40, 09124, Cagliari, CA, Italy
| | - Giovanni Di Lorenzo
- Institute for Maternal and Child Health—IRCCS ‘Burlo Garofolo’, Via dell'Istria 65/1, Trieste, 34137, TS, Italy
| | - Daniela Mazzà
- Institute for Maternal and Child Health—IRCCS ‘Burlo Garofolo’, Via dell'Istria 65/1, Trieste, 34137, TS, Italy
| | - Francesco De Seta
- Institute for Maternal and Child Health—IRCCS ‘Burlo Garofolo’, Via dell'Istria 65/1, Trieste, 34137, TS, Italy
| | - Giorgia Girotto
- Institute for Maternal and Child Health—IRCCS ‘Burlo Garofolo’, Via dell'Istria 65/1, Trieste, 34137, TS, Italy
- Department of Medicine, Surgery and Health Sciences, University of Trieste, Piazzale Europa 1, Trieste, 34137, TS, Italy
| | - Serena Sanna
- Institute of Genetic and Biomedical Research (IRGB), National Research Council (CNR), c/o Cittadella Universitaria di Monserrato, SS554 Km 4500, Monserrato, 09042, CA, Italy
- Department of Genetics, University Medical Center Groningen, Hanzeplein 1, 97123 GZ, Groningen, The Netherlands
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15
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Bai BYH, Reppell M, Smaoui N, Waring JF, Pivorunas V, Guay H, Lin S, Chanchlani N, Bewshea C, Goodhand JR, Kennedy NA, Ahmad T, Anderson CA. Baseline Expression of Immune Gene Modules in Blood is Associated With Primary Response to Anti-TNF Therapy in Crohn's Disease Patients. J Crohns Colitis 2024; 18:431-445. [PMID: 37776235 PMCID: PMC10906954 DOI: 10.1093/ecco-jcc/jjad166] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/06/2023] [Revised: 08/22/2023] [Accepted: 09/28/2023] [Indexed: 10/02/2023]
Abstract
BACKGROUND AND AIMS Anti-tumour necrosis factor [anti-TNF] therapy is widely used for the treatment of inflammatory bowel disease, yet many patients are primary non-responders, failing to respond to induction therapy. We aimed to identify blood gene expression differences between primary responders and primary non-responders to anti-TNF monoclonal antibodies [infliximab and adalimumab], and to predict response status from blood gene expression and clinical data. METHODS The Personalised Anti-TNF Therapy in Crohn's Disease [PANTS] study is a UK-wide prospective observational cohort study of anti-TNF therapy outcome in anti-TNF-naive Crohn's disease patients [ClinicalTrials.gov identifier: NCT03088449]. Blood gene expression in 324 unique patients was measured by RNA-sequencing at baseline [week 0], and at weeks 14, 30, and 54 after treatment initiation [total sample size = 814]. RESULTS After adjusting for clinical covariates and estimated blood cell composition, baseline expression of major histocompatibility complex, antigen presentation, myeloid cell enriched receptor, and other innate immune gene modules was significantly higher in anti-TNF responders vs non-responders. Expression changes from baseline to week 14 were generally of consistent direction but greater magnitude [i.e. amplified] in responders, but interferon-related genes were upregulated uniquely in non-responders. Expression differences between responders and non-responders observed at week 14 were maintained at weeks 30 and 54. Prediction of response status from baseline clinical data, cell composition, and module expression was poor. CONCLUSIONS Baseline gene module expression was associated with primary response to anti-TNF therapy in PANTS patients. However, these baseline expression differences did not predict response with sufficient sensitivity for clinical use.
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Affiliation(s)
- Benjamin Y H Bai
- Genomics of Inflammation and Immunity Group, Wellcome Sanger Institute, Hinxton, UK
- Postgraduate School of Life Sciences, University of Cambridge, Cambridge, UK
| | | | | | | | | | | | - Simeng Lin
- Department of Gastroenterology, Royal Devon University Healthcare NHS Foundation Trust, Exeter, UK
- Exeter Inflammatory Bowel Disease and Pharmacogenetics Research Group, University of Exeter, Exeter, UK
| | - Neil Chanchlani
- Department of Gastroenterology, Royal Devon University Healthcare NHS Foundation Trust, Exeter, UK
- Exeter Inflammatory Bowel Disease and Pharmacogenetics Research Group, University of Exeter, Exeter, UK
| | - Claire Bewshea
- Exeter Inflammatory Bowel Disease and Pharmacogenetics Research Group, University of Exeter, Exeter, UK
| | - James R Goodhand
- Department of Gastroenterology, Royal Devon University Healthcare NHS Foundation Trust, Exeter, UK
- Exeter Inflammatory Bowel Disease and Pharmacogenetics Research Group, University of Exeter, Exeter, UK
| | - Nicholas A Kennedy
- Department of Gastroenterology, Royal Devon University Healthcare NHS Foundation Trust, Exeter, UK
- Exeter Inflammatory Bowel Disease and Pharmacogenetics Research Group, University of Exeter, Exeter, UK
| | - Tariq Ahmad
- Department of Gastroenterology, Royal Devon University Healthcare NHS Foundation Trust, Exeter, UK
- Exeter Inflammatory Bowel Disease and Pharmacogenetics Research Group, University of Exeter, Exeter, UK
| | - Carl A Anderson
- Genomics of Inflammation and Immunity Group, Wellcome Sanger Institute, Hinxton, UK
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16
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Hu S, Bourgonje AR, Gacesa R, Jansen BH, Björk JR, Bangma A, Hidding IJ, van Dullemen HM, Visschedijk MC, Faber KN, Dijkstra G, Harmsen HJM, Festen EAM, Vich Vila A, Spekhorst LM, Weersma RK. Mucosal host-microbe interactions associate with clinical phenotypes in inflammatory bowel disease. Nat Commun 2024; 15:1470. [PMID: 38368394 PMCID: PMC10874382 DOI: 10.1038/s41467-024-45855-2] [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: 01/12/2023] [Accepted: 02/05/2024] [Indexed: 02/19/2024] Open
Abstract
Disrupted host-microbe interactions at the mucosal level are key to the pathophysiology of IBD. This study aimed to comprehensively examine crosstalk between mucosal gene expression and microbiota in patients with IBD. To study tissue-specific interactions, we perform transcriptomic (RNA-seq) and microbial (16S-rRNA-seq) profiling of 697 intestinal biopsies (645 derived from 335 patients with IBD and 52 from 16 non-IBD controls). Mucosal gene expression patterns in IBD are mainly determined by tissue location and inflammation, whereas the mucosal microbiota composition shows a high degree of individual specificity. Analysis of transcript-bacteria interactions identifies six distinct groups of inflammation-related pathways that are associated with intestinal microbiota (adjusted P < 0.05). An increased abundance of Bifidobacterium is associated with higher expression of genes involved in fatty acid metabolism, while Bacteroides correlates with increased metallothionein signaling. In patients with fibrostenosis, a transcriptional network dominated by immunoregulatory genes is associated with Lachnoclostridium bacteria in non-stenotic tissue (adjusted P < 0.05), while being absent in CD without fibrostenosis. In patients using TNF-α-antagonists, a transcriptional network dominated by fatty acid metabolism genes is linked to Ruminococcaceae (adjusted P < 0.05). Mucosal microbiota composition correlates with enrichment of intestinal epithelial cells, macrophages, and NK-cells. Overall, these data demonstrate the presence of context-specific mucosal host-microbe interactions in IBD, revealing significantly altered inflammation-associated gene-taxa modules, particularly in patients with fibrostenotic CD and patients using TNF-α-antagonists. This study provides compelling insights into host-microbe interactions that may guide microbiota-directed precision medicine and fuels the rationale for microbiota-targeted therapeutics as a strategy to alter disease course in IBD.
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Affiliation(s)
- Shixian Hu
- Department of Gastroenterology and Hepatology, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands
- Department of Genetics, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands
- Institute of Precision Medicine, the First Affiliated Hospital of Sun Yat-Sen University, Sun Yat-Sen University, Guangzhou, Guangdong, China
| | - Arno R Bourgonje
- Department of Gastroenterology and Hepatology, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands
| | - Ranko Gacesa
- Department of Gastroenterology and Hepatology, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands
- Department of Genetics, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands
| | - Bernadien H Jansen
- Department of Gastroenterology and Hepatology, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands
| | - Johannes R Björk
- Department of Gastroenterology and Hepatology, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands
| | - Amber Bangma
- Department of Gastroenterology and Hepatology, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands
| | - Iwan J Hidding
- Department of Gastroenterology and Hepatology, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands
| | - Hendrik M van Dullemen
- Department of Gastroenterology and Hepatology, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands
| | - Marijn C Visschedijk
- Department of Gastroenterology and Hepatology, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands
| | - Klaas Nico Faber
- Department of Gastroenterology and Hepatology, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands
| | - Gerard Dijkstra
- Department of Gastroenterology and Hepatology, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands
| | - Hermie J M Harmsen
- Department of Medical Microbiology, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands
| | - Eleonora A M Festen
- Department of Gastroenterology and Hepatology, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands
| | - Arnau Vich Vila
- Department of Gastroenterology and Hepatology, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands
- Department of Genetics, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands
| | - Lieke M Spekhorst
- Department of Gastroenterology and Hepatology, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands
- Department of Gastroenterology and Hepatology, Medisch Spectrum Twente, Enschede, the Netherlands
| | - Rinse K Weersma
- Department of Gastroenterology and Hepatology, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands.
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17
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Zhernakova DV, Wang D, Liu L, Andreu-Sánchez S, Zhang Y, Ruiz-Moreno AJ, Peng H, Plomp N, Del Castillo-Izquierdo Á, Gacesa R, Lopera-Maya EA, Temba GS, Kullaya VI, van Leeuwen SS, Xavier RJ, de Mast Q, Joosten LAB, Riksen NP, Rutten JHW, Netea MG, Sanna S, Wijmenga C, Weersma RK, Zhernakova A, Harmsen HJM, Fu J. Host genetic regulation of human gut microbial structural variation. Nature 2024; 625:813-821. [PMID: 38172637 PMCID: PMC10808065 DOI: 10.1038/s41586-023-06893-w] [Citation(s) in RCA: 56] [Impact Index Per Article: 56.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2022] [Accepted: 11/23/2023] [Indexed: 01/05/2024]
Abstract
Although the impact of host genetics on gut microbial diversity and the abundance of specific taxa is well established1-6, little is known about how host genetics regulates the genetic diversity of gut microorganisms. Here we conducted a meta-analysis of associations between human genetic variation and gut microbial structural variation in 9,015 individuals from four Dutch cohorts. Strikingly, the presence rate of a structural variation segment in Faecalibacterium prausnitzii that harbours an N-acetylgalactosamine (GalNAc) utilization gene cluster is higher in individuals who secrete the type A oligosaccharide antigen terminating in GalNAc, a feature that is jointly determined by human ABO and FUT2 genotypes, and we could replicate this association in a Tanzanian cohort. In vitro experiments demonstrated that GalNAc can be used as the sole carbohydrate source for F. prausnitzii strains that carry the GalNAc-metabolizing pathway. Further in silico and in vitro studies demonstrated that other ABO-associated species can also utilize GalNAc, particularly Collinsella aerofaciens. The GalNAc utilization genes are also associated with the host's cardiometabolic health, particularly in individuals with mucosal A-antigen. Together, the findings of our study demonstrate that genetic associations across the human genome and bacterial metagenome can provide functional insights into the reciprocal host-microbiome relationship.
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Affiliation(s)
- Daria V Zhernakova
- University of Groningen, University Medical Center Groningen, Department of Genetics, Groningen, The Netherlands
| | - Daoming Wang
- University of Groningen, University Medical Center Groningen, Department of Genetics, Groningen, The Netherlands
- University of Groningen, University Medical Center Groningen, Department of Pediatrics, Groningen, The Netherlands
| | - Lei Liu
- University of Groningen, University Medical Center Groningen, Department of Medical Microbiology and Infection Prevention, Groningen, The Netherlands
| | - Sergio Andreu-Sánchez
- University of Groningen, University Medical Center Groningen, Department of Genetics, Groningen, The Netherlands
- University of Groningen, University Medical Center Groningen, Department of Pediatrics, Groningen, The Netherlands
| | - Yue Zhang
- University of Groningen, University Medical Center Groningen, Department of Genetics, Groningen, The Netherlands
- University of Groningen, University Medical Center Groningen, Department of Pediatrics, Groningen, The Netherlands
| | - Angel J Ruiz-Moreno
- University of Groningen, University Medical Center Groningen, Department of Genetics, Groningen, The Netherlands
- University of Groningen, University Medical Center Groningen, Department of Pediatrics, Groningen, The Netherlands
| | - Haoran Peng
- University of Groningen, University Medical Center Groningen, Department of Genetics, Groningen, The Netherlands
| | - Niels Plomp
- University of Groningen, University Medical Center Groningen, Department of Medical Microbiology and Infection Prevention, Groningen, The Netherlands
- University of Groningen, University Medical Center Groningen, Department of Gastroenterology and Hepatology, Groningen, The Netherlands
| | - Ángela Del Castillo-Izquierdo
- University of Groningen, University Medical Center Groningen, Department of Genetics, Groningen, The Netherlands
- University of Groningen, University Medical Center Groningen, Department of Medical Microbiology and Infection Prevention, Groningen, The Netherlands
| | - Ranko Gacesa
- University of Groningen, University Medical Center Groningen, Department of Genetics, Groningen, The Netherlands
- University of Groningen, University Medical Center Groningen, Department of Gastroenterology and Hepatology, Groningen, The Netherlands
| | - Esteban A Lopera-Maya
- University of Groningen, University Medical Center Groningen, Department of Genetics, Groningen, The Netherlands
| | - Godfrey S Temba
- Department of Internal Medicine, Radboud University Medical Center, Nijmegen, The Netherlands
- Department of Medical Biochemistry and Molecular Biology, Kilimanjaro Christian Medical University College, Moshi, Tanzania
- Radboud Center for Infectious Diseases, Radboud University Medical Center, Nijmegen, The Netherlands
| | - Vesla I Kullaya
- Department of Medical Biochemistry and Molecular Biology, Kilimanjaro Christian Medical University College, Moshi, Tanzania
- Kilimanjaro Clinical Research Institute, Kilimanjaro Christian Medical Center, Moshi, Tanzania
| | - Sander S van Leeuwen
- University of Groningen, University Medical Center Groningen, Department of Laboratory Medicine, Groningen, The Netherlands
| | - Ramnik J Xavier
- Broad Institute of MIT and Harvard, Cambridge, MA, USA
- Center for Computational and Integrative Biology, Department of Molecular Biology, Massachusetts General Hospital, Boston, MA, USA
| | - Quirijn de Mast
- Department of Internal Medicine, Radboud University Medical Center, Nijmegen, The Netherlands
- Radboud Center for Infectious Diseases, Radboud University Medical Center, Nijmegen, The Netherlands
| | - Leo A B Joosten
- Department of Internal Medicine, Radboud University Medical Center, Nijmegen, The Netherlands
- Department of Medical Genetics, Iuliu Haţieganu University of Medicine and Pharmacy, Cluj-Napoca, Romania
| | - Niels P Riksen
- Department of Internal Medicine, Radboud University Medical Center, Nijmegen, The Netherlands
| | - Joost H W Rutten
- Department of Internal Medicine, Radboud University Medical Center, Nijmegen, The Netherlands
| | - Mihai G Netea
- Department of Internal Medicine, Radboud University Medical Center, Nijmegen, The Netherlands
- Radboud Center for Infectious Diseases, Radboud University Medical Center, Nijmegen, The Netherlands
- Department of Immunology and Metabolism, Life and Medical Sciences Institute, University of Bonn, Bonn, Germany
- Human Genomics Laboratory, Craiova University of Medicine and Pharmacy, Craiova, Romania
| | - Serena Sanna
- University of Groningen, University Medical Center Groningen, Department of Genetics, Groningen, The Netherlands
- Institute for Genetic and Biomedical Research, National Research Council, Cagliari, Italy
| | - Cisca Wijmenga
- University of Groningen, University Medical Center Groningen, Department of Genetics, Groningen, The Netherlands
| | - Rinse K Weersma
- University of Groningen, University Medical Center Groningen, Department of Gastroenterology and Hepatology, Groningen, The Netherlands
| | - Alexandra Zhernakova
- University of Groningen, University Medical Center Groningen, Department of Genetics, Groningen, The Netherlands
| | - Hermie J M Harmsen
- University of Groningen, University Medical Center Groningen, Department of Medical Microbiology and Infection Prevention, Groningen, The Netherlands.
| | - Jingyuan Fu
- University of Groningen, University Medical Center Groningen, Department of Genetics, Groningen, The Netherlands.
- University of Groningen, University Medical Center Groningen, Department of Pediatrics, Groningen, The Netherlands.
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18
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Fagundes RR, Bravo-Ruiseco G, Hu S, Kierans SJ, Weersma RK, Taylor CT, Dijkstra G, Harmsen HJM, Faber KN. Faecalibacterium prausnitzii promotes intestinal epithelial IL-18 production through activation of the HIF1α pathway. Front Microbiol 2023; 14:1298304. [PMID: 38163085 PMCID: PMC10755969 DOI: 10.3389/fmicb.2023.1298304] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2023] [Accepted: 11/20/2023] [Indexed: 01/03/2024] Open
Abstract
Introduction Intestinal epithelial cells produce interleukin-18 (IL-18), a key factor in promoting epithelial barrier integrity. Here, we analyzed the potential role of gut bacteria and the hypoxia-inducible factor 1α (HIF1α) pathway in regulating mucosal IL18 expression in inflammatory bowel disease (IBD). Methods Mucosal samples from patients with IBD (n = 760) were analyzed for bacterial composition, IL18 levels and HIF1α pathway activation. Wild-type Caco-2 and CRISPR/Cas9-engineered Caco-2-HIF1A-null cells were cocultured with Faecalibacterium prausnitzii in a "Human oxygen-Bacteria anaerobic" in vitro system and analyzed by RNA sequencing. Results Mucosal IL18 mRNA levels correlated positively with the abundance of mucosal-associated butyrate-producing bacteria, in particular F. prausnitzii, and with HIF1α pathway activation in patients with IBD. HIF1α-mediated expression of IL18, either by a pharmacological agonist (dimethyloxallyl glycine) or F. prausnitzii, was abrogated in Caco-2-HIF1A-null cells. Conclusion Butyrate-producing gut bacteria like F. prausnitzii regulate mucosal IL18 expression in a HIF1α-dependent manner that may aid in mucosal healing in IBD.
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Affiliation(s)
- Raphael R. Fagundes
- Department of Gastroenterology and Hepatology, University of Groningen, University Medical Center Groningen, Groningen, Netherlands
| | - Gabriela Bravo-Ruiseco
- Department of Medical Microbiology and Infection Prevention, University of Groningen, University Medical Center Groningen, Groningen, Netherlands
| | - Shixian Hu
- Department of Gastroenterology and Hepatology, University of Groningen, University Medical Center Groningen, Groningen, Netherlands
| | - Sarah J. Kierans
- School of Medicine and Medical Science and the Conway Institute, University College Dublin, Dublin, Ireland
| | - Rinse K. Weersma
- Department of Gastroenterology and Hepatology, University of Groningen, University Medical Center Groningen, Groningen, Netherlands
| | - Cormac T. Taylor
- School of Medicine and Medical Science and the Conway Institute, University College Dublin, Dublin, Ireland
| | - Gerard Dijkstra
- Department of Gastroenterology and Hepatology, University of Groningen, University Medical Center Groningen, Groningen, Netherlands
| | - Hermie J. M. Harmsen
- Department of Medical Microbiology and Infection Prevention, University of Groningen, University Medical Center Groningen, Groningen, Netherlands
| | - Klaas Nico Faber
- Department of Gastroenterology and Hepatology, University of Groningen, University Medical Center Groningen, Groningen, Netherlands
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19
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Geertsema S, Jansen BH, van Goor H, Dijkstra G, Faber KN, Bourgonje AR. Unsuitability of the Oxidation-Reduction Potential Measurement for the Quantification of Fecal Redox Status in Inflammatory Bowel Disease. Biomedicines 2023; 11:3107. [PMID: 38137328 PMCID: PMC10741202 DOI: 10.3390/biomedicines11123107] [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: 09/28/2023] [Revised: 10/27/2023] [Accepted: 11/01/2023] [Indexed: 12/24/2023] Open
Abstract
Oxidative stress is a key pathophysiological process associated with the development and progression of inflammatory bowel disease (IBD). Biomarkers for oxidative stress, however, are scarce, as are diagnostic tools that can interrogate an individual's gut redox status. This proof-of-concept study aimed to evaluate the potential utility of an oxidation-reduction potential (ORP) measurement probe, to quantify redox status in the feces of both patients with IBD and healthy controls. Previous studies using this ORP measurement probe demonstrated promising data when comparing ORP from severely malnourished individuals with that of healthy controls. To date, ORP analyses have not been performed in the context of IBD. We hypothesized that measuring the ORP of fecal water in patients with IBD might have diagnostic value. The current study, however, did not show significant differences in ORP measurement values between patients with IBD (median [IQR] 46.5 [33.0-61.2] mV) and healthy controls (25 [8.0-52.0] mV; p = 0.221). Additionally, ORP measurements were highly unstable and rapidly fluctuated throughout time, with ORP values varying from +24 to +303 mV. Due to potential biological processes and limitations of the measuring equipment, this study was unable to reliably measure ORP. As a result, our findings indicate that ORP quantification may not be a suitable method for assessing fecal redox status and, therefore, does not currently support further exploration as a diagnostic or monitoring tool.
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Affiliation(s)
- Sem Geertsema
- Department of Gastroenterology and Hepatology, University of Groningen, University Medical Center Groningen, 9713 GZ Groningen, The Netherlands; (S.G.); (B.H.J.); (G.D.); (K.N.F.)
| | - Bernadien H. Jansen
- Department of Gastroenterology and Hepatology, University of Groningen, University Medical Center Groningen, 9713 GZ Groningen, The Netherlands; (S.G.); (B.H.J.); (G.D.); (K.N.F.)
| | - Harry van Goor
- Department of Pathology and Medical Biology, University of Groningen, University Medical Center Groningen, 9713 GZ Groningen, The Netherlands;
| | - Gerard Dijkstra
- Department of Gastroenterology and Hepatology, University of Groningen, University Medical Center Groningen, 9713 GZ Groningen, The Netherlands; (S.G.); (B.H.J.); (G.D.); (K.N.F.)
| | - Klaas Nico Faber
- Department of Gastroenterology and Hepatology, University of Groningen, University Medical Center Groningen, 9713 GZ Groningen, The Netherlands; (S.G.); (B.H.J.); (G.D.); (K.N.F.)
| | - Arno R. Bourgonje
- Department of Gastroenterology and Hepatology, University of Groningen, University Medical Center Groningen, 9713 GZ Groningen, The Netherlands; (S.G.); (B.H.J.); (G.D.); (K.N.F.)
- The Henry D. Janowitz Division of Gastroenterology, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
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20
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Fiocchi C. Omics and Multi-Omics in IBD: No Integration, No Breakthroughs. Int J Mol Sci 2023; 24:14912. [PMID: 37834360 PMCID: PMC10573814 DOI: 10.3390/ijms241914912] [Citation(s) in RCA: 15] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2023] [Revised: 09/27/2023] [Accepted: 10/02/2023] [Indexed: 10/15/2023] Open
Abstract
The recent advent of sophisticated technologies like sequencing and mass spectroscopy platforms combined with artificial intelligence-powered analytic tools has initiated a new era of "big data" research in various complex diseases of still-undetermined cause and mechanisms. The investigation of these diseases was, until recently, limited to traditional in vitro and in vivo biological experimentation, but a clear switch to in silico methodologies is now under way. This review tries to provide a comprehensive assessment of state-of-the-art knowledge on omes, omics and multi-omics in inflammatory bowel disease (IBD). The notion and importance of omes, omics and multi-omics in both health and complex diseases like IBD is introduced, followed by a discussion of the various omics believed to be relevant to IBD pathogenesis, and how multi-omics "big data" can generate new insights translatable into useful clinical tools in IBD such as biomarker identification, prediction of remission and relapse, response to therapy, and precision medicine. The pitfalls and limitations of current IBD multi-omics studies are critically analyzed, revealing that, regardless of the types of omes being analyzed, the majority of current reports are still based on simple associations of descriptive retrospective data from cross-sectional patient cohorts rather than more powerful longitudinally collected prospective datasets. Given this limitation, some suggestions are provided on how IBD multi-omics data may be optimized for greater clinical and therapeutic benefit. The review concludes by forecasting the upcoming incorporation of multi-omics analyses in the routine management of IBD.
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Affiliation(s)
- Claudio Fiocchi
- Department of Inflammation & Immunity, Lerner Research Institute, Cleveland, OH 44195, USA;
- Department of Gastroenterology, Hepatology and Nutrition, Digestive Disease and Surgery Institute, Cleveland Clinic, Cleveland, OH 44195, USA
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21
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Jagirdhar GSK, Perez JA, Perez AB, Surani S. Integration and implementation of precision medicine in the multifaceted inflammatory bowel disease. World J Gastroenterol 2023; 29:5211-5225. [PMID: 37901450 PMCID: PMC10600960 DOI: 10.3748/wjg.v29.i36.5211] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/01/2023] [Revised: 07/31/2023] [Accepted: 09/06/2023] [Indexed: 09/20/2023] Open
Abstract
Inflammatory bowel disease (IBD) is a complex disease with variability in genetic, environmental, and lifestyle factors affecting disease presentation and course. Precision medicine has the potential to play a crucial role in managing IBD by tailoring treatment plans based on the heterogeneity of clinical and temporal variability of patients. Precision medicine is a population-based approach to managing IBD by integrating environmental, genomic, epigenomic, transcriptomic, proteomic, and metabolomic factors. It is a recent and rapidly developing medicine. The widespread adoption of precision medicine worldwide has the potential to result in the early detection of diseases, optimal utilization of healthcare resources, enhanced patient outcomes, and, ultimately, improved quality of life for individuals with IBD. Though precision medicine is promising in terms of better quality of patient care, inadequacies exist in the ongoing research. There is discordance in study conduct, and data collection, utilization, interpretation, and analysis. This review aims to describe the current literature on precision medicine, its multiomics approach, and future directions for its application in IBD.
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Affiliation(s)
| | - Jose Andres Perez
- Department of Medicine, Saint Francis Health Systems, Tulsa, OK 74133, United States
| | - Andrea Belen Perez
- Department of Research, Columbia University, New York, NY 10027, United States
| | - Salim Surani
- Department of Medicine and Pharmacology, Texas A&M University, College Station, TX 77413, United States
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22
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Gois MFB, Fernández-Pato A, Huss A, Gacesa R, Wijmenga C, Weersma RK, Fu J, Vermeulen RCH, Zhernakova A, Lenters VC, Kurilshikov A. Impact of occupational pesticide exposure on the human gut microbiome. Front Microbiol 2023; 14:1223120. [PMID: 37637104 PMCID: PMC10448898 DOI: 10.3389/fmicb.2023.1223120] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2023] [Accepted: 07/24/2023] [Indexed: 08/29/2023] Open
Abstract
The rising use of pesticides in modern agriculture has led to a shift in disease burden in which exposure to these chemicals plays an increasingly important role. The human gut microbiome, which is partially responsible for the biotransformation of xenobiotics, is also known to promote biotransformation of environmental pollutants. Understanding the effects of occupational pesticide exposure on the gut microbiome can thus provide valuable insights into the mechanisms underlying the impact of pesticide exposure on health. Here we investigate the impact of occupational pesticide exposure on human gut microbiome composition in 7198 participants from the Dutch Microbiome Project of the Lifelines Study. We used job-exposure matrices in combination with occupational codes to retrieve categorical and cumulative estimates of occupational exposures to general pesticides, herbicides, insecticides and fungicides. Approximately 4% of our cohort was occupationally exposed to at least one class of pesticides, with predominant exposure to multiple pesticide classes. Most participants reported long-term employment, suggesting a cumulative profile of exposure. We demonstrate that contact with insecticides, fungicides and a general "all pesticides" class was consistently associated with changes in the gut microbiome, showing significant associations with decreased alpha diversity and a differing beta diversity. We also report changes in the abundance of 39 different bacterial taxa upon exposure to the different pesticide classes included in this study. Together, the extent of statistically relevant associations between gut microbial changes and pesticide exposure in our findings highlights the impact of these compounds on the human gut microbiome.
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Affiliation(s)
- Milla F. Brandao Gois
- Department of Genetics and Department of Gastroenterology and Hepatology University of Groningen, University Medical Center Groningen, Groningen, Netherlands
| | - Asier Fernández-Pato
- Department of Genetics and Department of Gastroenterology and Hepatology University of Groningen, University Medical Center Groningen, Groningen, Netherlands
| | - Anke Huss
- Department of Population Health Sciences, Institute for Risk Assessment Sciences (IRAS), Utrecht University, Utrecht, Netherlands
| | - Ranko Gacesa
- Department of Genetics and Department of Gastroenterology and Hepatology University of Groningen, University Medical Center Groningen, Groningen, Netherlands
- Department of Gastroenterology and Hepatology, University of Groningen, University Medical Center Groningen, Groningen, Netherlands
| | - Cisca Wijmenga
- Department of Genetics and Department of Gastroenterology and Hepatology University of Groningen, University Medical Center Groningen, Groningen, Netherlands
| | - Rinse K. Weersma
- Department of Genetics and Department of Gastroenterology and Hepatology University of Groningen, University Medical Center Groningen, Groningen, Netherlands
- Department of Gastroenterology and Hepatology, University of Groningen, University Medical Center Groningen, Groningen, Netherlands
| | - Jingyuan Fu
- Department of Genetics and Department of Gastroenterology and Hepatology University of Groningen, University Medical Center Groningen, Groningen, Netherlands
- Department of Pediatrics, University of Groningen, University Medical Center Groningen, Groningen, Netherlands
| | - Roel C. H. Vermeulen
- Department of Population Health Sciences, Institute for Risk Assessment Sciences (IRAS), Utrecht University, Utrecht, Netherlands
| | - Alexandra Zhernakova
- Department of Genetics and Department of Gastroenterology and Hepatology University of Groningen, University Medical Center Groningen, Groningen, Netherlands
| | - Virissa C. Lenters
- Department of Population Health Sciences, Institute for Risk Assessment Sciences (IRAS), Utrecht University, Utrecht, Netherlands
| | - Alexander Kurilshikov
- Department of Genetics and Department of Gastroenterology and Hepatology University of Groningen, University Medical Center Groningen, Groningen, Netherlands
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23
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Zhou L, Zhu L, Wu X, Hu S, Zhang S, Ning M, Yu J, Chen M. Decreased TMIGD1 aggravates colitis and intestinal barrier dysfunction via the BANF1-NF-κB pathway in Crohn's disease. BMC Med 2023; 21:287. [PMID: 37542259 PMCID: PMC10403950 DOI: 10.1186/s12916-023-02989-2] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/16/2023] [Accepted: 07/20/2023] [Indexed: 08/06/2023] Open
Abstract
BACKGROUND Disrupted intestinal epithelial barrier is one of the major causes of Crohn's disease (CD). Novel molecular targets for intestinal epithelial barrier are essential to treatment of CD. Transmembrane and immunoglobulin domain-containing protein 1 (TMIGD1) is an adhesion molecule that regulates cell adhesion, migration, and enterocyte differentiation. However, the function and mechanism of TMIGD1 in CD and intestinal epithelial barrier has rarely been studied. Furthermore, the association between TMIGD1 and the clinical features of CD remains unclear. METHODS Transcriptome analysis on colonic mucosa from CD patients and healthy individuals were performed to identify dysregulated genes. Multi-omics integration of the 1000IBD cohort including genomics, transcriptomics of intestinal biopsies, and serum proteomics identified the association between genes and characteristics of CD. Inflammation was assessed by cytokine production in cell lines, organoids and intestinal-specific Tmigd1 knockout (Tmigd1INT-KO) mice. Epithelial barrier integrity was evaluated by trans-epithelium electrical resistance (TEER), paracellular permeability, and apical junction complex (AJC) expression. Co-immunoprecipitation, GST pull-down assays, mass spectrometry, proteomics, and transcriptome analysis were used to explore downstream mechanisms. RESULTS Multi-omics integration suggested that TMIGD1 was negatively associated with inflammatory characteristics of CD. TMIGD1 was downregulated in inflamed intestinal mucosa of patients with CD and mice colitis models. Tmigd1INT-KO mice were more susceptible to chemically induced colitis. In epithelial cell lines and colonic organoids, TMIGD1 knockdown caused impaired intestinal barrier integrity evidenced by increased paracellular permeability and reduced TEER and AJC expression. TMIGD1 knockdown in intestinal epithelial cells also induced pro-inflammatory cytokine production. Mechanistically, TMIGD1 directly interacted with cytoplasmic BAF nuclear assembly factor 1 (BANF1) to inhibit NF-κB activation. Exogenous expression of TMIGD1 and BANF1 restored intestinal barrier function and inhibited inflammation in vitro and in vivo. TMIGD1 expression predicted response to anti-TNF treatment in patients with CD. CONCLUSIONS Our study demonstrated that TMIGD1 maintained intestinal barrier integrity and inactivated inflammation, and was therefore a potential therapeutic target for CD.
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Affiliation(s)
- Longyuan Zhou
- Department of Gastroenterology, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, Guangdong, People's Republic of China
| | - Liguo Zhu
- Department of Gastroenterology, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, Guangdong, People's Republic of China
| | - Xiaomin Wu
- Department of Gastroenterology, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, Guangdong, People's Republic of China
| | - Shixian Hu
- Institute of Precision Medicine, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, Guangdong, People's Republic of China
| | - Shenghong Zhang
- Department of Gastroenterology, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, Guangdong, People's Republic of China
| | - Min Ning
- Department of Gastroenterology, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, Guangdong, People's Republic of China
| | - Jun Yu
- State Key Laboratory of Digestive Disease, Institute of Digestive Disease and The Department of Medicine and Therapeutics, Li Ka Shing Institute of Health Sciences, CUHK Shenzhen Research Institute, The Chinese University of Hong Kong, Hong Kong SAR, China
| | - Minhu Chen
- Department of Gastroenterology, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, Guangdong, People's Republic of China.
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24
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Vich Vila A, Hu S, Andreu-Sánchez S, Collij V, Jansen BH, Augustijn HE, Bolte LA, Ruigrok RAAA, Abu-Ali G, Giallourakis C, Schneider J, Parkinson J, Al-Garawi A, Zhernakova A, Gacesa R, Fu J, Weersma RK. Faecal metabolome and its determinants in inflammatory bowel disease. Gut 2023; 72:1472-1485. [PMID: 36958817 PMCID: PMC10359577 DOI: 10.1136/gutjnl-2022-328048] [Citation(s) in RCA: 62] [Impact Index Per Article: 31.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/14/2022] [Accepted: 03/05/2023] [Indexed: 03/25/2023]
Abstract
OBJECTIVE Inflammatory bowel disease (IBD) is a multifactorial immune-mediated inflammatory disease of the intestine, comprising Crohn's disease and ulcerative colitis. By characterising metabolites in faeces, combined with faecal metagenomics, host genetics and clinical characteristics, we aimed to unravel metabolic alterations in IBD. DESIGN We measured 1684 different faecal metabolites and 8 short-chain and branched-chain fatty acids in stool samples of 424 patients with IBD and 255 non-IBD controls. Regression analyses were used to compare concentrations of metabolites between cases and controls and determine the relationship between metabolites and each participant's lifestyle, clinical characteristics and gut microbiota composition. Moreover, genome-wide association analysis was conducted on faecal metabolite levels. RESULTS We identified over 300 molecules that were differentially abundant in the faeces of patients with IBD. The ratio between a sphingolipid and L-urobilin could discriminate between IBD and non-IBD samples (AUC=0.85). We found changes in the bile acid pool in patients with dysbiotic microbial communities and a strong association between faecal metabolome and gut microbiota. For example, the abundance of Ruminococcus gnavus was positively associated with tryptamine levels. In addition, we found 158 associations between metabolites and dietary patterns, and polymorphisms near NAT2 strongly associated with coffee metabolism. CONCLUSION In this large-scale analysis, we identified alterations in the metabolome of patients with IBD that are independent of commonly overlooked confounders such as diet and surgical history. Considering the influence of the microbiome on faecal metabolites, our results pave the way for future interventions targeting intestinal inflammation.
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Affiliation(s)
- Arnau Vich Vila
- Department of Genetics, University Medical Centre, Groningen, The Netherlands
- Department of Pediatrics, University Medical Centre, Groningen, The Netherlands
| | - Shixian Hu
- Department of Genetics, University Medical Centre, Groningen, The Netherlands
- Department of Pediatrics, University Medical Centre, Groningen, The Netherlands
| | - Sergio Andreu-Sánchez
- Department of Pediatrics, University Medical Centre, Groningen, The Netherlands
- Department of Gastroenterology and Hepatology, University Medical Centre, Groningen, The Netherlands
| | - Valerie Collij
- Department of Genetics, University Medical Centre, Groningen, The Netherlands
- Department of Pediatrics, University Medical Centre, Groningen, The Netherlands
| | - Bernadien H Jansen
- Department of Genetics, University Medical Centre, Groningen, The Netherlands
| | - Hannah E Augustijn
- Department of Pediatrics, University Medical Centre, Groningen, The Netherlands
| | - Laura A Bolte
- Department of Genetics, University Medical Centre, Groningen, The Netherlands
| | - Renate A A A Ruigrok
- Department of Genetics, University Medical Centre, Groningen, The Netherlands
- Department of Pediatrics, University Medical Centre, Groningen, The Netherlands
| | - Galeb Abu-Ali
- Gastroenterology Drug Discovery Unit, Takeda Pharmaceutical, Cambridge, Massachusetts, USA
| | - Cosmas Giallourakis
- Gastroenterology Drug Discovery Unit, Takeda Pharmaceutical, Cambridge, Massachusetts, USA
| | - Jessica Schneider
- Gastroenterology Drug Discovery Unit, Takeda Pharmaceutical, Cambridge, Massachusetts, USA
| | - John Parkinson
- Gastroenterology Drug Discovery Unit, Takeda Pharmaceutical, Cambridge, Massachusetts, USA
| | - Amal Al-Garawi
- Gastroenterology Drug Discovery Unit, Takeda Pharmaceutical, Cambridge, Massachusetts, USA
| | | | - Ranko Gacesa
- Department of Genetics, University Medical Centre, Groningen, The Netherlands
- Department of Pediatrics, University Medical Centre, Groningen, The Netherlands
| | - Jingyuan Fu
- Department of Pediatrics, University Medical Centre, Groningen, The Netherlands
- Department of Gastroenterology and Hepatology, University Medical Centre, Groningen, The Netherlands
| | - Rinse K Weersma
- Department of Genetics, University Medical Centre, Groningen, The Netherlands
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Rodríguez-Lago I, Blackwell J, Mateos B, Marigorta UM, Barreiro-de Acosta M, Pollok R. Recent Advances and Potential Multi-Omics Approaches in the Early Phases of Inflammatory Bowel Disease. J Clin Med 2023; 12:jcm12103418. [PMID: 37240524 DOI: 10.3390/jcm12103418] [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: 03/20/2023] [Revised: 05/01/2023] [Accepted: 05/09/2023] [Indexed: 05/28/2023] Open
Abstract
Inflammatory bowel disease leads to debilitating gastrointestinal symptoms and reduced quality of life, resulting in a significant burden on healthcare utilization and costs. Despite substantial advancements in diagnosis and treatment, there may still be considerable delays in diagnosing some patients. To reduce disease progression before the full disease spectrum appears and improve prognostic outcomes, several strategies have concentrated on early intervention and prevention. Recent evidence shows that initial immune response changes and endoscopic lesions may exist for years before diagnosis, implying the existence of a preclinical phase of inflammatory bowel disease comparable to findings in other immune-mediated disorders. In this review, we highlight the most relevant findings regarding preclinical inflammatory bowel disease and the prospective role of novel omics techniques in this field.
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Affiliation(s)
- Iago Rodríguez-Lago
- Gastroenterology Department, Hospital Universitario de Galdakao, 48960 Galdakao, Spain
- Biocruces Bizkaia Health Research Institute, 48960 Galdakao, Spain
- Deusto University, 48007 Bilbao, Spain
| | | | - Beatriz Mateos
- Integrative Genomics Lab, Center for Cooperative Research in Biosciences (CIC bioGUNE), Basque Research and Technology Alliance (BRTA), Bizkaia Technology Park, 48160 Derio, Spain
| | - Urko M Marigorta
- Integrative Genomics Lab, Center for Cooperative Research in Biosciences (CIC bioGUNE), Basque Research and Technology Alliance (BRTA), Bizkaia Technology Park, 48160 Derio, Spain
- IKERBASQUE, Basque Foundation for Sciences, 48009 Bilbao, Spain
| | - Manuel Barreiro-de Acosta
- Gastroenterology Department, Hospital Clínico Universitario de Santiago, 15706 Santiago de Compostela, Spain
| | - Richard Pollok
- Gastroenterology Department, St George's University of London, London SW17 0RE, UK
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Gulyaeva A, Garmaeva S, Kurilshikov A, Vich Vila A, Riksen NP, Netea MG, Weersma RK, Fu J, Zhernakova A. Diversity and Ecology of Caudoviricetes Phages with Genome Terminal Repeats in Fecal Metagenomes from Four Dutch Cohorts. Viruses 2022; 14:2305. [PMID: 36298860 PMCID: PMC9610469 DOI: 10.3390/v14102305] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2022] [Revised: 10/14/2022] [Accepted: 10/17/2022] [Indexed: 11/17/2022] Open
Abstract
The human gut harbors numerous viruses infecting the human host, microbes, and other inhabitants of the gastrointestinal tract. Most of these viruses remain undiscovered, and their influence on human health is unknown. Here, we characterize viral genomes in gut metagenomic data from 1950 individuals from four population and patient cohorts. We focus on a subset of viruses that is highly abundant in the gut, remains largely uncharacterized, and allows confident complete genome identification—phages that belong to the class Caudoviricetes and possess genome terminal repeats. We detect 1899 species-level units belonging to this subset, 19% of which do not have complete representative genomes in major public gut virome databases. These units display diverse genomic features, are predicted to infect a wide range of microbial hosts, and on average account for <1% of metagenomic reads. Analysis of longitudinal data from 338 individuals shows that the composition of this fraction of the virome remained relatively stable over a period of 4 years. We also demonstrate that 54 species-level units are highly prevalent (detected in >5% of individuals in a cohort). Finally, we find 34 associations between highly prevalent phages and human phenotypes, 24 of which can be explained by the relative abundance of potential hosts.
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Affiliation(s)
- Anastasia Gulyaeva
- Department of Genetics, University of Groningen, University Medical Center Groningen, 9713GZ Groningen, The Netherlands
| | - Sanzhima Garmaeva
- Department of Genetics, University of Groningen, University Medical Center Groningen, 9713GZ Groningen, The Netherlands
| | - Alexander Kurilshikov
- Department of Genetics, University of Groningen, University Medical Center Groningen, 9713GZ Groningen, The Netherlands
| | - Arnau Vich Vila
- Department of Genetics, University of Groningen, University Medical Center Groningen, 9713GZ Groningen, The Netherlands
- Department of Gastroenterology and Hepatology, University Medical Center Groningen, 9713GZ Groningen, The Netherlands
| | - Niels P. Riksen
- Department of Internal Medicine, Radboud University Medical Center, 6525GA Nijmegen, The Netherlands
| | - Mihai G. Netea
- Department of Internal Medicine, Radboud University Medical Center, 6525GA Nijmegen, The Netherlands
| | - Rinse K. Weersma
- Department of Genetics, University of Groningen, University Medical Center Groningen, 9713GZ Groningen, The Netherlands
- Department of Gastroenterology and Hepatology, University Medical Center Groningen, 9713GZ Groningen, The Netherlands
| | - Jingyuan Fu
- Department of Genetics, University of Groningen, University Medical Center Groningen, 9713GZ Groningen, The Netherlands
- Department of Pediatrics, University of Groningen, University Medical Center Groningen, 9713GZ Groningen, The Netherlands
| | - Alexandra Zhernakova
- Department of Genetics, University of Groningen, University Medical Center Groningen, 9713GZ Groningen, The Netherlands
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Proteomic analyses do not reveal subclinical inflammation in fatigued patients with clinically quiescent inflammatory bowel disease. Sci Rep 2022; 12:14581. [PMID: 36028644 PMCID: PMC9418325 DOI: 10.1038/s41598-022-17504-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2022] [Accepted: 07/26/2022] [Indexed: 11/08/2022] Open
Abstract
Fatigue is a common and clinically challenging symptom in patients with inflammatory bowel diseases (IBD), occurring in ~ 50% of patients with quiescent disease. In this study, we aimed to investigate whether fatigue in patients with clinically quiescent IBD is reflected by circulating inflammatory proteins, which might reflect ongoing subclinical inflammation. Ninety-two (92) different inflammation-related proteins were measured in plasma of 350 patients with clinically quiescent IBD. Quiescent IBD was defined as clinical (Harvey-Bradshaw Index < 5 or Simple Clinical Colitis Activity Index < 2.5) and biochemical remission (C-reactive protein < 5 mg/L and absence of anemia) at time of fatigue assessment. Leukemia inhibitory factor receptor (LIF-R) concentrations were inversely associated with severe fatigue, also after adjustment for confounding factors (nominal P < 0.05). Although solely LIF-R showed weak ability to discriminate between mild and severe fatigue (area under the curve [AUC] = 0.61, 95%CI: 0.53–0.69, P < 0.05), a combined set of the top seven (7) fatigue-associated proteins (all P < 0.10) was observed to have reasonable discriminative performance (AUC = 0.82 [95%CI: 0.74–0.91], P < 0.01). Fatigue in patients with IBD is not clearly reflected by distinct protein signatures, suggesting there is no subclinical inflammation defined by the studied inflammatory proteins. Future studies are warranted to investigate other proteomic markers that may reflect fatigue in clinically quiescent IBD.
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28
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Fagundes RR, Bourgonje AR, Hu S, Barbieri R, Jansen BH, Sinnema N, Blokzijl T, Taylor CT, Weersma RK, Faber KN, Dijkstra G. HIF1α-Dependent Induction of TFRC by a Combination of Intestinal Inflammation and Systemic Iron Deficiency in Inflammatory Bowel Disease. Front Physiol 2022; 13:889091. [PMID: 35755436 PMCID: PMC9214203 DOI: 10.3389/fphys.2022.889091] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2022] [Accepted: 05/20/2022] [Indexed: 01/04/2023] Open
Abstract
Background and Aims: Iron deficiency (ID) is a frequent extra-intestinal manifestation in patients with Inflammatory Bowel Disease (IBD), who often do not respond to iron supplementation. Iron is a cofactor for hydroxylases that suppress the hypoxia-inducible factor-1α (HIF1α), a transcription factor regulating iron homeostasis. We hypothesized that iron deficiency affects mucosal HIF1α activity in IBD. Methods: IBD patients (n = 101) were subdivided based on iron status (ferritin levels or transferrin saturation) and systemic inflammation (C-reactive protein levels). 154 corresponding ileal and colonic biopsies were analyzed for differential expression of 20 HIF1α pathway-associated genes and related to iron and inflammation status. In vitro expression of selected HIF1α pathway genes were analyzed in wild-type and HIF1A-null Caco-2 cells. Results: Gene expression of the mucosal HIF1α pathway was most affected by intestinal location and inflammatory status. Especially, ileal mucosal TFRC expression, encoding the transferrin receptor TFR1, was increased in inflamed tissue (p < 0.001), and further enhanced in ID. Accordingly, TFRC expression in inflamed tissue associated negatively with serum iron levels, which was not observed in the non-inflamed mucosa. The HIF1α pathway agonist DMOG increased TFRC expression in Caco-2 cells, which was blunted in HIF1A-null cells. Conclusion: We demonstrate that inflammation and anatomical location primarily determine HIF1α pathway activation and downstream TFRC expression in the intestinal mucosa. IBD patients with ID may benefit from treatment with HIF1α-agonists by 1) increasing TFRC-mediated iron absorption in non-inflamed tissue and 2) decreasing mucosal inflammation, thereby improving their responsiveness to oral iron supplementation.
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Affiliation(s)
- Raphael R Fagundes
- Department of Gastroenterology and Hepatology, University of Groningen, University Medical Center Groningen, Groningen, Netherlands
| | - Arno R Bourgonje
- Department of Gastroenterology and Hepatology, University of Groningen, University Medical Center Groningen, Groningen, Netherlands
| | - Shixian Hu
- Department of Gastroenterology and Hepatology, University of Groningen, University Medical Center Groningen, Groningen, Netherlands
| | - Ruggero Barbieri
- Department of Gastroenterology and Hepatology, University of Groningen, University Medical Center Groningen, Groningen, Netherlands
| | - Bernadien H Jansen
- Department of Gastroenterology and Hepatology, University of Groningen, University Medical Center Groningen, Groningen, Netherlands
| | - Nienke Sinnema
- Department of Gastroenterology and Hepatology, University of Groningen, University Medical Center Groningen, Groningen, Netherlands
| | - Tjasso Blokzijl
- Department of Gastroenterology and Hepatology, University of Groningen, University Medical Center Groningen, Groningen, Netherlands
| | - Cormac T Taylor
- School of Medicine and Medical Science and the Conway Institute, University College Dublin, Dublin, Ireland
| | - Rinse K Weersma
- Department of Gastroenterology and Hepatology, University of Groningen, University Medical Center Groningen, Groningen, Netherlands
| | - Klaas Nico Faber
- Department of Gastroenterology and Hepatology, University of Groningen, University Medical Center Groningen, Groningen, Netherlands
| | - Gerard Dijkstra
- Department of Gastroenterology and Hepatology, University of Groningen, University Medical Center Groningen, Groningen, Netherlands
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Fiocchi C, Iliopoulos D. Inflammatory Bowel Disease Therapy: Beyond the Immunome. Front Immunol 2022; 13:864762. [PMID: 35615360 PMCID: PMC9124778 DOI: 10.3389/fimmu.2022.864762] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2022] [Accepted: 04/11/2022] [Indexed: 12/19/2022] Open
Affiliation(s)
- Claudio Fiocchi
- Department of Inflammation & Immunity, Lerner Research Institute Cleveland, Cleveland, OH, United States
- Department of Gastroenterology, Hepatology & Nutrition, Digestive Disease and Surgery Institute, Cleveland Clinic, Cleveland, OH, United States
- *Correspondence: Claudio Fiocchi,
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30
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Schwärzler J, Mayr L, Vich Vila A, Grabherr F, Niederreiter L, Philipp M, Grander C, Meyer M, Jukic A, Tröger S, Enrich B, Przysiecki N, Tschurtschenthaler M, Sommer F, Kronberger I, Koch J, Hilbe R, Hess MW, Oberhuber G, Sprung S, Ran Q, Koch R, Effenberger M, Kaneider NC, Wieser V, Keller MA, Weersma RK, Aden K, Rosenstiel P, Blumberg RS, Kaser A, Tilg H, Adolph TE. PUFA-Induced Metabolic Enteritis as a Fuel for Crohn's Disease. Gastroenterology 2022; 162:1690-1704. [PMID: 35031299 DOI: 10.1053/j.gastro.2022.01.004] [Citation(s) in RCA: 39] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/13/2021] [Revised: 12/16/2021] [Accepted: 01/04/2022] [Indexed: 02/06/2023]
Abstract
BACKGROUND & AIMS Crohn's disease (CD) globally emerges with Westernization of lifestyle and nutritional habits. However, a specific dietary constituent that comprehensively evokes gut inflammation in human inflammatory bowel diseases remains elusive. We aimed to delineate how increased intake of polyunsaturated fatty acids (PUFAs) in a Western diet, known to impart risk for developing CD, affects gut inflammation and disease course. We hypothesized that the unfolded protein response and antioxidative activity of glutathione peroxidase 4 (GPX4), which are compromised in human CD epithelium, compensates for metabolic perturbation evoked by dietary PUFAs. METHODS We phenotyped and mechanistically dissected enteritis evoked by a PUFA-enriched Western diet in 2 mouse models exhibiting endoplasmic reticulum (ER) stress consequent to intestinal epithelial cell (IEC)-specific deletion of X-box binding protein 1 (Xbp1) or Gpx4. We translated the findings to human CD epithelial organoids and correlated PUFA intake, as estimated by a dietary questionnaire or stool metabolomics, with clinical disease course in 2 independent CD cohorts. RESULTS PUFA excess in a Western diet potently induced ER stress, driving enteritis in Xbp1-/-IEC and Gpx4+/-IEC mice. ω-3 and ω-6 PUFAs activated the epithelial endoplasmic reticulum sensor inositol-requiring enzyme 1α (IRE1α) by toll-like receptor 2 (TLR2) sensing of oxidation-specific epitopes. TLR2-controlled IRE1α activity governed PUFA-induced chemokine production and enteritis. In active human CD, ω-3 and ω-6 PUFAs instigated epithelial chemokine expression, and patients displayed a compatible inflammatory stress signature in the serum. Estimated PUFA intake correlated with clinical and biochemical disease activity in a cohort of 160 CD patients, which was similarly demonstrable in an independent metabolomic stool analysis from 199 CD patients. CONCLUSIONS We provide evidence for the concept of PUFA-induced metabolic gut inflammation which may worsen the course of human CD. Our findings provide a basis for targeted nutritional therapy.
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Affiliation(s)
- Julian Schwärzler
- Department of Internal Medicine I, Gastroenterology, Hepatology, Endocrinology, and Metabolism, Medical University of Innsbruck, Innsbruck, Austria
| | - Lisa Mayr
- Department of Internal Medicine I, Gastroenterology, Hepatology, Endocrinology, and Metabolism, Medical University of Innsbruck, Innsbruck, Austria
| | - Arnau Vich Vila
- Department of Gastroenterology and Hepatology, University of Groningen and Groningen University Medical Center, Groningen, the Netherlands
| | - Felix Grabherr
- Department of Internal Medicine I, Gastroenterology, Hepatology, Endocrinology, and Metabolism, Medical University of Innsbruck, Innsbruck, Austria
| | - Lukas Niederreiter
- Department of Internal Medicine I, Gastroenterology, Hepatology, Endocrinology, and Metabolism, Medical University of Innsbruck, Innsbruck, Austria
| | - Maureen Philipp
- Department of Internal Medicine I, Gastroenterology, Hepatology, Endocrinology, and Metabolism, Medical University of Innsbruck, Innsbruck, Austria
| | - Christoph Grander
- Department of Internal Medicine I, Gastroenterology, Hepatology, Endocrinology, and Metabolism, Medical University of Innsbruck, Innsbruck, Austria
| | - Moritz Meyer
- Department of Internal Medicine I, Gastroenterology, Hepatology, Endocrinology, and Metabolism, Medical University of Innsbruck, Innsbruck, Austria
| | - Almina Jukic
- Department of Internal Medicine I, Gastroenterology, Hepatology, Endocrinology, and Metabolism, Medical University of Innsbruck, Innsbruck, Austria
| | - Simone Tröger
- Department of Internal Medicine I, Gastroenterology, Hepatology, Endocrinology, and Metabolism, Medical University of Innsbruck, Innsbruck, Austria
| | - Barbara Enrich
- Department of Internal Medicine I, Gastroenterology, Hepatology, Endocrinology, and Metabolism, Medical University of Innsbruck, Innsbruck, Austria
| | - Nicole Przysiecki
- Department of Internal Medicine I, Gastroenterology, Hepatology, Endocrinology, and Metabolism, Medical University of Innsbruck, Innsbruck, Austria
| | - Markus Tschurtschenthaler
- Institute for Experimental Cancer Therapy, Center for Translational Cancer Research (TranslaTUM), Klinikum rechts der Isar, Technical University of Munich, Munich, Germany; Department of Internal Medicine II, Klinikum rechts der Isar, Technical University of Munich, Munich, Germany
| | - Felix Sommer
- Institute of Clinical Molecular Biology, Christian Albrecht University Kiel and Schleswig-Holstein University Hospital, Kiel, Germany
| | - Irmgard Kronberger
- Department of Visceral, Transplant, and Thoracic Surgery, Medical University of Innsbruck, Innsbruck, Austria
| | - Jakob Koch
- Institute of Human Genetics, Medical University of Innsbruck, Innsbruck, Austria
| | - Richard Hilbe
- Department of Internal Medicine II, Infectious Diseases, Immunology, Rheumatology, Pneumology, Medical University of Innsbruck, Innsbruck, Austria
| | - Michael W Hess
- Institute of Histology and Embryology, Medical University of Innsbruck, Innsbruck, Austria
| | - Georg Oberhuber
- INNPATH, Innsbruck Medical University Hospital, Innsbruck, Austria
| | - Susanne Sprung
- Department of Pathology, Medical University of Innsbruck, Innsbruck, Austria
| | - Qitao Ran
- Department of Cell Systems and Anatomy, UT Health San Antonio, San Antonio, Texas
| | - Robert Koch
- Department of Internal Medicine I, Gastroenterology, Hepatology, Endocrinology, and Metabolism, Medical University of Innsbruck, Innsbruck, Austria
| | - Maria Effenberger
- Department of Internal Medicine I, Gastroenterology, Hepatology, Endocrinology, and Metabolism, Medical University of Innsbruck, Innsbruck, Austria
| | - Nicole C Kaneider
- Division of Gastroenterology and Hepatology, Department of Medicine, Addenbrooke's Hospital, University of Cambridge, Cambridge, United Kingdom
| | - Verena Wieser
- Department of Obstetrics and Gynecology, Medical University of Innsbruck, Innsbruck, Austria
| | - Markus A Keller
- Institute of Human Genetics, Medical University of Innsbruck, Innsbruck, Austria
| | - Rinse K Weersma
- Department of Gastroenterology and Hepatology, University of Groningen and Groningen University Medical Center, Groningen, the Netherlands
| | - Konrad Aden
- Institute of Clinical Molecular Biology, Christian Albrecht University Kiel and Schleswig-Holstein University Hospital, Kiel, Germany
| | - Philip Rosenstiel
- Institute of Clinical Molecular Biology, Christian Albrecht University Kiel and Schleswig-Holstein University Hospital, Kiel, Germany
| | - Richard S Blumberg
- Gastroenterology Division, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts
| | - Arthur Kaser
- Division of Gastroenterology and Hepatology, Department of Medicine, Addenbrooke's Hospital, University of Cambridge, Cambridge, United Kingdom
| | - Herbert Tilg
- Department of Internal Medicine I, Gastroenterology, Hepatology, Endocrinology, and Metabolism, Medical University of Innsbruck, Innsbruck, Austria
| | - Timon E Adolph
- Department of Internal Medicine I, Gastroenterology, Hepatology, Endocrinology, and Metabolism, Medical University of Innsbruck, Innsbruck, Austria.
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16S rRNA and metagenomic shotgun sequencing data revealed consistent patterns of gut microbiome signature in pediatric ulcerative colitis. Sci Rep 2022; 12:6421. [PMID: 35440670 PMCID: PMC9018687 DOI: 10.1038/s41598-022-07995-7] [Citation(s) in RCA: 29] [Impact Index Per Article: 9.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2021] [Accepted: 02/24/2022] [Indexed: 12/12/2022] Open
Abstract
Dysbiosis of human gut microbiota has been reported in association with ulcerative colitis (UC) in both children and adults using either 16S rRNA gene or shotgun sequencing data. However, these studies used either 16S rRNA or metagenomic shotgun sequencing but not both. We sequenced feces samples from 19 pediatric UC and 23 healthy children ages between 7 to 21 years using both 16S rRNA and metagenomic shotgun sequencing. The samples were analyzed using three different types of data: 16S rRNA genus level abundance, microbial species and pathway abundance profiles. We demonstrated that (a) the alpha diversity of pediatric UC cases is lower than that of healthy controls; (b) the beta diversity within children with UC is more variable than within the healthy children; (c) several microbial families including Akkermansiaceae, Clostridiaceae, Eggerthellaceae, Lachnospiraceae, and Oscillospiraceae, contain species that are depleted in pediatric UC compared to controls; (d) a few associated species unique to pediatric UC, but not adult UC, were also identified, e.g. some species in the Christensenellaceae family were found to be depleted and some species in the Enterobacteriaceae family were found to be enriched in pediatric UC; and (e) both 16S rRNA and shotgun sequencing data can predict pediatric UC status with area under the receiver operating characteristic curve (AUROC) of close to 0.90 based on cross validation. We showed that 16S rRNA data yielded similar results as shotgun data in terms of alpha diversity, beta diversity, and prediction accuracy. Our study demonstrated that pediatric UC subjects harbor a dysbiotic and less diverse gut microbial population with distinct differences from healthy children. We also showed that 16S rRNA data yielded accurate disease prediction results in comparison to shotgun data, which can be more expensive and laborious. These conclusions were confirmed in an independent data set of 7 pediatric UC cases and 8 controls.
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32
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Gacesa R, Kurilshikov A, Vich Vila A, Sinha T, Klaassen MAY, Bolte LA, Andreu-Sánchez S, Chen L, Collij V, Hu S, Dekens JAM, Lenters VC, Björk JR, Swarte JC, Swertz MA, Jansen BH, Gelderloos-Arends J, Jankipersadsing S, Hofker M, Vermeulen RCH, Sanna S, Harmsen HJM, Wijmenga C, Fu J, Zhernakova A, Weersma RK. Environmental factors shaping the gut microbiome in a Dutch population. Nature 2022; 604:732-739. [PMID: 35418674 DOI: 10.1038/s41586-022-04567-7] [Citation(s) in RCA: 383] [Impact Index Per Article: 127.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/23/2020] [Accepted: 02/18/2022] [Indexed: 12/22/2022]
Abstract
The gut microbiome is associated with diverse diseases1-3, but a universal signature of a healthy or unhealthy microbiome has not been identified, and there is a need to understand how genetics, exposome, lifestyle and diet shape the microbiome in health and disease. Here we profiled bacterial composition, function, antibiotic resistance and virulence factors in the gut microbiomes of 8,208 Dutch individuals from a three-generational cohort comprising 2,756 families. We correlated these to 241 host and environmental factors, including physical and mental health, use of medication, diet, socioeconomic factors and childhood and current exposome. We identify that the microbiome is shaped primarily by the environment and cohabitation. Only around 6.6% of taxa are heritable, whereas the variance of around 48.6% of taxa is significantly explained by cohabitation. By identifying 2,856 associations between the microbiome and health, we find that seemingly unrelated diseases share a common microbiome signature that is independent of comorbidities. Furthermore, we identify 7,519 associations between microbiome features and diet, socioeconomics and early life and current exposome, with numerous early-life and current factors being significantly associated with microbiome function and composition. Overall, this study provides a comprehensive overview of gut microbiome and the underlying impact of heritability and exposures that will facilitate future development of microbiome-targeted therapies.
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Affiliation(s)
- R Gacesa
- University of Groningen and University Medical Center Groningen, Department of Gastroenterology and Hepatology, Groningen, The Netherlands.,University of Groningen and University Medical Center Groningen, Department of Genetics, Groningen, The Netherlands
| | - A Kurilshikov
- University of Groningen and University Medical Center Groningen, Department of Genetics, Groningen, The Netherlands
| | - A Vich Vila
- University of Groningen and University Medical Center Groningen, Department of Gastroenterology and Hepatology, Groningen, The Netherlands.,University of Groningen and University Medical Center Groningen, Department of Genetics, Groningen, The Netherlands
| | - T Sinha
- University of Groningen and University Medical Center Groningen, Department of Genetics, Groningen, The Netherlands
| | - M A Y Klaassen
- University of Groningen and University Medical Center Groningen, Department of Gastroenterology and Hepatology, Groningen, The Netherlands.,University of Groningen and University Medical Center Groningen, Department of Genetics, Groningen, The Netherlands
| | - L A Bolte
- University of Groningen and University Medical Center Groningen, Department of Gastroenterology and Hepatology, Groningen, The Netherlands.,University of Groningen and University Medical Center Groningen, Department of Genetics, Groningen, The Netherlands
| | - S Andreu-Sánchez
- University of Groningen and University Medical Center Groningen, Department of Genetics, Groningen, The Netherlands.,Department of Pediatrics, University of Groningen and University Medical Center Groningen, Groningen, The Netherlands
| | - L Chen
- University of Groningen and University Medical Center Groningen, Department of Genetics, Groningen, The Netherlands.,Department of Pediatrics, University of Groningen and University Medical Center Groningen, Groningen, The Netherlands
| | - V Collij
- University of Groningen and University Medical Center Groningen, Department of Gastroenterology and Hepatology, Groningen, The Netherlands.,University of Groningen and University Medical Center Groningen, Department of Genetics, Groningen, The Netherlands
| | - S Hu
- University of Groningen and University Medical Center Groningen, Department of Gastroenterology and Hepatology, Groningen, The Netherlands.,University of Groningen and University Medical Center Groningen, Department of Genetics, Groningen, The Netherlands
| | - J A M Dekens
- University of Groningen and University Medical Center Groningen, Department of Genetics, Groningen, The Netherlands.,Center of Development and Innovation, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
| | - V C Lenters
- University Medical Centre Utrecht, Julius Center for Health Sciences and Primary Care, Utrecht, The Netherlands
| | - J R Björk
- University of Groningen and University Medical Center Groningen, Department of Gastroenterology and Hepatology, Groningen, The Netherlands.,University of Groningen and University Medical Center Groningen, Department of Genetics, Groningen, The Netherlands
| | - J C Swarte
- University of Groningen and University Medical Center Groningen, Department of Gastroenterology and Hepatology, Groningen, The Netherlands.,University of Groningen and University Medical Center Groningen, Department of Genetics, Groningen, The Netherlands
| | - M A Swertz
- University of Groningen and University Medical Center Groningen, Department of Genetics, Groningen, The Netherlands.,University of Groningen and University Medical Center Groningen, Genomics Coordination Center, Groningen, The Netherlands
| | - B H Jansen
- University of Groningen and University Medical Center Groningen, Department of Gastroenterology and Hepatology, Groningen, The Netherlands.,University of Groningen and University Medical Center Groningen, Department of Genetics, Groningen, The Netherlands
| | - J Gelderloos-Arends
- University of Groningen and University Medical Center Groningen, Department of Genetics, Groningen, The Netherlands
| | - S Jankipersadsing
- University of Groningen and University Medical Center Groningen, Department of Genetics, Groningen, The Netherlands
| | - M Hofker
- Department of Pediatrics, University of Groningen and University Medical Center Groningen, Groningen, The Netherlands
| | - R C H Vermeulen
- University Medical Centre Utrecht, Julius Center for Health Sciences and Primary Care, Utrecht, The Netherlands.,Utrecht University, Institute for Risk Assessment Sciences (IRAS), Department of Population Health Sciences, Utrecht, The Netherlands
| | - S Sanna
- University of Groningen and University Medical Center Groningen, Department of Genetics, Groningen, The Netherlands.,Institute for Genetic and Biomedical Research (IRGB), National Research Council (CNR), Cagliari, Italy
| | - H J M Harmsen
- Department of Medical Microbiology and Infection prevention, University of Groningen and University Medical Center Groningen, Groningen, The Netherlands
| | - C Wijmenga
- University of Groningen and University Medical Center Groningen, Department of Genetics, Groningen, The Netherlands
| | - J Fu
- University of Groningen and University Medical Center Groningen, Department of Genetics, Groningen, The Netherlands. .,Department of Pediatrics, University of Groningen and University Medical Center Groningen, Groningen, The Netherlands.
| | - A Zhernakova
- University of Groningen and University Medical Center Groningen, Department of Genetics, Groningen, The Netherlands.
| | - R K Weersma
- University of Groningen and University Medical Center Groningen, Department of Gastroenterology and Hepatology, Groningen, The Netherlands.
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33
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van der Sloot KWJ, Tiems JL, Visschedijk MC, Festen EAM, van Dullemen HM, Weersma RK, Kats-Ugurlu G, Dijkstra G. Cigarette Smoke Increases Risk for Colorectal Neoplasia in Inflammatory Bowel Disease. Clin Gastroenterol Hepatol 2022; 20:798-805.e1. [PMID: 33453400 DOI: 10.1016/j.cgh.2021.01.015] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/09/2020] [Revised: 12/05/2020] [Accepted: 01/10/2021] [Indexed: 02/07/2023]
Abstract
BACKGROUND & AIMS Patients with inflammatory bowel disease are at increased risk of colorectal neoplasia (CRN) due to mucosal inflammation. As current surveillance guidelines form a burden on patients and healthcare costs, stratification of high-risk patients is crucial. Cigarette smoke reduces inflammation in ulcerative colitis (UC) but not Crohn's disease (CD) and forms a known risk factor for CRN in the general population. Due to this divergent association, the effect of smoking on CRN in IBD is unclear and subject of this study. METHODS In this retrospective cohort study, 1,386 IBD patients with previous biopsies analyzed and reported in the PALGA register were screened for development of CRN. Clinical factors and cigarette smoke were evaluated. Patients were stratified for guideline-based risk of CRN. Cox-regression modeling was used to estimate the effect of cigarette smoke and its additive effect within the current risk stratification for prediction of CRN. RESULTS 153 (11.5%) patients developed CRN. Previously described risk factors, i.e. first-degree family member with CRN in CD (p-value=.001), presence of post-inflammatory polyps in UC (p-value=.005), were replicated. Former smoking increased risk of CRN in UC (HR 1.73; 1.05-2.85), whereas passive smoke exposure yielded no effect. For CD, active smoking (2.20; 1.02-4.76) and passive smoke exposure (1.87; 1.09-3.20) significantly increased CRN risk. Addition of smoke exposure to the current risk-stratification model significantly improved model fit for CD. CONCLUSIONS This study is the first to describe the important role of cigarette smoke in CRN development in IBD patients. Adding this risk factor improves the current risk stratification for CRN surveillance strategies.
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Affiliation(s)
- Kimberley W J van der Sloot
- Department of Gastroenterology and Hepatology, Groningen, the Netherlands; Department of Epidemiology, Groningen, the Netherlands.
| | | | | | - Eleonora A M Festen
- Department of Gastroenterology and Hepatology, Groningen, the Netherlands; Department of Genetics, University of Groningen and University Medical Center Groningen, Groningen, the Netherlands
| | | | - Rinse K Weersma
- Department of Gastroenterology and Hepatology, Groningen, the Netherlands
| | | | - Gerard Dijkstra
- Department of Gastroenterology and Hepatology, Groningen, the Netherlands
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34
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Feakins R, Torres J, Borralho-Nunes P, Burisch J, Cúrdia Gonçalves T, De Ridder L, Driessen A, Lobatón T, Menchén L, Mookhoek A, Noor N, Svrcek M, Villanacci V, Zidar N, Tripathi M. ECCO Topical Review on Clinicopathological Spectrum and Differential Diagnosis of Inflammatory Bowel Disease. J Crohns Colitis 2022; 16:343-368. [PMID: 34346490 DOI: 10.1093/ecco-jcc/jjab141] [Citation(s) in RCA: 26] [Impact Index Per Article: 8.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
INTRODUCTION Many diseases can imitate inflammatory bowel disease [IBD] clinically and pathologically. This review outlines the differential diagnosis of IBD and discusses morphological pointers and ancillary techniques that assist with the distinction between IBD and its mimics. METHODS European Crohn's and Colitis Organisation [ECCO] Topical Reviews are the result of an expert consensus. For this review, ECCO announced an open call to its members and formed three working groups [WGs] to study clinical aspects, pathological considerations, and the value of ancillary techniques. All WGs performed a systematic literature search. RESULTS Each WG produced a draft text and drew up provisional Current Practice Position [CPP] statements that highlighted the most important conclusions. Discussions and a preliminary voting round took place, with subsequent revision of CPP statements and text and a further meeting to agree on final statements. CONCLUSIONS Clinicians and pathologists encounter a wide variety of mimics of IBD, including infection, drug-induced disease, vascular disorders, diverticular disease, diversion proctocolitis, radiation damage, and immune disorders. Reliable distinction requires a multidisciplinary approach.
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Affiliation(s)
- Roger Feakins
- Department of Cellular Pathology, Royal Free Hospital, London, and University College London, UK
| | - Joana Torres
- Department of Gastroenterology, Hospital Beatriz Ângelo, Loures, Portugal
| | - Paula Borralho-Nunes
- Department of Pathology, Hospital Cuf Descobertas, Lisboa and Faculdade de Medicina da Universidade de Lisboa, Lisbon, Portugal
| | - Johan Burisch
- Gastrounit, Medical Division, Hvidovre Hospital, University of Copenhagen, Denmark
| | - Tiago Cúrdia Gonçalves
- Department of Gastroenterology, Hospital da Senhora da Oliveira, Guimarães, Portugal.,School of Medicine, University of Minho, Braga/Guimarães, Portugal.,ICVS/3B's-PT Government Associate Laboratory, Braga/Guimarães, Portugal
| | - Lissy De Ridder
- Department of Paediatric Gastroenterology, Erasmus MC Sophia Children's Hospital, University Medical Center Rotterdam, The Netherlands
| | - Ann Driessen
- Department of Pathology, University Hospital Antwerp, University Antwerp, Edegem, Belgium
| | - Triana Lobatón
- Department of Gastroenterology, Ghent University Hospital, Ghent, Belgium
| | - Luis Menchén
- Department of Digestive System Medicine, Hospital General Universitario-Insitituto de Investigación Sanitaria Gregorio Marañón, Madrid, Spain.,Department of Medicine, Universidad Complutense, Madrid, Spain.,Centro de Investigación Biomédica En Red de Enfermedades Hepáticas y Digestivas [CIBEREHD], Madrid, Spain
| | - Aart Mookhoek
- Department of Pathology, Amsterdam UMC, Amsterdam, The Netherlands
| | - Nurulamin Noor
- Department of Gastroenterology, Addenbrooke's Hospital, Cambridge University Hospitals NHS Trust, Cambridge, UK
| | - Magali Svrcek
- Department of Pathology, Sorbonne Université, AP-HP, Saint-Antoine Hospital, Paris, France
| | - Vincenzo Villanacci
- Department of Histopathology, Spedali Civili and University of Brescia, Brescia, Italy
| | - Nina Zidar
- Institute of Pathology, Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia
| | - Monika Tripathi
- Department of Histopathology, Cambridge Biomedical Campus, Addenbrooke's Hospital, Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK
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35
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Gulyaeva A, Garmaeva S, Ruigrok RAAA, Wang D, Riksen NP, Netea MG, Wijmenga C, Weersma RK, Fu J, Vila AV, Kurilshikov A, Zhernakova A. Discovery, diversity, and functional associations of crAss-like phages in human gut metagenomes from four Dutch cohorts. Cell Rep 2022; 38:110204. [PMID: 35021085 DOI: 10.1016/j.celrep.2021.110204] [Citation(s) in RCA: 33] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2021] [Revised: 09/03/2021] [Accepted: 12/13/2021] [Indexed: 12/16/2022] Open
Abstract
The crAss-like phages are a diverse group of related viruses that includes some of the most abundant viruses of the human gut. To explore their diversity and functional role in human population and clinical cohorts, we analyze gut metagenomic data collected from 1,950 individuals from the Netherlands. We identify 1,556 crAss-like phage genomes, including 125 species-level and 32 genus-level clusters absent from the reference databases used. Analysis of their genomic features shows that closely related crAss-like phages can possess strikingly divergent regions responsible for transcription, presumably acquired through recombination. Prediction of crAss-like phage hosts points primarily to bacteria of the phylum Bacteroidetes, consistent with previous reports. Finally, we explore the temporal stability of crAss-like phages over a 4-year period and identify associations between the abundance of crAss-like phages and several human phenotypes, including depletion of crAss-like phages in inflammatory bowel disease patients.
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Affiliation(s)
- Anastasia Gulyaeva
- Department of Genetics, University of Groningen, University Medical Center Groningen, Groningen 9713GZ, the Netherlands.
| | - Sanzhima Garmaeva
- Department of Genetics, University of Groningen, University Medical Center Groningen, Groningen 9713GZ, the Netherlands
| | - Renate A A A Ruigrok
- Department of Genetics, University of Groningen, University Medical Center Groningen, Groningen 9713GZ, the Netherlands; Department of Gastroenterology and Hepatology, University Medical Center Groningen, Groningen 9713GZ, the Netherlands
| | - Daoming Wang
- Department of Genetics, University of Groningen, University Medical Center Groningen, Groningen 9713GZ, the Netherlands
| | - Niels P Riksen
- Department of Internal Medicine, Radboud University Medical Center, Nijmegen 6525GA, the Netherlands
| | - Mihai G Netea
- Department of Internal Medicine, Radboud University Medical Center, Nijmegen 6525GA, the Netherlands
| | - Cisca Wijmenga
- Department of Genetics, University of Groningen, University Medical Center Groningen, Groningen 9713GZ, the Netherlands
| | - Rinse K Weersma
- Department of Genetics, University of Groningen, University Medical Center Groningen, Groningen 9713GZ, the Netherlands; Department of Gastroenterology and Hepatology, University Medical Center Groningen, Groningen 9713GZ, the Netherlands
| | - Jingyuan Fu
- Department of Genetics, University of Groningen, University Medical Center Groningen, Groningen 9713GZ, the Netherlands; Department of Pediatrics, University of Groningen, University Medical Center Groningen, Groningen 9713GZ, the Netherlands
| | - Arnau Vich Vila
- Department of Genetics, University of Groningen, University Medical Center Groningen, Groningen 9713GZ, the Netherlands; Department of Gastroenterology and Hepatology, University Medical Center Groningen, Groningen 9713GZ, the Netherlands
| | - Alexander Kurilshikov
- Department of Genetics, University of Groningen, University Medical Center Groningen, Groningen 9713GZ, the Netherlands
| | - Alexandra Zhernakova
- Department of Genetics, University of Groningen, University Medical Center Groningen, Groningen 9713GZ, the Netherlands.
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Nguyen QV, Chong LC, Hor YY, Lew LC, Rather IA, Choi SB. Role of Probiotics in the Management of COVID-19: A Computational Perspective. Nutrients 2022; 14:274. [PMID: 35057455 PMCID: PMC8781206 DOI: 10.3390/nu14020274] [Citation(s) in RCA: 22] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2021] [Revised: 01/06/2022] [Accepted: 01/07/2022] [Indexed: 02/01/2023] Open
Abstract
Coronavirus disease 2019 (COVID-19) was declared a pandemic at the beginning of 2020, causing millions of deaths worldwide. Millions of vaccine doses have been administered worldwide; however, outbreaks continue. Probiotics are known to restore a stable gut microbiota by regulating innate and adaptive immunity within the gut, demonstrating the possibility that they may be used to combat COVID-19 because of several pieces of evidence suggesting that COVID-19 has an adverse impact on gut microbiota dysbiosis. Thus, probiotics and their metabolites with known antiviral properties may be used as an adjunctive treatment to combat COVID-19. Several clinical trials have revealed the efficacy of probiotics and their metabolites in treating patients with SARS-CoV-2. However, its molecular mechanism has not been unraveled. The availability of abundant data resources and computational methods has significantly changed research finding molecular insights between probiotics and COVID-19. This review highlights computational approaches involving microbiome-based approaches and ensemble-driven docking approaches, as well as a case study proving the effects of probiotic metabolites on SARS-CoV-2.
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Affiliation(s)
- Quang Vo Nguyen
- Centre for Bioinformatics, School of Data Sciences, Perdana University, Suite 9.2, 9th Floor, Wisma Chase Perdana, Changkat Semantan, Wilayah Persekutuan, Kuala Lumpur 50490, Malaysia;
| | - Li Chuin Chong
- Beykoz Institute of Life Sciences and Biotechnology, Bezmialem Vakif University, Beykoz, Istanbul 34820, Turkey;
| | - Yan-Yan Hor
- Department of Biotechnology, Yeungnam University, 280 Daehak-Ro, Gyeongsan 38541, Gyeongbuk, Korea;
| | - Lee-Ching Lew
- Probionic Corporation, Jeonbuk Institute for Food-Bioindustry, Jeonju 54810, Korea;
| | - Irfan A. Rather
- Department of Biological Sciences, Faculty of Science, King Abdulaziz University, P.O. Box 80203, Jeddah 21589, Saudi Arabia
- Center of Excellence in Bionanoscience Research, King Abdulaziz University, P.O. Box 80203, Jeddah 21589, Saudi Arabia
| | - Sy-Bing Choi
- Centre for Bioinformatics, School of Data Sciences, Perdana University, Suite 9.2, 9th Floor, Wisma Chase Perdana, Changkat Semantan, Wilayah Persekutuan, Kuala Lumpur 50490, Malaysia;
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37
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Gacesa R, Vich Vila A, Collij V, Mujagic Z, Kurilshikov A, Voskuil M, Festen E, Wijmenga C, Jonkers D, Dijkstra G, Fu J, Zhernakova A, Imhann F, Weersma R. A combination of fecal calprotectin and human beta-defensin 2 facilitates diagnosis and monitoring of inflammatory bowel disease. Gut Microbes 2021; 13:1943288. [PMID: 34313538 PMCID: PMC8317932 DOI: 10.1080/19490976.2021.1943288] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/04/2023] Open
Abstract
Inflammatory bowel disease (IBD) and irritable bowel syndrome (IBS) show a large overlap in clinical presentation, which presents diagnostic challenges. As a consequence, invasive and burdensome endoscopies are often used to distinguish between IBD and IBS. Here, we aimed to develop a noninvasive fecal test that can distinguish between IBD and IBS and reduce the number of endoscopies.We used shotgun metagenomic sequencing to analyze the composition and function of gut microbiota of 169 IBS patients, 447 IBD patients and 1044 population controls and measured fecal Calprotectin (FCal), human beta defensin 2 (HBD2), and chromogranin A (CgA) in these samples. These measurements were used to construct training sets (75% of data) for logistic regression and machine learning models to differentiate IBS from IBD and inactive from active IBD. The results were replicated on test sets (remaining 25% of the data) and microbiome data obtained using 16S sequencing.Fecal HBD2 showed high sensitivity and specificity for differentiating between IBD and IBS (sensitivity = 0.89, specificity = 0.76), while the inclusion of microbiome data with biomarkers (HBD2 and FCal) showed a potential for improvement in predictive power (optimal sensitivity = 0.87, specificity = 0.93). Shotgun sequencing-based models produced comparable results using 16S-sequencing data. HBD2 and FCal were found to have predictive power for IBD disease activity (AUC ≈ 0.7).HBD2 is a novel biomarker for IBD in patients with gastro-intestinal complaints, especially when used in combination with FCal and potentially in combination with gut microbiome data.
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Affiliation(s)
- R. Gacesa
- University of Groningen, University Medical Center Groningen, Department of Gastroenterology and Hepatology, Groningen, The Netherlands,University of Groningen and University Medical Center Groningen, Department of Genetics, Groningen, The Netherlands
| | - A. Vich Vila
- University of Groningen, University Medical Center Groningen, Department of Gastroenterology and Hepatology, Groningen, The Netherlands,University of Groningen and University Medical Center Groningen, Department of Genetics, Groningen, The Netherlands
| | - V. Collij
- University of Groningen, University Medical Center Groningen, Department of Gastroenterology and Hepatology, Groningen, The Netherlands,University of Groningen and University Medical Center Groningen, Department of Genetics, Groningen, The Netherlands
| | - Z. Mujagic
- Maastricht University Medical Center, Division of Gastroenterology-Hepatology, NUTRIM School for Nutrition and Translational Research in Metabolism, Maastricht, The Netherlands
| | - A. Kurilshikov
- University of Groningen and University Medical Center Groningen, Department of Genetics, Groningen, The Netherlands
| | - M.D. Voskuil
- University of Groningen, University Medical Center Groningen, Department of Gastroenterology and Hepatology, Groningen, The Netherlands,University of Groningen and University Medical Center Groningen, Department of Genetics, Groningen, The Netherlands
| | - E.A.M. Festen
- University of Groningen, University Medical Center Groningen, Department of Gastroenterology and Hepatology, Groningen, The Netherlands,University of Groningen and University Medical Center Groningen, Department of Genetics, Groningen, The Netherlands
| | - C. Wijmenga
- University of Groningen and University Medical Center Groningen, Department of Genetics, Groningen, The Netherlands
| | - D.M.A.E. Jonkers
- Maastricht University Medical Center, Division of Gastroenterology-Hepatology, NUTRIM School for Nutrition and Translational Research in Metabolism, Maastricht, The Netherlands
| | - G. Dijkstra
- University of Groningen, University Medical Center Groningen, Department of Gastroenterology and Hepatology, Groningen, The Netherlands
| | - J. Fu
- University of Groningen, University Medical Center Groningen, Department of Gastroenterology and Hepatology, Groningen, The Netherlands,University of Groningen and University Medical Center Groningen, Department of Pediatrics, Groningen, The Netherlands
| | - A. Zhernakova
- University of Groningen and University Medical Center Groningen, Department of Genetics, Groningen, The Netherlands
| | - F. Imhann
- University of Groningen, University Medical Center Groningen, Department of Gastroenterology and Hepatology, Groningen, The Netherlands,University of Groningen and University Medical Center Groningen, Department of Genetics, Groningen, The Netherlands,CONTACT F. Imhann University of Groningen, University Medical Center Groningen, Department of Gastroenterology and Hepatology, Groningen, The Netherlands
| | - R.K. Weersma
- University of Groningen, University Medical Center Groningen, Department of Gastroenterology and Hepatology, Groningen, The Netherlands
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38
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Klusmann B, Fleer J, Tovote KA, Weersma RK, van Dullemen HM, Dijkstra G, Schroevers MJ. Trajectories of Fatigue in Inflammatory Bowel Disease. Inflamm Bowel Dis 2021; 27:1919-1930. [PMID: 33769489 DOI: 10.1093/ibd/izab007] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/18/2020] [Indexed: 12/24/2022]
Abstract
BACKGROUND Fatigue is one of the most frequently reported symptoms by patients with inflammatory bowel disease (IBD), both during active disease phases as well as during clinical remission. This study addressed whether different trajectories of fatigue over time can be identified among patients with IBD. Subsequently, we compared the demographic and clinical characteristics between trajectories. METHODS The current study included 849 patients with IBD diagnosed with either Crohn disease (CD; n = 511) or ulcerative colitis (UC; n = 338) who visited the University Medical Center in Groningen (the Netherlands) at least 3 times during a 9-year follow-up. We conducted latent class growth analyses to identify distinct trajectories. RESULTS In all patients with IBD (and in the subgroup with CD), we found 5 trajectories for fatigue. In the UC subgroup, we found 4 fatigue trajectories. One trajectory present in both patients with CD (11.45%) and patients with UC (4.75%) was characterized by chronic elevated levels of fatigue across time. Women and parents were more prevalent in trajectories with higher fatigue severity. We also found significant associations among the fatigue trajectories with disease activity and psychological well-being. CONCLUSIONS The results clearly showed the existence of distinct fatigue paths over time in patients with IBD. Those reporting more chronic elevated levels of fatigue also reported greater disease activity and reduced well-being. Therefore, reducing disease activity may be important for the treatment of fatigue. In addition, given the significant association with well-being, it is possible that reducing fatigue may improve self-reported well-being.
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Affiliation(s)
- Birte Klusmann
- Department of Health Sciences, University of Groningen and University Medical Center, Groningen, the Netherlands
| | - Joke Fleer
- Department of Health Sciences, University of Groningen and University Medical Center, Groningen, the Netherlands
| | - K Annika Tovote
- Department of Health Sciences, University of Groningen and University Medical Center, Groningen, the Netherlands
| | - Rinse K Weersma
- Department of Gastroenterology and Hepatology, University of Groningen and University Medical Center Groningen, Groningen, the Netherlands
| | - Hendrik M van Dullemen
- Department of Gastroenterology and Hepatology, University of Groningen and University Medical Center Groningen, Groningen, the Netherlands
| | - Gerard Dijkstra
- Department of Gastroenterology and Hepatology, University of Groningen and University Medical Center Groningen, Groningen, the Netherlands
| | - Maya J Schroevers
- Department of Health Sciences, University of Groningen and University Medical Center, Groningen, the Netherlands
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39
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Thomas JP, Modos D, Korcsmaros T, Brooks-Warburton J. Network Biology Approaches to Achieve Precision Medicine in Inflammatory Bowel Disease. Front Genet 2021; 12:760501. [PMID: 34745229 PMCID: PMC8566351 DOI: 10.3389/fgene.2021.760501] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/18/2021] [Accepted: 10/08/2021] [Indexed: 12/22/2022] Open
Abstract
Inflammatory bowel disease (IBD) is a chronic immune-mediated condition arising due to complex interactions between multiple genetic and environmental factors. Despite recent advances, the pathogenesis of the condition is not fully understood and patients still experience suboptimal clinical outcomes. Over the past few years, investigators are increasingly capturing multi-omics data from patient cohorts to better characterise the disease. However, reaching clinically translatable endpoints from these complex multi-omics datasets is an arduous task. Network biology, a branch of systems biology that utilises mathematical graph theory to represent, integrate and analyse biological data through networks, will be key to addressing this challenge. In this narrative review, we provide an overview of various types of network biology approaches that have been utilised in IBD including protein-protein interaction networks, metabolic networks, gene regulatory networks and gene co-expression networks. We also include examples of multi-layered networks that have combined various network types to gain deeper insights into IBD pathogenesis. Finally, we discuss the need to incorporate other data sources including metabolomic, histopathological, and high-quality clinical meta-data. Together with more robust network data integration and analysis frameworks, such efforts have the potential to realise the key goal of precision medicine in IBD.
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Affiliation(s)
- John P Thomas
- Earlham Institute, Norwich, United Kingdom
- Quadram Institute Bioscience, Norwich, United Kingdom
- Department of Gastroenterology, Norfolk and Norwich University Hospital, Norwich, United Kingdom
| | - Dezso Modos
- Earlham Institute, Norwich, United Kingdom
- Quadram Institute Bioscience, Norwich, United Kingdom
| | - Tamas Korcsmaros
- Earlham Institute, Norwich, United Kingdom
- Quadram Institute Bioscience, Norwich, United Kingdom
| | - Johanne Brooks-Warburton
- Department of Gastroenterology, Lister Hospital, Stevenage, United Kingdom
- Department of Clinical, Pharmaceutical and Biological Sciences, University of Hertfordshire, Hatfield, United Kingdom
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40
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Torres J, Halfvarson J, Rodríguez-Lago I, Hedin CRH, Jess T, Dubinsky M, Croitoru K, Colombel JF. Results of the Seventh Scientific Workshop of ECCO: Precision Medicine in IBD-Prediction and Prevention of Inflammatory Bowel Disease. J Crohns Colitis 2021; 15:1443-1454. [PMID: 33730755 DOI: 10.1093/ecco-jcc/jjab048] [Citation(s) in RCA: 43] [Impact Index Per Article: 10.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
Inflammatory bowel disease [IBD] is a complex chronic disorder with no clear aetiology and no known cure. Despite recent advances in overall disease management and improved therapeutics, patients with IBD still experience a substantial burden. Furthermore, as the incidence continues to increase in developing areas of the world, it is expected that the burden of IBD to society will increase and exert tremendous pressure on health care systems worldwide. Therefore, new strategies to prevent the global increase of IBD are urgently required. Data are being progressively acquired on the period preceding disease diagnosis, which support the concept that IBD has a preclinical period that may reveal the triggers of disease and may be amenable to early intervention. Having a better knowledge of this preclinical period will increase the potential not only for improved understanding of disease pathogenesis and improved therapeutics, but also for disease prediction and prevention.
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Affiliation(s)
- Joana Torres
- Division of Gastroenterology, Hospital Beatriz Ângelo, Loures, Portugal.,Faculdade de Medicina, Universidade de Lisboa, Lisboa, Portugal
| | - Jonas Halfvarson
- Department of Gastroenterology, Faculty of Medicine and Health, Örebro University, Örebro, Sweden
| | - Iago Rodríguez-Lago
- Department of Gastroenterology, Hospital de Galdakao, and Biocruces Bizkaia Health Research Institute, Bilbao, Spain
| | - Charlotte R H Hedin
- Karolinska Institutet, Department of Medicine Solna, Stockholm, Sweden.,Karolinska University Hospital, Gastroenterology unit, Department of Gastroenterology, Dermatovenereology and Rheumatology, Stockholm, Sweden
| | - Tine Jess
- Department of Epidemiology Research, Statens Serum Institut, Copenhagen S, Denmark.,PREDICT, Institute of Clinical Medicine, Aalborg University, Aalborg, Denmark
| | - Marla Dubinsky
- Division of Pediatric Gastroenterology and Nutrition, Susan and Leonard Feinstein Inflammatory Bowel Disease Clinical Center, Icahn School of Medicine Mount Sinai, New York, NY, USA
| | - Kenneth Croitoru
- Center for Inflammatory Bowel Disease, Mount Sinai Hospital, Toronto, ON, Canada.,Division of Gastroenterology and Hepatology, University of Toronto, Toronto, ON, Canada
| | - Jean-Frédéric Colombel
- Division of Gastroenterology, Icahn School of Medicine at Mount Sinai, New York, NY, USA
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41
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Karmi N, Bangma A, Spekhorst LM, van Dullemen HM, Visschedijk MC, Dijkstra G, Weersma RK, Voskuil MD, Festen EAM. Polygenetic risk scores do not add predictive power to clinical models for response to anti-TNFα therapy in inflammatory bowel disease. PLoS One 2021; 16:e0256860. [PMID: 34534227 PMCID: PMC8448323 DOI: 10.1371/journal.pone.0256860] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2020] [Accepted: 08/16/2021] [Indexed: 12/30/2022] Open
Abstract
Background Anti-tumour necrosis factor alpha (TNFα) therapy is widely used in the management of Crohn’s disease (CD) and ulcerative colitis (UC). However, up to a third of patients do not respond to induction therapy and another third of patients lose response over time. To aid patient stratification, polygenetic risk scores have been identified as predictors of response to anti-TNFα therapy. We aimed to replicate the association between polygenetic risk scores and response to anti-TNFα therapy in an independent cohort of patients, to establish its clinical validity. Materials and methods Primary non-response, primary response, durable response and loss of response to anti-TNFα therapy was retrospectively assessed for each patient using stringent definitions. Genome wide genotyping was performed and previously described polygenetic risk scores for primary non-response and durable response were calculated. We compared polygenetic risk scores between patients with primary response and primary non-response, and between patients with durable response and loss of response, using separate analyses for CD and UC. Results Out of 334 patients with CD, 15 (4%) patients met criteria for primary non-response, 221 (66%) for primary response, 115 (34%) for durable response and 35 (10%) for loss of response. Out of 112 patients with UC, 12 (11%) met criteria for primary non-response, 68 (61%) for primary response, 19 (17%) for durable response and 20 (18%) for loss of response. No significant differences in polygenetic risk scores were found between primary non-responders and primary responders, and between durable responders and loss of responders. Conclusions We could not replicate the previously reported association between polygenetic risk scores and response to anti-TNFα therapy in an independent cohort of patients with CD or UC. Currently, there is insufficient evidence to use polygenetic risk scores to predict response to anti-TNFα therapy in patients with IBD.
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Affiliation(s)
- Naomi Karmi
- Department of Gastroenterology and Hepatology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
- Department of Genetics, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
| | - Amber Bangma
- Department of Gastroenterology and Hepatology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
- Department of Genetics, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
| | - Lieke M. Spekhorst
- Department of Gastroenterology and Hepatology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
| | - Hendrik M. van Dullemen
- Department of Gastroenterology and Hepatology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
| | - Marijn C. Visschedijk
- Department of Gastroenterology and Hepatology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
| | - Gerard Dijkstra
- Department of Gastroenterology and Hepatology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
| | - Rinse K. Weersma
- Department of Gastroenterology and Hepatology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
| | - Michiel D. Voskuil
- Department of Gastroenterology and Hepatology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
- Department of Genetics, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
| | - Eleonora A. M. Festen
- Department of Gastroenterology and Hepatology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
- Department of Genetics, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
- * E-mail:
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Machine Learning Modeling from Omics Data as Prospective Tool for Improvement of Inflammatory Bowel Disease Diagnosis and Clinical Classifications. Genes (Basel) 2021; 12:genes12091438. [PMID: 34573420 PMCID: PMC8466305 DOI: 10.3390/genes12091438] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2021] [Revised: 08/21/2021] [Accepted: 09/14/2021] [Indexed: 12/14/2022] Open
Abstract
Research of inflammatory bowel disease (IBD) has identified numerous molecular players involved in the disease development. Even so, the understanding of IBD is incomplete, while disease treatment is still far from the precision medicine. Reliable diagnostic and prognostic biomarkers in IBD are limited which may reduce efficient therapeutic outcomes. High-throughput technologies and artificial intelligence emerged as powerful tools in search of unrevealed molecular patterns that could give important insights into IBD pathogenesis and help to address unmet clinical needs. Machine learning, a subtype of artificial intelligence, uses complex mathematical algorithms to learn from existing data in order to predict future outcomes. The scientific community has been increasingly employing machine learning for the prediction of IBD outcomes from comprehensive patient data-clinical records, genomic, transcriptomic, proteomic, metagenomic, and other IBD relevant omics data. This review aims to present fundamental principles behind machine learning modeling and its current application in IBD research with the focus on studies that explored genomic and transcriptomic data. We described different strategies used for dealing with omics data and outlined the best-performing methods. Before being translated into clinical settings, the developed machine learning models should be tested in independent prospective studies as well as randomized controlled trials.
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Bourgonje AR, Hu S, Spekhorst LM, Zhernakova DV, Vich Vila A, Li Y, Voskuil MD, van Berkel LA, Bley Folly B, Charrout M, Mahfouz A, Reinders MJT, van Heck JIP, Joosten LAB, Visschedijk MC, van Dullemen HM, Faber KN, Samsom JN, Festen EAM, Dijkstra G, Weersma RK. The Effect of Phenotype and Genotype on the Plasma Proteome in Patients with Inflammatory Bowel Disease. J Crohns Colitis 2021; 16:414-429. [PMID: 34491321 PMCID: PMC8919819 DOI: 10.1093/ecco-jcc/jjab157] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/03/2023]
Abstract
BACKGROUND AND AIMS Protein profiling in patients with inflammatory bowel diseases [IBD] for diagnostic and therapeutic purposes is underexplored. This study analysed the association between phenotype, genotype, and the plasma proteome in IBD. METHODS A total of 92 inflammation-related proteins were quantified in plasma of 1028 patients with IBD (567 Crohn's disease [CD]; 461 ulcerative colitis [UC]) and 148 healthy individuals to assess protein-phenotype associations. Corresponding whole-exome sequencing and global screening array data of 919 patients with IBD were included to analyse the effect of genetics on protein levels (protein quantitative trait loci [pQTL] analysis). Intestinal mucosal RNA sequencing and faecal metagenomic data were used for complementary analyses. RESULTS Thirty-two proteins were differentially abundant between IBD and healthy individuals, of which 22 proteins were independent of active inflammation; 69 proteins were associated with 15 demographic and clinical factors. Fibroblast growth factor-19 levels were decreased in CD patients with ileal disease or a history of ileocecal resection. Thirteen novel cis-pQTLs were identified and 10 replicated from previous studies. One trans-pQTL of the fucosyltransferase 2 [FUT2] gene [rs602662] and two independent cis-pQTLs of C-C motif chemokine 25 [CCL25] affected plasma CCL25 levels. Intestinal gene expression data revealed an overlapping cis-expression [e]QTL-variant [rs3745387] of the CCL25 gene. The FUT2 rs602662 trans-pQTL was associated with reduced abundances of faecal butyrate-producing bacteria. CONCLUSIONS This study shows that genotype and multiple disease phenotypes strongly associate with the plasma inflammatory proteome in IBD, and identifies disease-associated pathways that may help to improve disease management in the future.
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Affiliation(s)
| | | | | | - Daria V Zhernakova
- Department of Genetics, University Medical Center Groningen, Groningen, The Netherlands,Laboratory of Genomic Diversity, Center for Computer Technologies, ITMO University, St Petersburg, Russia
| | - Arnau Vich Vila
- Department of Gastroenterology and Hepatology, University Medical Center Groningen, Groningen, The Netherlands,Department of Genetics, University Medical Center Groningen, Groningen, The Netherlands
| | - Yanni Li
- Department of Gastroenterology and Hepatology, University Medical Center Groningen, Groningen, The Netherlands,Department of Genetics, University Medical Center Groningen, Groningen, The Netherlands
| | - Michiel D Voskuil
- Department of Gastroenterology and Hepatology, University Medical Center Groningen, Groningen, The Netherlands,Department of Genetics, University Medical Center Groningen, Groningen, The Netherlands
| | - Lisette A van Berkel
- Department of Pediatrics, Division of Gastroenterology, Erasmus University Medical Center, Rotterdam, The Netherlands
| | - Brenda Bley Folly
- Department of Pediatrics, Division of Gastroenterology, Erasmus University Medical Center, Rotterdam, The Netherlands
| | - Mohammed Charrout
- Delft Bioinformatics Lab, Delft University of Technology, Delft, The Netherlands,Leiden Computational Biology Center, Leiden University Medical Center, Leiden, The Netherlands
| | - Ahmed Mahfouz
- Delft Bioinformatics Lab, Delft University of Technology, Delft, The Netherlands,Leiden Computational Biology Center, Leiden University Medical Center, Leiden, The Netherlands,Department of Human Genetics, Leiden University Medical Center, Leiden, The Netherlands
| | - Marcel J T Reinders
- Delft Bioinformatics Lab, Delft University of Technology, Delft, The Netherlands,Leiden Computational Biology Center, Leiden University Medical Center, Leiden, The Netherlands
| | - Julia I P van Heck
- Department of Internal Medicine and Radboud Institute of Molecular Life Sciences, Radboud University Medical Center, Nijmegen, The Netherlands
| | - Leo A B Joosten
- Department of Internal Medicine and Radboud Institute of Molecular Life Sciences, Radboud University Medical Center, Nijmegen, The Netherlands
| | - Marijn C Visschedijk
- Department of Gastroenterology and Hepatology, University Medical Center Groningen, Groningen, The Netherlands
| | - Hendrik M van Dullemen
- Department of Gastroenterology and Hepatology, University Medical Center Groningen, Groningen, The Netherlands
| | - Klaas Nico Faber
- Department of Gastroenterology and Hepatology, University Medical Center Groningen, Groningen, The Netherlands
| | - Janneke N Samsom
- Department of Pediatrics, Division of Gastroenterology, Erasmus University Medical Center, Rotterdam, The Netherlands
| | - Eleonora A M Festen
- Department of Gastroenterology and Hepatology, University Medical Center Groningen, Groningen, The Netherlands,Department of Genetics, University Medical Center Groningen, Groningen, The Netherlands
| | - Gerard Dijkstra
- Department of Gastroenterology and Hepatology, University Medical Center Groningen, Groningen, The Netherlands
| | - Rinse K Weersma
- Corresponding author: Prof. Rinse K. Weersma, MD, PhD, Department of Gastroenterology and Hepatology, University of Groningen and University Medical Center Groningen, P.O. Box 30.001, 9700 RB Groningen, The Netherlands. Tel.: +31 50 361 26 20; fax: +31 50 361 93 06;
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Javaid A, Shahab O, Adorno W, Fernandes P, May E, Syed S. Machine Learning Predictive Outcomes Modeling in Inflammatory Bowel Diseases. Inflamm Bowel Dis 2021; 28:819-829. [PMID: 34417815 PMCID: PMC9165557 DOI: 10.1093/ibd/izab187] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/19/2021] [Indexed: 12/14/2022]
Abstract
There is a rising interest in use of big data approaches to personalize treatment of inflammatory bowel diseases (IBDs) and to predict and prevent outcomes such as disease flares and therapeutic nonresponse. Machine learning (ML) provides an avenue to identify and quantify features across vast quantities of data to produce novel insights in disease management. In this review, we cover current approaches in ML-driven predictive outcomes modeling for IBD and relate how advances in other fields of medicine may be applied to improve future IBD predictive models. Numerous studies have incorporated clinical, laboratory, or omics data to predict significant outcomes in IBD, including hospitalizations, outpatient corticosteroid use, biologic response, and refractory disease after colectomy, among others, with considerable health care dollars saved as a result. Encouraging results in other fields of medicine support efforts to use ML image analysis-including analysis of histopathology, endoscopy, and radiology-to further advance outcome predictions in IBD. Though obstacles to clinical implementation include technical barriers, bias within data sets, and incongruence between limited data sets preventing model validation in larger cohorts, ML-predictive analytics have the potential to transform the clinical management of IBD. Future directions include the development of models that synthesize all aforementioned approaches to produce more robust predictive metrics.
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Affiliation(s)
- Aamir Javaid
- Division of Pediatric Gastroenterology and Hepatology, Department of Pediatrics, University of Virginia, Charlottesville, VA, USA
| | - Omer Shahab
- Division of Gastroenterology and Hepatology, Department of Medicine, Virginia Commonwealth University, Richmond, VA, USA
| | - William Adorno
- School of Data Science, University of Virginia, Charlottesville, VA, USA
| | - Philip Fernandes
- Division of Pediatric Gastroenterology and Hepatology, Department of Pediatrics, University of Virginia, Charlottesville, VA, USA
| | - Eve May
- Division of Gastroenterology and Hepatology, Department of Pediatrics, Children’s National Hospital, Washington, DC, USA
| | - Sana Syed
- Division of Pediatric Gastroenterology and Hepatology, Department of Pediatrics, University of Virginia, Charlottesville, VA, USA,School of Data Science, University of Virginia, Charlottesville, VA, USA,Address Correspondence to: Sana Syed, MD, MSCR, MSDS, Division of Pediatric Gastroenterology and Hepatology, Department of Pediatrics, University of Virginia, 409 Lane Rd, Room 2035B, Charlottesville, VA, 22908, USA ()
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Athreya AP, Lazaridis KN. Discovery and Opportunities With Integrative Analytics Using Multiple-Omics Data. Hepatology 2021; 74:1081-1087. [PMID: 33539039 PMCID: PMC8333231 DOI: 10.1002/hep.31733] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/17/2020] [Revised: 12/18/2020] [Accepted: 01/15/2021] [Indexed: 12/26/2022]
Affiliation(s)
- Arjun P Athreya
- Department of Molecular Pharmacology and Experimental TherapeuticsMayo ClinicRochesterMN
| | - Konstantinos N Lazaridis
- Center for Individualized MedicineCollege of MedicineMayo ClinicRochesterMN.,Division of Gastroenterology and HepatologyCollege of MedicineMayo ClinicRochesterMN
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Bolte LA, Vich Vila A, Imhann F, Collij V, Gacesa R, Peters V, Wijmenga C, Kurilshikov A, Campmans-Kuijpers MJE, Fu J, Dijkstra G, Zhernakova A, Weersma RK. Long-term dietary patterns are associated with pro-inflammatory and anti-inflammatory features of the gut microbiome. Gut 2021; 70:1287-1298. [PMID: 33811041 PMCID: PMC8223641 DOI: 10.1136/gutjnl-2020-322670] [Citation(s) in RCA: 336] [Impact Index Per Article: 84.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/28/2020] [Revised: 02/13/2021] [Accepted: 02/15/2021] [Indexed: 12/20/2022]
Abstract
OBJECTIVE The microbiome directly affects the balance of pro-inflammatory and anti-inflammatory responses in the gut. As microbes thrive on dietary substrates, the question arises whether we can nourish an anti-inflammatory gut ecosystem. We aim to unravel interactions between diet, gut microbiota and their functional ability to induce intestinal inflammation. DESIGN We investigated the relation between 173 dietary factors and the microbiome of 1425 individuals spanning four cohorts: Crohn's disease, ulcerative colitis, irritable bowel syndrome and the general population. Shotgun metagenomic sequencing was performed to profile gut microbial composition and function. Dietary intake was assessed through food frequency questionnaires. We performed unsupervised clustering to identify dietary patterns and microbial clusters. Associations between diet and microbial features were explored per cohort, followed by a meta-analysis and heterogeneity estimation. RESULTS We identified 38 associations between dietary patterns and microbial clusters. Moreover, 61 individual foods and nutrients were associated with 61 species and 249 metabolic pathways in the meta-analysis across healthy individuals and patients with IBS, Crohn's disease and UC (false discovery rate<0.05). Processed foods and animal-derived foods were consistently associated with higher abundances of Firmicutes, Ruminococcus species of the Blautia genus and endotoxin synthesis pathways. The opposite was found for plant foods and fish, which were positively associated with short-chain fatty acid-producing commensals and pathways of nutrient metabolism. CONCLUSION We identified dietary patterns that consistently correlate with groups of bacteria with shared functional roles in both, health and disease. Moreover, specific foods and nutrients were associated with species known to infer mucosal protection and anti-inflammatory effects. We propose microbial mechanisms through which the diet affects inflammatory responses in the gut as a rationale for future intervention studies.
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Affiliation(s)
- Laura A Bolte
- Department of Gastroenterology and Hepatology, University of Groningen and University Medical Centre Groningen, Groningen, The Netherlands
- Department of Genetics, University of Groningen and University Medical Centre Groningen, Groningen, The Netherlands
| | - Arnau Vich Vila
- Department of Gastroenterology and Hepatology, University of Groningen and University Medical Centre Groningen, Groningen, The Netherlands
- Department of Genetics, University of Groningen and University Medical Centre Groningen, Groningen, The Netherlands
| | - Floris Imhann
- Department of Gastroenterology and Hepatology, University of Groningen and University Medical Centre Groningen, Groningen, The Netherlands
- Department of Genetics, University of Groningen and University Medical Centre Groningen, Groningen, The Netherlands
| | - Valerie Collij
- Department of Gastroenterology and Hepatology, University of Groningen and University Medical Centre Groningen, Groningen, The Netherlands
- Department of Genetics, University of Groningen and University Medical Centre Groningen, Groningen, The Netherlands
| | - Ranko Gacesa
- Department of Gastroenterology and Hepatology, University of Groningen and University Medical Centre Groningen, Groningen, The Netherlands
- Department of Genetics, University of Groningen and University Medical Centre Groningen, Groningen, The Netherlands
| | - Vera Peters
- Department of Gastroenterology and Hepatology, University of Groningen and University Medical Centre Groningen, Groningen, The Netherlands
| | - Cisca Wijmenga
- Department of Genetics, University of Groningen and University Medical Centre Groningen, Groningen, The Netherlands
| | - Alexander Kurilshikov
- Department of Genetics, University of Groningen and University Medical Centre Groningen, Groningen, The Netherlands
| | - Marjo J E Campmans-Kuijpers
- Department of Gastroenterology and Hepatology, University of Groningen and University Medical Centre Groningen, Groningen, The Netherlands
| | - Jingyuan Fu
- Department of Genetics, University of Groningen and University Medical Centre Groningen, Groningen, The Netherlands
- Department of Pediatrics, University of Groningen and University Medical Centre Groningen, Groningen, The Netherlands
| | - Gerard Dijkstra
- Department of Gastroenterology and Hepatology, University of Groningen and University Medical Centre Groningen, Groningen, The Netherlands
| | - Alexandra Zhernakova
- Department of Genetics, University of Groningen and University Medical Centre Groningen, Groningen, The Netherlands
| | - Rinse K Weersma
- Department of Gastroenterology and Hepatology, University of Groningen and University Medical Centre Groningen, Groningen, The Netherlands
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Bangma A, Voskuil MD, Weersma RK. TNFα-Antagonist Use and Mucosal Inflammation Are Associated with Increased Intestinal Expression of SARS-CoV-2 Host Protease TMPRSS2 in Patients with Inflammatory Bowel Disease. Gastroenterology 2021; 160:2621-2622. [PMID: 32553760 PMCID: PMC7834454 DOI: 10.1053/j.gastro.2020.05.091] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/23/2020] [Accepted: 05/28/2020] [Indexed: 12/11/2022]
Affiliation(s)
| | | | - Rinse K Weersma
- Department of Gastroenterology and Hepatology, University of Groningen, University Medical Centre Groningen, Groningen, the Netherlands
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Abstract
BACKGROUND Systems biology is a rapidly advancing field of science that allows us to look into disease mechanisms, patient diagnosis and stratification, and drug development in a completely new light. It is based on the utilization of unbiased computational systems free of the traditional experimental approaches based on personal choices of what is important and what select experiments should be performed to obtain the expected results. METHODS Systems biology can be applied to inflammatory bowel disease (IBD) by learning basic concepts of omes and omics and how omics-derived "big data" can be integrated to discover the biological networks underlying highly complex diseases like IBD. Once these biological networks (interactomes) are identified, then the molecules controlling the disease network can be singled out and specific blockers developed. RESULTS The field of systems biology in IBD is just emerging, and there is still limited information on how to best utilize its power to advance our understanding of Crohn disease and ulcerative colitis to develop novel therapeutic strategies. Few centers have embraced systems biology in IBD, but the creation of international consortia and large biobanks will make biosamples available to basic and clinical IBD investigators for further research studies. CONCLUSIONS The implementation of systems biology is indispensable and unavoidable, and the patient and medical communities will both benefit immensely from what it will offer in the near future.
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Affiliation(s)
- Claudio Fiocchi
- Department of Inflammation & Immunity, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio, USA.,Department of Gastroenterology, Hepatology and Nutrition, Digestive Disease and Surgery Institute, Cleveland Clinic, Cleveland, Ohio, USA
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49
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van der Sloot KWJ, Geertsema P, Rijkmans HC, Voskuil MD, van Dullemen HM, Visschedijk MC, Festen EAM, Weersma RK, Alizadeh BZ, Dijkstra G. Environmental factors associated with biological use and surgery in inflammatory bowel disease. J Gastroenterol Hepatol 2021; 36:1022-1034. [PMID: 32839987 PMCID: PMC8247347 DOI: 10.1111/jgh.15223] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/29/2020] [Revised: 06/30/2020] [Accepted: 08/16/2020] [Indexed: 12/23/2022]
Abstract
BACKGROUND AND AIM While major efforts were made studying the complex etiology of inflammatory bowel disease (IBD) including environmental factors, less is known about underlying causes leading to the heterogeneous and highly variable course of disease. As cigarette smoking cessation is the best-known environmental factor with beneficial effect in Crohn's disease (CD), more exposome factors are likely involved. Further insights into the role of the exposome in heterogeneity of disease might not only further knowledge of underlying pathways, but also allow for better risk stratification. METHODS Seven hundred twenty-eight IBD patients completed the validated Groningen IBD Environmental Questionnaire, collecting exposome data for 93 exposome factors. Associations with disease course, that is, for need for surgery or biological therapy, were evaluated using univariate and multivariate-adjusted logistic regression modeling. RESULTS No significant associations were seen after Bonferroni correction. However, 11 novel exposome factors were identified with P < 0.05. Two factors were associated with course of CD and ulcerative colitis (UC): beer (CD OR0.3/UC OR0.3) and cannabis (0.5/2.2). While in CD, carpet flooring (0.5) was associated with biological use, and four factors were associated with surgery: working shifts (1.8), appendectomy (2.4), frequent tooth brushing (2.8), and large household size (0.1). For UC, migrants more often required biologicals (10.2). Childhood underweight (3.4), amphetamine use (6.2), and cocaine use (4.8) were associated with surgery. Five factors were replicated. CONCLUSIONS We identified 16 environmental factors nominally associated with biological use and surgery in established IBD. These new insights form an important stepping stone to guide research on biological pathways involved, risk stratification, tailor-made interventions, and preventive strategies in IBD.
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Affiliation(s)
- Kimberley W J van der Sloot
- Department of Gastroenterology and Hepatology, University of GroningenUniversity Medical Center GroningenGroningenThe Netherlands,Department of Epidemiology, University of GroningenUniversity Medical Center GroningenGroningenThe Netherlands
| | - Paul Geertsema
- Department of Gastroenterology and Hepatology, University of GroningenUniversity Medical Center GroningenGroningenThe Netherlands
| | - Hanneke C Rijkmans
- Department of Gastroenterology and Hepatology, University of GroningenUniversity Medical Center GroningenGroningenThe Netherlands
| | - Michiel D Voskuil
- Department of Epidemiology, University of GroningenUniversity Medical Center GroningenGroningenThe Netherlands
| | - Hendrik M van Dullemen
- Department of Gastroenterology and Hepatology, University of GroningenUniversity Medical Center GroningenGroningenThe Netherlands
| | - Marijn C Visschedijk
- Department of Gastroenterology and Hepatology, University of GroningenUniversity Medical Center GroningenGroningenThe Netherlands
| | - Eleonora A M Festen
- Department of Gastroenterology and Hepatology, University of GroningenUniversity Medical Center GroningenGroningenThe Netherlands
| | - Rinse K Weersma
- Department of Gastroenterology and Hepatology, University of GroningenUniversity Medical Center GroningenGroningenThe Netherlands
| | - Behrooz Z Alizadeh
- Department of Epidemiology, University of GroningenUniversity Medical Center GroningenGroningenThe Netherlands
| | - Gerard Dijkstra
- Department of Gastroenterology and Hepatology, University of GroningenUniversity Medical Center GroningenGroningenThe Netherlands
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50
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Tarris G, de Rougemont A, Charkaoui M, Michiels C, Martin L, Belliot G. Enteric Viruses and Inflammatory Bowel Disease. Viruses 2021; 13:v13010104. [PMID: 33451106 PMCID: PMC7828589 DOI: 10.3390/v13010104] [Citation(s) in RCA: 48] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2020] [Revised: 01/04/2021] [Accepted: 01/08/2021] [Indexed: 12/16/2022] Open
Abstract
Inflammatory bowel diseases (IBD), including ulcerative colitis (UC) and Crohn’s disease (CD), is a multifactorial disease in which dietary, genetic, immunological, and microbial factors are at play. The role of enteric viruses in IBD remains only partially explored. To date, epidemiological studies have not fully described the role of enteric viruses in inflammatory flare-ups, especially that of human noroviruses and rotaviruses, which are the main causative agents of viral gastroenteritis. Genome-wide association studies have demonstrated the association between IBD, polymorphisms of the FUT2 and FUT3 genes (which drive the synthesis of histo-blood group antigens), and ligands for norovirus and rotavirus in the intestine. The role of autophagy in defensin-deficient Paneth cells and the perturbations of cytokine secretion in T-helper 1 and T-helper 17 inflammatory pathways following enteric virus infections have been demonstrated as well. Enteric virus interactions with commensal bacteria could play a significant role in the modulation of enteric virus infections in IBD. Based on the currently incomplete knowledge of the complex phenomena underlying IBD pathogenesis, future studies using multi-sampling and data integration combined with new techniques such as human intestinal enteroids could help to decipher the role of enteric viruses in IBD.
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Affiliation(s)
- Georges Tarris
- Department of Pathology, University Hospital of Dijon, F 21000 Dijon, France; (G.T.); (L.M.)
- National Reference Centre for Gastroenteritis Viruses, Laboratory of Virology, University Hospital of Dijon, F 21000 Dijon, France;
| | - Alexis de Rougemont
- National Reference Centre for Gastroenteritis Viruses, Laboratory of Virology, University Hospital of Dijon, F 21000 Dijon, France;
| | - Maëva Charkaoui
- Department of Hepatogastroenterology, University Hospital of Dijon, F 21000 Dijon, France; (M.C.); (C.M.)
| | - Christophe Michiels
- Department of Hepatogastroenterology, University Hospital of Dijon, F 21000 Dijon, France; (M.C.); (C.M.)
| | - Laurent Martin
- Department of Pathology, University Hospital of Dijon, F 21000 Dijon, France; (G.T.); (L.M.)
| | - Gaël Belliot
- National Reference Centre for Gastroenteritis Viruses, Laboratory of Virology, University Hospital of Dijon, F 21000 Dijon, France;
- Correspondence: ; Tel.: +33-380-293-171; Fax: +33-380-293-280
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