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Huang W, Zhu W, Lin Y, Chan FKL, Xu Z, Ng SC. Roseburia hominis improves host metabolism in diet-induced obesity. Gut Microbes 2025; 17:2467193. [PMID: 39976263 PMCID: PMC11845086 DOI: 10.1080/19490976.2025.2467193] [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: 07/24/2024] [Revised: 02/05/2025] [Accepted: 02/10/2025] [Indexed: 02/21/2025] Open
Abstract
Next-generation live biotherapeutics are promising to aid the treatment of obesity and metabolic diseases. Here, we reported a novel anti-obesity probiotic candidate, Roseburia hominis, that was depleted in stool samples of obese subjects compared with lean controls, and its abundance was negatively correlated with body mass index and serum triglycerides. Supplementation of R. hominis prevented body weight gain and disorders of glucose and lipid metabolism, prevented fatty liver, inhibited white adipose tissue expansion and brown adipose tissue whitening in mice fed with high-fat diet, and boosted the abundance of lean-related species. The effects of R. hominis could be partially attributed to the production of nicotinamide riboside and upregulation of the Sirtuin1/mTOR signaling pathway. These results indicated that R. hominis is a promising candidate for the development of next-generation live biotherapeutics for the prevention of obesity and metabolic diseases.
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Affiliation(s)
- Wenli Huang
- Microbiota I-Center (MagIC), Hong Kong, China
- Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Hong Kong, China
- Institute of Digestive Disease, State Key Laboratory of Digestive Diseases, Li Ka Shing Institute of Health Science, The Chinese University of Hong Kong, Hong Kong, China
| | - Wenyi Zhu
- Microbiota I-Center (MagIC), Hong Kong, China
- Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Hong Kong, China
- Institute of Digestive Disease, State Key Laboratory of Digestive Diseases, Li Ka Shing Institute of Health Science, The Chinese University of Hong Kong, Hong Kong, China
| | - Yu Lin
- Microbiota I-Center (MagIC), Hong Kong, China
- Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Hong Kong, China
- Institute of Digestive Disease, State Key Laboratory of Digestive Diseases, Li Ka Shing Institute of Health Science, The Chinese University of Hong Kong, Hong Kong, China
| | - Francis K. L. Chan
- Microbiota I-Center (MagIC), Hong Kong, China
- Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Hong Kong, China
- Center for Gut Microbiota Research, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong, China
| | - Zhilu Xu
- Microbiota I-Center (MagIC), Hong Kong, China
- Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Hong Kong, China
- Institute of Digestive Disease, State Key Laboratory of Digestive Diseases, Li Ka Shing Institute of Health Science, The Chinese University of Hong Kong, Hong Kong, China
| | - Siew C. Ng
- Microbiota I-Center (MagIC), Hong Kong, China
- Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Hong Kong, China
- Institute of Digestive Disease, State Key Laboratory of Digestive Diseases, Li Ka Shing Institute of Health Science, The Chinese University of Hong Kong, Hong Kong, China
- Center for Gut Microbiota Research, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong, China
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Hetta HF, Ahmed R, Ramadan YN, Fathy H, Khorshid M, Mabrouk MM, Hashem M. Gut virome: New key players in the pathogenesis of inflammatory bowel disease. World J Methodol 2025; 15:92592. [DOI: 10.5662/wjm.v15.i2.92592] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/30/2024] [Revised: 05/28/2024] [Accepted: 07/23/2024] [Indexed: 11/27/2024] Open
Abstract
Inflammatory bowel disease (IBD) is a chronic inflammatory illness of the intestine. While the mechanism underlying the pathogenesis of IBD is not fully understood, it is believed that a complex combination of host immunological response, environmental exposure, particularly the gut microbiota, and genetic susceptibility represents the major determinants. The gut virome is a group of viruses found in great frequency in the gastrointestinal tract of humans. The gut virome varies greatly among individuals and is influenced by factors including lifestyle, diet, health and disease conditions, geography, and urbanization. The majority of research has focused on the significance of gut bacteria in the progression of IBD, although viral populations represent an important component of the microbiome. We conducted this review to highlight the viral communities in the gut and their expected roles in the etiopathogenesis of IBD regarding published research to date.
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Affiliation(s)
- Helal F Hetta
- Department of Medical Microbiology and Immunology, Faculty of Medicine, Assiut University, Assiut 71515, Egypt
- Division of Microbiology, Immunology and Biotechnology, Faculty of pharmacy, University of Tabuk, Tabuk 71491, Saudi Arabia
| | - Rehab Ahmed
- Division of Microbiology, Immunology and Biotechnology, Department of Natural Products and Alternative Medicine, Faculty of Pharmacy, University of Tabuk, Tabuk 71491, Saudi Arabia
| | - Yasmin N Ramadan
- Department of Medical Microbiology and Immunology, Faculty of Medicine, Assiut University, Assiut 71515, Egypt
| | - Hayam Fathy
- Department of Internal Medicine, Division Hepatogastroenterology, Assiut University, Assiut 71515, Egypt
| | - Mohammed Khorshid
- Department of Clinical Research, Egyptian Developers of Gastroenterology and Endoscopy Foundation, Cairo 11936, Egypt
| | - Mohamed M Mabrouk
- Department of Internal Medicine, Faculty of Medicine. Tanta University, Tanta 31527, Egypt
| | - Mai Hashem
- Department of Tropical Medicine, Gastroenterology and Hepatology, Assiut University Hospital, Assiut 71515, Egypt
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3
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Avery EG, Haag LM, McParland V, Kedziora SM, Zigra GJ, Valdes DS, Kirchner M, Popp O, Geisberger S, Nonn O, Karlsen TV, N’Diaye G, Yarritu A, Bartolomaeus H, Bartolomaeus TUP, Tagiyeva NA, Wimmer MI, Haase N, Zhang YD, Wilhelm A, Grütz G, Tenstad O, Wilck N, Forslund SK, Klopfleisch R, Kühl AA, Atreya R, Kempa S, Mertins P, Siegmund B, Wiig H, Müller DN. Intestinal interstitial fluid isolation provides novel insight into the human host-microbiome interface. Cardiovasc Res 2025; 121:803-816. [PMID: 39804196 PMCID: PMC12101326 DOI: 10.1093/cvr/cvae267] [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: 07/26/2024] [Revised: 10/13/2024] [Accepted: 11/12/2024] [Indexed: 03/28/2025] Open
Abstract
AIMS The gastrointestinal (GI) tract is composed of distinct sub-regions, which exhibit segment-specific differences in microbial colonization and (patho)physiological characteristics. Gut microbes can be collectively considered as an active endocrine organ. Microbes produce metabolites, which can be taken up by the host and can actively communicate with the immune cells in the gut lamina propria with consequences for cardiovascular health. Variation in bacterial load and composition along the GI tract may influence the mucosal microenvironment and thus be reflected its interstitial fluid (IF). Characterization of the segment-specific microenvironment is challenging and largely unexplored because of lack of available tools. METHODS AND RESULTS Here, we developed methods, namely tissue centrifugation and elution, to collect IF from the mucosa of different intestinal segments. These methods were first validated in rats and mice, and the tissue elution method was subsequently translated for use in humans. These new methods allowed us to quantify microbiota-derived metabolites, mucosa-derived cytokines, and proteins at their site-of-action. Quantification of short-chain fatty acids showed enrichment in the colonic IF. Metabolite and cytokine analyses revealed differential abundances within segments, often significantly increased compared to plasma, and proteomics revealed that proteins annotated to the extracellular phase were site-specifically identifiable in IF. Lipopolysaccharide injections in rats showed significantly higher ileal IL-1β levels in IF compared to the systemic circulation, suggesting the potential of local as well as systemic effect. CONCLUSION Collection of IF from defined segments and the direct measurement of mediators at the site-of-action in rodents and humans bypasses the limitations of indirect analysis of faecal samples or serum, providing direct insight into this understudied compartment.
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Affiliation(s)
- Ellen G Avery
- Max Delbrück Center for Molecular Medicine in the Helmholtz Association, Berlin, Germany
- Experimental and Clinical Research Center, a Cooperation of Charité-Universitätsmedizin Berlin and Max Delbrück Center for Molecular Medicine, Berlin, Germany
- Charité—Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany
- DZHK (German Centre for Cardiovascular Research), Partner Site Berlin, Berlin, Germany
- Department of Biology, Chemistry, and Pharmacy, Freie Universität Berlin, Berlin, Germany
| | - Lea-Maxie Haag
- Department for Medicine (Gastroenterology, Infectious Diseases, Rheumatology) Charité—Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin and Berlin Institute of Health, Campus Benjamin Franklin, Berlin, Germany
- Berlin Institute of Health at Charité—Universitätsmedizin Berlin, BIH Biomedical Innovation Academy, BIH Charité Clinician Scientist Program, Charitéplatz 1, Berlin 10117, Germany
| | - Victoria McParland
- Max Delbrück Center for Molecular Medicine in the Helmholtz Association, Berlin, Germany
- Experimental and Clinical Research Center, a Cooperation of Charité-Universitätsmedizin Berlin and Max Delbrück Center for Molecular Medicine, Berlin, Germany
- Charité—Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany
| | - Sarah M Kedziora
- Max Delbrück Center for Molecular Medicine in the Helmholtz Association, Berlin, Germany
- Experimental and Clinical Research Center, a Cooperation of Charité-Universitätsmedizin Berlin and Max Delbrück Center for Molecular Medicine, Berlin, Germany
- Charité—Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany
- DZHK (German Centre for Cardiovascular Research), Partner Site Berlin, Berlin, Germany
| | - Gabriel J Zigra
- Department for Medicine (Gastroenterology, Infectious Diseases, Rheumatology) Charité—Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin and Berlin Institute of Health, Campus Benjamin Franklin, Berlin, Germany
| | - Daniela S Valdes
- Max Delbrück Center for Molecular Medicine in the Helmholtz Association, Berlin, Germany
- Experimental and Clinical Research Center, a Cooperation of Charité-Universitätsmedizin Berlin and Max Delbrück Center for Molecular Medicine, Berlin, Germany
- Charité—Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany
- DZHK (German Centre for Cardiovascular Research), Partner Site Berlin, Berlin, Germany
| | - Marieluise Kirchner
- Core Unit Proteomics, Berlin Institute of Health at Charite—Universitätsmedizin Berlin, Berlin, Germany
- Proteomics Platform, Max Delbrück Center for Molecular Medicine, Berlin, Germany
| | - Oliver Popp
- Proteomics Platform, Max Delbrück Center for Molecular Medicine, Berlin, Germany
| | - Sabrina Geisberger
- Max Delbrück Center for Molecular Medicine in the Helmholtz Association, Berlin, Germany
- Integrative Proteomics and Metabolomics Platform, Max-Delbrück-Center for Molecular Medicine in the Helmholtz Association, Berlin Institute for Medical Systems Biology (BIMSB), Berlin, Germany
| | - Olivia Nonn
- Max Delbrück Center for Molecular Medicine in the Helmholtz Association, Berlin, Germany
- Experimental and Clinical Research Center, a Cooperation of Charité-Universitätsmedizin Berlin and Max Delbrück Center for Molecular Medicine, Berlin, Germany
- Charité—Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany
- DZHK (German Centre for Cardiovascular Research), Partner Site Berlin, Berlin, Germany
| | - Tine V Karlsen
- Department of Biomedicine, University of Bergen, Jonas Lies vei 91, Bergen N-5009, Norway
| | - Gabriele N’Diaye
- Experimental and Clinical Research Center, a Cooperation of Charité-Universitätsmedizin Berlin and Max Delbrück Center for Molecular Medicine, Berlin, Germany
- Charité—Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany
| | - Alex Yarritu
- Max Delbrück Center for Molecular Medicine in the Helmholtz Association, Berlin, Germany
- Experimental and Clinical Research Center, a Cooperation of Charité-Universitätsmedizin Berlin and Max Delbrück Center for Molecular Medicine, Berlin, Germany
- Charité—Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany
- DZHK (German Centre for Cardiovascular Research), Partner Site Berlin, Berlin, Germany
| | - Hendrik Bartolomaeus
- Max Delbrück Center for Molecular Medicine in the Helmholtz Association, Berlin, Germany
- Experimental and Clinical Research Center, a Cooperation of Charité-Universitätsmedizin Berlin and Max Delbrück Center for Molecular Medicine, Berlin, Germany
- Charité—Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany
- DZHK (German Centre for Cardiovascular Research), Partner Site Berlin, Berlin, Germany
| | - Theda U P Bartolomaeus
- Max Delbrück Center for Molecular Medicine in the Helmholtz Association, Berlin, Germany
- Experimental and Clinical Research Center, a Cooperation of Charité-Universitätsmedizin Berlin and Max Delbrück Center for Molecular Medicine, Berlin, Germany
- Charité—Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany
- DZHK (German Centre for Cardiovascular Research), Partner Site Berlin, Berlin, Germany
| | - Nurana A Tagiyeva
- Max Delbrück Center for Molecular Medicine in the Helmholtz Association, Berlin, Germany
- Experimental and Clinical Research Center, a Cooperation of Charité-Universitätsmedizin Berlin and Max Delbrück Center for Molecular Medicine, Berlin, Germany
- Charité—Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany
- DZHK (German Centre for Cardiovascular Research), Partner Site Berlin, Berlin, Germany
| | - Moritz I Wimmer
- Max Delbrück Center for Molecular Medicine in the Helmholtz Association, Berlin, Germany
- Experimental and Clinical Research Center, a Cooperation of Charité-Universitätsmedizin Berlin and Max Delbrück Center for Molecular Medicine, Berlin, Germany
- Charité—Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany
- Faculty of Medicine, Universität Tübingen, Tübingen, Germany
| | - Nadine Haase
- Max Delbrück Center for Molecular Medicine in the Helmholtz Association, Berlin, Germany
- Experimental and Clinical Research Center, a Cooperation of Charité-Universitätsmedizin Berlin and Max Delbrück Center for Molecular Medicine, Berlin, Germany
- Charité—Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany
- DZHK (German Centre for Cardiovascular Research), Partner Site Berlin, Berlin, Germany
| | - Yiming D Zhang
- Max Delbrück Center for Molecular Medicine in the Helmholtz Association, Berlin, Germany
- Integrative Proteomics and Metabolomics Platform, Max-Delbrück-Center for Molecular Medicine in the Helmholtz Association, Berlin Institute for Medical Systems Biology (BIMSB), Berlin, Germany
| | - Andreas Wilhelm
- CheckImmune GmbH, BerlinBioCube, Robert-Rössle Str. 10, Berlin 13125, Germany
| | - Gerald Grütz
- CheckImmune GmbH, BerlinBioCube, Robert-Rössle Str. 10, Berlin 13125, Germany
| | - Olav Tenstad
- Department of Biomedicine, University of Bergen, Jonas Lies vei 91, Bergen N-5009, Norway
| | - Nicola Wilck
- Max Delbrück Center for Molecular Medicine in the Helmholtz Association, Berlin, Germany
- Experimental and Clinical Research Center, a Cooperation of Charité-Universitätsmedizin Berlin and Max Delbrück Center for Molecular Medicine, Berlin, Germany
- Charité—Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany
- DZHK (German Centre for Cardiovascular Research), Partner Site Berlin, Berlin, Germany
- Medizinische Klinik mit Schwerpunkt Nephrologie und Internistische Intensivmedizin, Charité—Universitätsmedizin Berlin, Berlin 13353, Germany
| | - Sofia K Forslund
- Max Delbrück Center for Molecular Medicine in the Helmholtz Association, Berlin, Germany
- Experimental and Clinical Research Center, a Cooperation of Charité-Universitätsmedizin Berlin and Max Delbrück Center for Molecular Medicine, Berlin, Germany
- Charité—Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany
- DZHK (German Centre for Cardiovascular Research), Partner Site Berlin, Berlin, Germany
| | - Robert Klopfleisch
- Department of Veterinary Medicine, Freie Universität Berlin, Berlin, Germany
| | - Anja A Kühl
- Department for Medicine (Gastroenterology, Infectious Diseases, Rheumatology) Charité—Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin and Berlin Institute of Health, Campus Benjamin Franklin, Berlin, Germany
- Charité-Universitätsmedizin Berlin, Corporate Member of Freie Univeristät Berlin and Humboldt Universität zu Berlin, iPATH, Berlin, Berlin, Germany
| | - Raja Atreya
- Department of Medicine 1, Friedrich-Alexander University, Erlangen, Germany
| | - Stefan Kempa
- Max Delbrück Center for Molecular Medicine in the Helmholtz Association, Berlin, Germany
- Integrative Proteomics and Metabolomics Platform, Max-Delbrück-Center for Molecular Medicine in the Helmholtz Association, Berlin Institute for Medical Systems Biology (BIMSB), Berlin, Germany
| | - Philipp Mertins
- Core Unit Proteomics, Berlin Institute of Health at Charite—Universitätsmedizin Berlin, Berlin, Germany
- Proteomics Platform, Max Delbrück Center for Molecular Medicine, Berlin, Germany
| | - Britta Siegmund
- Department for Medicine (Gastroenterology, Infectious Diseases, Rheumatology) Charité—Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin and Berlin Institute of Health, Campus Benjamin Franklin, Berlin, Germany
| | - Helge Wiig
- Department of Biomedicine, University of Bergen, Jonas Lies vei 91, Bergen N-5009, Norway
| | - Dominik N Müller
- Max Delbrück Center for Molecular Medicine in the Helmholtz Association, Berlin, Germany
- Experimental and Clinical Research Center, a Cooperation of Charité-Universitätsmedizin Berlin and Max Delbrück Center for Molecular Medicine, Berlin, Germany
- Charité—Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany
- DZHK (German Centre for Cardiovascular Research), Partner Site Berlin, Berlin, Germany
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Sen I, Trzaskalski NA, Hsiao YT, Liu PP, Shimizu I, Derumeaux GA. Aging at the Crossroads of Organ Interactions: Implications for the Heart. Circ Res 2025; 136:1286-1305. [PMID: 40403108 DOI: 10.1161/circresaha.125.325637] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/12/2025] [Revised: 04/18/2025] [Accepted: 04/19/2025] [Indexed: 05/24/2025]
Abstract
Aging processes underlie common chronic cardiometabolic diseases such as heart failure and diabetes. Cross-organ/tissue interactions can accelerate aging through cellular senescence, tissue wasting, accelerated atherosclerosis, increased vascular stiffness, and reduction in blood flow, leading to organ remodeling and premature failure. This interorgan/tissue crosstalk can accelerate aging-related dysfunction through inflammation, senescence-associated secretome, and metabolic and mitochondrial changes resulting in increased oxidative stress, microvascular dysfunction, cellular reprogramming, and tissue fibrosis. This may also underscore the rising incidence and co-occurrence of multiorgan dysfunction in cardiometabolic aging in the population. Examples include interactions between the heart and the lungs, kidneys, liver, muscles, and brain, among others. However, this phenomenon can also present new translational opportunities for identifying diagnostic biomarkers to define early risks of multiorgan dysfunction, gain mechanistic insights, and help to design precision-directed therapeutic interventions. Indeed, this opens new opportunities for therapeutic development in targeting multiple organs simultaneously to disrupt the crosstalk-driven process of mutual disease acceleration. New therapeutic targets could provide synergistic benefits across multiple organ systems in the same at-risk patient. Ultimately, these approaches may together slow the aging process itself throughout the body. In the future, with patient-centered multisystem coordinated approaches, we can initiate a new paradigm of multiorgan early risk prediction and tailored intervention. With emerging tools including artificial intelligence-assisted risk profiling and novel preventive strategies (eg, RNA-based therapeutics), we may be able to mitigate multiorgan cardiometabolic dysfunction much earlier and, perhaps, even slow the aging process itself.
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Affiliation(s)
- Ilke Sen
- Department of Physiology, INSERM U955 (Institut national de la santé et de la recherche médicale, Unité 955), Assistance Publique-Hôpitaux de Paris (AP-HP), Henri Mondor Hospital, Fédération Hospitalo-Universitaire (FHU SENCODE), Ecole Universitaire de Recherche LIVE (EUR LIVE), Université Paris-Est Créteil, France (I. Sen, G.A.D.)
| | - Natasha A Trzaskalski
- University of Ottawa Heart Institute, Brain-Heart Interconnectome, University of Ottawa, Ontario, Canada (N.A.T., P.P.L.)
| | - Yung-Ting Hsiao
- Department of Cardiovascular Aging, National Cerebral and Cardiovascular Center Research Institute, Osaka, Japan (Y.-T.H., I. Shimizu)
| | - Peter P Liu
- University of Ottawa Heart Institute, Brain-Heart Interconnectome, University of Ottawa, Ontario, Canada (N.A.T., P.P.L.)
| | - Ippei Shimizu
- Department of Cardiovascular Aging, National Cerebral and Cardiovascular Center Research Institute, Osaka, Japan (Y.-T.H., I. Shimizu)
- Department of Cardiovascular Medicine, National Cerebral and Cardiovascular Center, Osaka, Japan (I. Shimizu)
| | - Geneviève A Derumeaux
- Department of Physiology, INSERM U955 (Institut national de la santé et de la recherche médicale, Unité 955), Assistance Publique-Hôpitaux de Paris (AP-HP), Henri Mondor Hospital, Fédération Hospitalo-Universitaire (FHU SENCODE), Ecole Universitaire de Recherche LIVE (EUR LIVE), Université Paris-Est Créteil, France (I. Sen, G.A.D.)
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Snelson M, Muralitharan RR, Liu CF, Markó L, Forslund SK, Marques FZ, Tang WHW. Gut-Heart Axis: The Role of Gut Microbiota and Metabolites in Heart Failure. Circ Res 2025; 136:1382-1406. [PMID: 40403109 PMCID: PMC12101525 DOI: 10.1161/circresaha.125.325516] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/31/2025] [Revised: 04/03/2025] [Accepted: 04/06/2025] [Indexed: 05/24/2025]
Abstract
Heart failure is a global health issue with significant mortality and morbidity. There is increasing evidence that alterations in the gastrointestinal microbiome, gut epithelial permeability, and gastrointestinal disorders contribute to heart failure progression through various pathways, including systemic inflammation, metabolic dysregulation, and modulation of cardiac function. Moreover, several medications used to treat heart failure directly impact the microbiome. The relationship between the gastrointestinal tract and the heart is bidirectional, termed the gut-heart axis. It is increasingly understood that diet-derived microbial metabolites are key mechanistic drivers of the gut-heart axis. This includes, for example, trimethylamine N-oxide and short-chain fatty acids. This review discusses current insights into the interplay between heart failure, its associated risk factors, and the gut microbiome, focusing on key metabolic pathways, the role of dietary interventions, and the potential for gut-targeted therapies. Understanding these complex interactions could pave the way for novel strategies to mitigate heart failure progression and improve patient outcomes.
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Affiliation(s)
- Matthew Snelson
- Hypertension Research Laboratory, Department of Pharmacology, Biomedical Discovery Institute, Faculty of Medicine, Nursing and Health Sciences, Monash University, Melbourne, Australia
- Victorian Heart Institute, Monash University, Melbourne, Australia
| | - Rikeish R. Muralitharan
- Hypertension Research Laboratory, Department of Pharmacology, Biomedical Discovery Institute, Faculty of Medicine, Nursing and Health Sciences, Monash University, Melbourne, Australia
- Victorian Heart Institute, Monash University, Melbourne, Australia
| | - Chia-Feng Liu
- Center for Microbiome and Human Health, Department of Cardiovascular and Metabolic Sciences, Lerner Research Institute, Cleveland Clinic, Cleveland OH, USA
- Department of Cardiovascular Medicine, Heart Vascular and Thoracic Institute, Cleveland Clinic, Cleveland OH, USA
| | - Lajos Markó
- Charité – Universitätsmedizin Berlin, Germany
- Max Delbrück Center for Molecular Medicine, Berlin, Germany
- Experimental and Clinical Research Center ( ECRC), Berlin, Germany
| | - Sofia K. Forslund
- Charité – Universitätsmedizin Berlin, Germany
- Max Delbrück Center for Molecular Medicine, Berlin, Germany
- Experimental and Clinical Research Center ( ECRC), Berlin, Germany
- DZHK (German Centre for Cardiovascular Research), Berlin, Germany
| | - Francine Z. Marques
- Hypertension Research Laboratory, Department of Pharmacology, Biomedical Discovery Institute, Faculty of Medicine, Nursing and Health Sciences, Monash University, Melbourne, Australia
- Victorian Heart Institute, Monash University, Melbourne, Australia
- Baker Heart and Diabetes Institute, Melbourne, Australia
| | - W. H. Wilson Tang
- Center for Microbiome and Human Health, Department of Cardiovascular and Metabolic Sciences, Lerner Research Institute, Cleveland Clinic, Cleveland OH, USA
- Department of Cardiovascular Medicine, Heart Vascular and Thoracic Institute, Cleveland Clinic, Cleveland OH, USA
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6
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Bi X, Sun L, Yeo MTY, Seaw KM, Leow MKS. Integration of metabolomics and machine learning for precise management and prevention of cardiometabolic risk in Asians. Clin Nutr 2025; 50:146-153. [PMID: 40414052 DOI: 10.1016/j.clnu.2025.05.011] [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: 03/18/2025] [Revised: 04/29/2025] [Accepted: 05/15/2025] [Indexed: 05/27/2025]
Abstract
Rapid changes in dietary patterns have led to a rise in cardiometabolic diseases (CMDs) worldwide, highlighting the urgent need for effective dietary strategies to address the health issues. Compared to Caucasians, Asians are more susceptible to CMDs. Understanding the complex factors driving this increased susceptibility is essential for developing targeted interventions and preventive measures for Asian populations. Metabolomics plays a key role in identifying specific metabolic markers and pathways associated with CMDs, providing insights into disease mechanisms and helping to create individualized risk profiles. However, metabolomics faces several challenges, including difficulties in interpreting results across diverse ethnic groups, limitations in study design, variability in analytical platforms, and inconsistencies in data processing methods. Overcoming these challenges requires the adoption of advanced technologies, standardized approaches, and integration of multi-omics data to maximize the utility of metabolomics in clinical settings. As the volume and complexity of metabolomic data continue to increase, machine learning (ML) algorithms have become essential for effective data integration, interpretation, and knowledge extraction. Advanced ML techniques, such as deep learning and network analysis, can reveal hidden patterns, relationships, and metabolic pathways within large datasets, leading to deeper insights into biological systems and disease processes. By combining metabolomics and ML, we can facilitate early detection, enable personalized interventions, and support the development of targeted nutritional strategies, ultimately improving therapeutic outcomes and reducing the socioeconomic burden of CMDs in this region.
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Affiliation(s)
- Xinyan Bi
- Singapore Institute of Food and Biotechnology Innovation (SIFBI), Agency for Science, Technology and Research (A∗STAR), 31 Biopolis Way, Nanos, Singapore, 138669, Singapore.
| | - Lijuan Sun
- Institute for Human Development and Potential (IHDP), Agency for Science, Technology and Research (A∗STAR), Singapore
| | - Michelle Ting Yun Yeo
- Singapore Institute of Food and Biotechnology Innovation (SIFBI), Agency for Science, Technology and Research (A∗STAR), 31 Biopolis Way, Nanos, Singapore, 138669, Singapore
| | - Ker Ming Seaw
- Singapore Institute of Food and Biotechnology Innovation (SIFBI), Agency for Science, Technology and Research (A∗STAR), 31 Biopolis Way, Nanos, Singapore, 138669, Singapore
| | - Melvin Khee Shing Leow
- Singapore Institute of Food and Biotechnology Innovation (SIFBI), Agency for Science, Technology and Research (A∗STAR), 31 Biopolis Way, Nanos, Singapore, 138669, Singapore; Institute for Human Development and Potential (IHDP), Agency for Science, Technology and Research (A∗STAR), Singapore; Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore; Department of Endocrinology, Tan Tock Seng Hospital, Singapore; Human Potential Translational Research Programme (HPTRP), Yong Loo Lin School of Medicine, National University of Singapore (NUS), Singapore; Cardiovascular and Metabolic Program, Duke-NUS Medical School, Singapore
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7
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Yang F, Qu G, Wu Y, Zhong P, Chu Z, He Z, Wang Y, Tang Y, Sun S, Luo F. A novel peptide from yak ameliorates hypoxia-induced cardiac dysfunction via targeting gut microbiota and HIF-1α pathway. J Dairy Sci 2025:S0022-0302(25)00358-3. [PMID: 40383391 DOI: 10.3168/jds.2024-26058] [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: 11/22/2024] [Accepted: 04/28/2025] [Indexed: 05/20/2025]
Abstract
Due to the high altitude and low oxygen levels, individuals residing or traveling in high-altitude regions often experience hypoxic cardiac dysfunction, which significantly affects their overall well-being and quality of life. Our previous investigations showed that peptide from yak milk residue exhibits notable antioxidant, anti-inflammatory, and anti-apoptotic properties that may have a good regulatory effect on hypoxic cardiac dysfunction. In this study, our results suggest that oral administration of yak milk peptide T3 improves the cardiac dysfunction of mice by the hypoxia-inducible factor 1α (HIF-1α) pathway, and these results may be related to the regulation of T3 on the gut microbiota of mice. Additionally, oral administration T3 enhances the permeability of the intestinal barrier and reduces intestinal inflammation. Further analysis revealed that the genera Oscillospira, Clostridium, and Staphylococcus are associated with aspartate aminotransferase, lactate dehydrogenase, and reactive oxygen species levels in heart tissues, which could ameliorate hypoxia-induced myocardial injury in mice. In vitro cell models have also confirmed that T3 intervention can activate the HIF-1α pathway and inhibit myocardial inflammation and cardiomyocyte apoptosis. These findings suggest that T3 may be a potential candidate for developing functional foods to reduce hypoxia-induced cardiac dysfunction.
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Affiliation(s)
- Feiyan Yang
- National Engineering Laboratory for Deep Process of Rice and Byproducts, Hunan Key Laboratory of Grain-oil Deep Process and Quality Control, Hunan Key Laboratory of Forestry Edible Resources Safety and Processing, College of Food Science and Engineering, Central South University of Forestry and Technology, Changsha 410004, Hunan, China
| | - Guangfan Qu
- National Engineering Laboratory for Deep Process of Rice and Byproducts, Hunan Key Laboratory of Grain-oil Deep Process and Quality Control, Hunan Key Laboratory of Forestry Edible Resources Safety and Processing, College of Food Science and Engineering, Central South University of Forestry and Technology, Changsha 410004, Hunan, China
| | - Yuchi Wu
- National Engineering Laboratory for Deep Process of Rice and Byproducts, Hunan Key Laboratory of Grain-oil Deep Process and Quality Control, Hunan Key Laboratory of Forestry Edible Resources Safety and Processing, College of Food Science and Engineering, Central South University of Forestry and Technology, Changsha 410004, Hunan, China
| | - Pingsheng Zhong
- National Engineering Laboratory for Deep Process of Rice and Byproducts, Hunan Key Laboratory of Grain-oil Deep Process and Quality Control, Hunan Key Laboratory of Forestry Edible Resources Safety and Processing, College of Food Science and Engineering, Central South University of Forestry and Technology, Changsha 410004, Hunan, China
| | - Zhongxing Chu
- National Engineering Laboratory for Deep Process of Rice and Byproducts, Hunan Key Laboratory of Grain-oil Deep Process and Quality Control, Hunan Key Laboratory of Forestry Edible Resources Safety and Processing, College of Food Science and Engineering, Central South University of Forestry and Technology, Changsha 410004, Hunan, China
| | - Zeyu He
- National Engineering Laboratory for Deep Process of Rice and Byproducts, Hunan Key Laboratory of Grain-oil Deep Process and Quality Control, Hunan Key Laboratory of Forestry Edible Resources Safety and Processing, College of Food Science and Engineering, Central South University of Forestry and Technology, Changsha 410004, Hunan, China
| | - Yuyan Wang
- National Engineering Laboratory for Deep Process of Rice and Byproducts, Hunan Key Laboratory of Grain-oil Deep Process and Quality Control, Hunan Key Laboratory of Forestry Edible Resources Safety and Processing, College of Food Science and Engineering, Central South University of Forestry and Technology, Changsha 410004, Hunan, China
| | - Yiping Tang
- National Engineering Laboratory for Deep Process of Rice and Byproducts, Hunan Key Laboratory of Grain-oil Deep Process and Quality Control, Hunan Key Laboratory of Forestry Edible Resources Safety and Processing, College of Food Science and Engineering, Central South University of Forestry and Technology, Changsha 410004, Hunan, China
| | - Shuguo Sun
- National Engineering Laboratory for Deep Process of Rice and Byproducts, Hunan Key Laboratory of Grain-oil Deep Process and Quality Control, Hunan Key Laboratory of Forestry Edible Resources Safety and Processing, College of Food Science and Engineering, Central South University of Forestry and Technology, Changsha 410004, Hunan, China.
| | - Feijun Luo
- National Engineering Laboratory for Deep Process of Rice and Byproducts, Hunan Key Laboratory of Grain-oil Deep Process and Quality Control, Hunan Key Laboratory of Forestry Edible Resources Safety and Processing, College of Food Science and Engineering, Central South University of Forestry and Technology, Changsha 410004, Hunan, China.
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8
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Connan C, Fromentin S, Benallaoua M, Alvarez AS, Pons N, Quinquis B, Morabito C, Nazare JA, Borezée-Durant E, Le French Gut Consortium, Haimet F, Ehrlich SD, Valeille K, Cavezza A, Blottière H, Veiga P, Almeida M, Doré J, Benamouzig R. Associations Among Diet, Health, Lifestyle, and Gut Microbiota Composition in the General French Population: Protocol for the Le French Gut - Le Microbiote Français Study. JMIR Res Protoc 2025; 14:e64894. [PMID: 40358997 PMCID: PMC12117270 DOI: 10.2196/64894] [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] [Subscribe] [Scholar Register] [Received: 07/30/2024] [Revised: 01/28/2025] [Accepted: 03/31/2025] [Indexed: 05/15/2025] Open
Abstract
BACKGROUND Over the past 2 decades, the gut microbiota has emerged as a key player in human health, being involved in many different clinical contexts. Yet, many aspects of the relationship with its host are poorly documented. One obstacle is the substantial variability in wet-laboratory procedures and data processing implemented during gut microbiota studies, which poses a challenge of comparability and potential meta-analysis. OBJECTIVE The study protocol described here aimed to better understand the relationship between health, dietary habits, and the observed heterogeneity of gut microbiota composition in the general population. "Le French Gut - Le microbiote français" aimed to collect, sequence, and analyze 100,000 fecal samples from French residents using a high-quality shotgun metagenomic pipeline, complemented with comprehensive health, lifestyle, and dietary metadata. METHODS "Le French Gut - Le microbiote français" is a prospective, noninterventional French national study involving individuals, the creation of a biological collection (feces), and the exploitation of data from questionnaires and the National Health Data System (Système National des Données de Santé). This national study is open to all metropolitan French adult residents, excluding those who have undergone a colectomy or digestive stoma, or who have had a colonoscopy or taken antibiotics in the last 3 months. This is a home-based trial in which volunteers complete a questionnaire with insights about their health and habits, and in which stool samples are self-collected. Data analysis is structured into 6 work packages, each focusing on a specific aspect of the gut microbiome, including its composition and associations with lifestyle, quality of life, and health. RESULTS This paper outlines the study protocol, with recruitment having started in September 2022 and expected to continue until the end of December 2025. As of January 2025, a total of 20,000 participants have been enrolled. The first scientific publications based on the data analysis are expected by mid-2025. CONCLUSIONS "Le French Gut" aims to provide a reference database and new ecosystem tools for understanding the relationship between the gut microbiota, its host, and diet. We expect to be able to find new signatures or targets and promote the design of innovative preventive strategies, personalized nutrition, and precision medicine. TRIAL REGISTRATION ClinicalTrials.gov NCT05758961; https://clinicaltrials.gov/study/NCT05758961. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID) DERR1-10.2196/64894.
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Affiliation(s)
- Chloe Connan
- Université Paris-Saclay, INRAE, MetaGenoPolis (MGP), Jouy-en-Josas, France
| | | | - Mourad Benallaoua
- Department of Gastroenterology, Avicenne Hospital, Assistance Publique-Hôpitaux de Paris, Université de Paris, Bobigny, France
| | | | - Nicolas Pons
- Université Paris-Saclay, INRAE, MetaGenoPolis (MGP), Jouy-en-Josas, France
| | - Benoît Quinquis
- Université Paris-Saclay, INRAE, MetaGenoPolis (MGP), Jouy-en-Josas, France
| | - Christian Morabito
- Université Paris-Saclay, INRAE, MetaGenoPolis (MGP), Jouy-en-Josas, France
| | - Julie-Anne Nazare
- Univ-Lyon, CarMeN Laboratory, Inserm, Inrae, Université Claude Bernard Lyon-1, Lyon, France
| | - Elise Borezée-Durant
- Université Paris-Saclay, INRAE, MetaGenoPolis (MGP), Jouy-en-Josas, France
- Université Paris-Saclay, INRAE, AgroParisTech, Micalis Institute, Jouy-en-Josas, France
| | | | - Florence Haimet
- Université Paris-Saclay, INRAE, MetaGenoPolis (MGP), Jouy-en-Josas, France
- INRAE Mica division, Jouy-en-Josas, France
| | | | - Karine Valeille
- Université Paris-Saclay, INRAE, MetaGenoPolis (MGP), Jouy-en-Josas, France
| | - Alexandre Cavezza
- Université Paris-Saclay, INRAE, MetaGenoPolis (MGP), Jouy-en-Josas, France
| | - Hervé Blottière
- Université Paris-Saclay, INRAE, MetaGenoPolis (MGP), Jouy-en-Josas, France
- Nantes Université, INRAE, UMR 1280, PhAN, Nantes, France
| | - Patrick Veiga
- Université Paris-Saclay, INRAE, MetaGenoPolis (MGP), Jouy-en-Josas, France
- Université Paris-Saclay, INRAE, AgroParisTech, Micalis Institute, Jouy-en-Josas, France
| | - Mathieu Almeida
- Université Paris-Saclay, INRAE, MetaGenoPolis (MGP), Jouy-en-Josas, France
| | - Joël Doré
- Université Paris-Saclay, INRAE, MetaGenoPolis (MGP), Jouy-en-Josas, France
- Université Paris-Saclay, INRAE, AgroParisTech, Micalis Institute, Jouy-en-Josas, France
| | - Robert Benamouzig
- Department of Gastroenterology, Avicenne Hospital, Assistance Publique-Hôpitaux de Paris, Université de Paris, Bobigny, France
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9
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Saeedi Saravi SS, Pugin B, Constancias F, Shabanian K, Spalinger M, Thomas A, Le Gludic S, Shabanian T, Karsai G, Colucci M, Menni C, Attaye I, Zhang X, Allemann MS, Lee P, Visconti A, Falchi M, Alimonti A, Ruschitzka F, Paneni F, Beer JH. Gut microbiota-dependent increase in phenylacetic acid induces endothelial cell senescence during aging. NATURE AGING 2025:10.1038/s43587-025-00864-8. [PMID: 40355758 DOI: 10.1038/s43587-025-00864-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/15/2023] [Accepted: 04/02/2025] [Indexed: 05/15/2025]
Abstract
Endothelial cell senescence is a key driver of cardiovascular aging, yet little is known about the mechanisms by which it is induced in vivo. Here we show that the gut bacterial metabolite phenylacetic acid (PAA) and its byproduct, phenylacetylglutamine (PAGln), are elevated in aged humans and mice. Metagenomic analyses reveal an age-related increase in PAA-producing microbial pathways, positively linked to the bacterium Clostridium sp. ASF356 (Clos). We demonstrate that colonization of young mice with Clos increases blood PAA levels and induces endothelial senescence and angiogenic incompetence. Mechanistically, we find that PAA triggers senescence through mitochondrial H2O2 production, exacerbating the senescence-associated secretory phenotype. By contrast, we demonstrate that fecal acetate levels are reduced with age, compromising its function as a Sirt1-dependent senomorphic, regulating proinflammatory secretion and redox homeostasis. These findings define PAA as a mediator of gut-vascular crosstalk in aging and identify sodium acetate as a potential microbiome-based senotherapy to promote healthy aging.
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Affiliation(s)
- Seyed Soheil Saeedi Saravi
- Center for Translational and Experimental Cardiology, Department of Cardiology, University Hospital Zurich, University of Zurich, Schlieren, Switzerland.
- University Heart Center, Department of Cardiology, University Hospital Zurich, Zurich, Switzerland.
| | - Benoit Pugin
- Laboratory of Food Biotechnology, Institute of Food, Nutrition and Health, Department of Health Sciences and Technology, ETH Zurich, Zurich, Switzerland
| | - Florentin Constancias
- Laboratory of Food Biotechnology, Institute of Food, Nutrition and Health, Department of Health Sciences and Technology, ETH Zurich, Zurich, Switzerland
| | - Khatereh Shabanian
- Center for Translational and Experimental Cardiology, Department of Cardiology, University Hospital Zurich, University of Zurich, Schlieren, Switzerland
- University Heart Center, Department of Cardiology, University Hospital Zurich, Zurich, Switzerland
| | - Marianne Spalinger
- Department for Gastroenterology and Hepatology, University Hospital Zurich, University of Zurich, Zurich, Switzerland
| | - Aurélien Thomas
- Faculty Unit of Toxicology, University Center of Legal Medicine, Lausanne University Hospital and University of Lausanne, Lausanne, Switzerland
- Unit of Forensic Toxicology and Chemistry, University Center of Legal Medicine, Lausanne University Hospital and University of Lausanne, Geneva University Hospital and University of Geneva, Lausanne, Geneva, Switzerland
| | - Sylvain Le Gludic
- Faculty Unit of Toxicology, University Center of Legal Medicine, Lausanne University Hospital and University of Lausanne, Lausanne, Switzerland
- Unit of Forensic Toxicology and Chemistry, University Center of Legal Medicine, Lausanne University Hospital and University of Lausanne, Geneva University Hospital and University of Geneva, Lausanne, Geneva, Switzerland
| | - Taraneh Shabanian
- Center for Translational and Experimental Cardiology, Department of Cardiology, University Hospital Zurich, University of Zurich, Schlieren, Switzerland
- University Heart Center, Department of Cardiology, University Hospital Zurich, Zurich, Switzerland
| | - Gergely Karsai
- Institute of Clinical Chemistry, University Hospital Zurich, Schlieren, Switzerland
| | - Manuel Colucci
- Institute of Oncology Research (IOR), Bellinzona, Switzerland
- Università della Svizzera Italiana, Lugano, Switzerland
| | - Cristina Menni
- Department of Twin Research, King's College London, St Thomas' Hospital Campus, London, UK
- Department of Pathophysiology and Transplantation, Università Degli Studi di Milano, Milan, Italy
- Fondazione IRCCS Cà Granda Ospedale Maggiore Policlinico, Angelo Bianchi Bonomi Hemophilia and Thrombosis Center, Milan, Italy
| | - Ilias Attaye
- Department of Twin Research, King's College London, St Thomas' Hospital Campus, London, UK
- Amsterdam Cardiovascular Sciences, Diabetes & Metabolism, Amsterdam, Netherlands
| | - Xinyuan Zhang
- Department of Twin Research, King's College London, St Thomas' Hospital Campus, London, UK
| | - Meret Sarah Allemann
- Center for Molecular Cardiology, University of Zurich, Schlieren, Switzerland
- Department of Internal Medicine, Cantonal Hospital Baden, Baden, Switzerland
| | - Pratintip Lee
- Center for Molecular Cardiology, University of Zurich, Schlieren, Switzerland
- Department of Internal Medicine, Cantonal Hospital Baden, Baden, Switzerland
| | - Alessia Visconti
- Department of Twin Research, King's College London, St Thomas' Hospital Campus, London, UK
- Centre for Biostatistics, Epidemiology, and Public Health, Department of Clinial and Biological Sciences, University of Turin, Turin, Italy
| | - Mario Falchi
- Department of Twin Research, King's College London, St Thomas' Hospital Campus, London, UK
| | - Andrea Alimonti
- Institute of Oncology Research (IOR), Bellinzona, Switzerland
- Università della Svizzera Italiana, Lugano, Switzerland
- Department of Medicine, University of Padova, Padova, Italy
- Department of Health Sciences and Technology (D-HEST), ETH Zurich, Zurich, Switzerland
- Oncology Institute of Southern Switzerland, Ente Ospedaliero Cantonale, Bellinzona, Switzerland
| | - Frank Ruschitzka
- Center for Translational and Experimental Cardiology, Department of Cardiology, University Hospital Zurich, University of Zurich, Schlieren, Switzerland
- University Heart Center, Department of Cardiology, University Hospital Zurich, Zurich, Switzerland
| | - Francesco Paneni
- Center for Translational and Experimental Cardiology, Department of Cardiology, University Hospital Zurich, University of Zurich, Schlieren, Switzerland
- University Heart Center, Department of Cardiology, University Hospital Zurich, Zurich, Switzerland
| | - Jürg H Beer
- Center for Molecular Cardiology, University of Zurich, Schlieren, Switzerland.
- Department of Internal Medicine, Cantonal Hospital Baden, Baden, Switzerland.
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10
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Qi Z, Zhang W, Zhang P, Qu Y, Zhong H, Zhou L, Zhou W, Yang W, Xu H, Zhao X, Wu H, Qian J, Ge J. The gut microbiota-bile acid-TGR5 axis orchestrates platelet activation and atherothrombosis. NATURE CARDIOVASCULAR RESEARCH 2025; 4:584-601. [PMID: 40217125 DOI: 10.1038/s44161-025-00637-x] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/23/2024] [Accepted: 03/12/2025] [Indexed: 05/18/2025]
Abstract
Gut microbiota-derived bile acids are crucial in the pathogenesis and treatment of metabolic diseases. However, their impact on platelet activation and thrombosis in coronary artery disease (CAD) remains poorly understood. In this study, we observed reduced serum deoxycholic acid (DCA) in patients with CAD and an underrepresentation of Bacteroides vulgatus in the gut microbiota of patients with CAD, affecting DCA metabolism. We used Takeda G-protein-coupled receptor 5 (TGR5) inhibitors and TGR5 knockout mice to show that DCA inhibited agonist-induced platelet activation and thrombosis by interacting with the platelet TGR5. Oral gavage treatments with DCA, B. vulgatus and stool from healthy individuals suppressed platelet hyperreactivity and thrombosis in atherosclerotic ApoE-/- mice, reduced microvascular thrombosis and protected the heart from myocardial ischemia/reperfusion injury. Here we describe the role of the bile acid DCA in platelet activation and suggest that targeting the gut microbiota and/or altering bile acid metabolism may be beneficial to treat CAD-associated thrombosis.
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Affiliation(s)
- Zhiyong Qi
- Department of Cardiology, Zhongshan Hospital, Fudan University, Shanghai Institute of Cardiovascular Diseases, National Clinical Research Center for Interventional Medicine, Shanghai, China
| | - Wei Zhang
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Fudan University, Shanghai, China
| | - Peng Zhang
- Department of Cardiology, Zhongshan Hospital, Fudan University, Shanghai Institute of Cardiovascular Diseases, National Clinical Research Center for Interventional Medicine, Shanghai, China
| | - Yanan Qu
- Department of Cardiology, Zhongshan Hospital, Fudan University, Shanghai Institute of Cardiovascular Diseases, National Clinical Research Center for Interventional Medicine, Shanghai, China
| | - Haoxuan Zhong
- Department of Cardiology, Zhongshan Hospital, Fudan University, Shanghai Institute of Cardiovascular Diseases, National Clinical Research Center for Interventional Medicine, Shanghai, China
| | - Luning Zhou
- Department of Cardiology, Zhongshan Hospital, Fudan University, Shanghai Institute of Cardiovascular Diseases, National Clinical Research Center for Interventional Medicine, Shanghai, China
| | - Wenxuan Zhou
- Department of Cardiology, Zhongshan Hospital, Fudan University, Shanghai Institute of Cardiovascular Diseases, National Clinical Research Center for Interventional Medicine, Shanghai, China
| | - Wenlong Yang
- Department of Cardiology, Zhongshan Hospital, Fudan University, Shanghai Institute of Cardiovascular Diseases, National Clinical Research Center for Interventional Medicine, Shanghai, China
| | - Huajie Xu
- Department of Cardiology, Zhongshan Hospital, Fudan University, Shanghai Institute of Cardiovascular Diseases, National Clinical Research Center for Interventional Medicine, Shanghai, China
| | - Xin Zhao
- Department of Cardiology, Zhongshan Hospital, Fudan University, Shanghai Institute of Cardiovascular Diseases, National Clinical Research Center for Interventional Medicine, Shanghai, China
| | - Hongyi Wu
- Department of Cardiology, Zhongshan Hospital, Fudan University, Shanghai Institute of Cardiovascular Diseases, National Clinical Research Center for Interventional Medicine, Shanghai, China.
| | - Juying Qian
- Department of Cardiology, Zhongshan Hospital, Fudan University, Shanghai Institute of Cardiovascular Diseases, National Clinical Research Center for Interventional Medicine, Shanghai, China.
| | - Junbo Ge
- Department of Cardiology, Zhongshan Hospital, Fudan University, Shanghai Institute of Cardiovascular Diseases, National Clinical Research Center for Interventional Medicine, Shanghai, China.
- Institutes of Biomedical Sciences, Fudan University, Shanghai, China.
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11
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Wu H, Lv B, Zhi L, Shao Y, Liu X, Mitteregger M, Chakaroun R, Tremaroli V, Hazen SL, Wang R, Bergström G, Bäckhed F. Microbiome-metabolome dynamics associated with impaired glucose control and responses to lifestyle changes. Nat Med 2025:10.1038/s41591-025-03642-6. [PMID: 40200054 DOI: 10.1038/s41591-025-03642-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2024] [Accepted: 03/05/2025] [Indexed: 04/10/2025]
Abstract
Type 2 diabetes (T2D) is a complex disease shaped by genetic and environmental factors, including the gut microbiome. Recent research revealed pathophysiological heterogeneity and distinct subgroups in both T2D and prediabetes, prompting exploration of personalized risk factors. Using metabolomics in two Swedish cohorts (n = 1,167), we identified over 500 blood metabolites associated with impaired glucose control, with approximately one-third linked to an altered gut microbiome. Our findings identified metabolic disruptions in microbiome-metabolome dynamics as potential mediators of compromised glucose homeostasis, as illustrated by the potential interactions between Hominifimenecus microfluidus and Blautia wexlerae via hippurate. Short-term lifestyle changes, for example, diet and exercise, modulated microbiome-associated metabolites in a lifestyle-specific manner. This study suggests that the microbiome-metabolome axis is a modifiable target for T2D management, with optimal health benefits achievable through a combination of lifestyle modifications.
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Affiliation(s)
- Hao Wu
- Center for Obesity and Hernia Surgery, Department of General Surgery, Huashan Hospital, and State Key Laboratory of Genetic Engineering, Fudan Microbiome Center, Human Phenome Institute, Fudan University, Shanghai, China.
| | - Bomin Lv
- Center for Obesity and Hernia Surgery, Department of General Surgery, Huashan Hospital, and State Key Laboratory of Genetic Engineering, Fudan Microbiome Center, Human Phenome Institute, Fudan University, Shanghai, China
| | - Luqian Zhi
- Center for Obesity and Hernia Surgery, Department of General Surgery, Huashan Hospital, and State Key Laboratory of Genetic Engineering, Fudan Microbiome Center, Human Phenome Institute, Fudan University, Shanghai, China
| | - Yikai Shao
- Center for Obesity and Hernia Surgery, Department of General Surgery, Huashan Hospital, and State Key Laboratory of Genetic Engineering, Fudan Microbiome Center, Human Phenome Institute, Fudan University, Shanghai, China
| | - Xinyan Liu
- Center for Obesity and Hernia Surgery, Department of General Surgery, Huashan Hospital, and State Key Laboratory of Genetic Engineering, Fudan Microbiome Center, Human Phenome Institute, Fudan University, Shanghai, China
| | - Matthias Mitteregger
- The Wallenberg Laboratory, Department of Molecular and Clinical Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
| | - Rima Chakaroun
- The Wallenberg Laboratory, Department of Molecular and Clinical Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
- Medical Department III - Endocrinology, Nephrology, Rheumatology, University of Leipzig Medical Center, Leipzig, Germany
| | - Valentina Tremaroli
- The Wallenberg Laboratory, Department of Molecular and Clinical Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
| | - Stanley L Hazen
- Department of Cardiovascular & Metabolic Sciences, Lerner Research Institute, Cleveland, OH, USA
- Center for Microbiome and Human Health, Cleveland Clinic, Cleveland, OH, USA
- Department of Cardiovascular Medicine, Heart, Vascular and Thoracic Institute, Cleveland Clinic, Cleveland, OH, USA
| | - Ru Wang
- School of Kinesiology, Key Laboratory of Exercise and Health Sciences of Ministry of Education, Shanghai University of Sport, Shanghai, China
| | - Göran Bergström
- The Wallenberg Laboratory, Department of Molecular and Clinical Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
- Department of Clinical Physiology, Region Västra Götaland, Sahlgrenska University Hospital, Gothenburg, Sweden
| | - Fredrik Bäckhed
- The Wallenberg Laboratory, Department of Molecular and Clinical Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
- Department of Clinical Physiology, Region Västra Götaland, Sahlgrenska University Hospital, Gothenburg, Sweden.
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12
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Yao X, Hu J, Zhang X, Hu J. Causal relationships between hundreds of plasma metabolites and PTSD: a bidirectional mendelian randomization study. BMC Psychiatry 2025; 25:349. [PMID: 40200279 PMCID: PMC11980153 DOI: 10.1186/s12888-025-06796-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/20/2023] [Accepted: 03/31/2025] [Indexed: 04/10/2025] Open
Abstract
BACKGROUND Recent studies have indicated a connection between plasma metabolites and Post-traumatic stress disorder (PTSD). Nevertheless, the precise causal relationship remains unclear. METHODS We performed bidirectional Mendelian Randomization (MR) using two metabolite and two PTSD GWAS datasets to examine causal relationships between PTSD and 1009 plasma metabolites. Forward MR tested metabolite causally effects on PTSD, while reverse MR assessed PTSD causally effects on metabolites. Primary analysis employed the IVW method, supported by four supplementary methods. Four IVW results per direction were meta-analyzed to identify high-credibility metabolites. Venn diagrams intersected results from the four IVW analyses, and this intersection was further compared with meta-analysis findings to generate a second Venn diagram. Sensitivity analyses addressed horizontal pleiotropy for robust results. RESULTS After sensitivity analyses, a robust set of 775 metabolites in the forward MR analysis and a set of 566 ones in the reverse process were identified. The meta-analysis of IVW method results (four results between two metabolites GWAS and two PTSD GWAS) revealed that 58 metabolites were significantly associated with the risk of PTSD (P < 0.05) in the forward MR analysis, and 19 metabolites might exhibit significant changes in PTSD (P < 0.05) in the reverse progress. Further Venn diagram intersection analysis among those four IVW results unveiled 4 metabolites with promoting or inhibiting effects on PTSD (P < 0.05) and 1 metabolites with notably increased plasma levels in PTSD (P < 0.05). The subsequent Venn diagram intersection analysis of the meta-analysis outcomes and the initial Venn diagram results identified 3 metabolites. In the forward analysis, 5-hydroxy-2-methylpyridine sulfate (OR = 1.05, P = 0.004) and levulinoylcarnitine (OR = 1.08, P = 0.005) from the Xenobiotics pathway were significantly associated with an increased risk of PTSD. Additionally, cysteinylglycine from the Amino Acid pathway significantly reduced the risk of PTSD (OR = 0.918, 95%CI: 0.868-0.971, P = 0.003). In the reverse analysis, no significant changes in plasma metabolites at the genetic level were found to causally influence the development of PTSD. CONCLUSIONS Our findings provide potential biomarkers for predicting and preventing PTSD, as well as possible therapeutic targets for that. However, further research is needed to confirm the clear mechanism.
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Affiliation(s)
- Xinjie Yao
- Department of Gastroenterology, Shengjing Hospital of China Medical University, Shenyang, 110004, Liaoning, China
| | - Jinxin Hu
- Liaoning Key Laboratory of Research and Application of Animal Models for Environmental and Metabolic Diseases, Medical Research Center, Shengjing Hospital of China Medical University, Shenyang, 110004, Liaoning, China
| | - Ximeng Zhang
- Department of Dermatology, Shengjing Hospital of China Medical University, Shenyang, 110004, Liaoning, China.
| | - Jiapeng Hu
- Department of Pediatrics, Shengjing Hospital of China Medical University, Shenyang, 110004, Liaoning, China.
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13
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Sprenger HG, Mittenbühler MJ, Sun Y, Van Vranken JG, Schindler S, Jayaraj A, Khetarpal SA, Smythers AL, Vargas-Castillo A, Puszynska AM, Spinelli JB, Armani A, Kunchok T, Ryback B, Seo HS, Song K, Sebastian L, O'Young C, Braithwaite C, Dhe-Paganon S, Burger N, Mills EL, Gygi SP, Paulo JA, Arthanari H, Chouchani ET, Sabatini DM, Spiegelman BM. Ergothioneine controls mitochondrial function and exercise performance via direct activation of MPST. Cell Metab 2025; 37:857-869.e9. [PMID: 39965563 DOI: 10.1016/j.cmet.2025.01.024] [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: 04/05/2024] [Revised: 01/14/2025] [Accepted: 01/24/2025] [Indexed: 02/20/2025]
Abstract
Ergothioneine (EGT) is a diet-derived, atypical amino acid that accumulates to high levels in human tissues. Reduced EGT levels have been linked to age-related disorders, including neurodegenerative and cardiovascular diseases, while EGT supplementation is protective in a broad range of disease and aging models. Despite these promising data, the direct and physiologically relevant molecular target of EGT has remained elusive. Here, we use a systematic approach to identify how mitochondria remodel their metabolome in response to exercise training. From these data, we find that EGT accumulates in muscle mitochondria upon exercise training. Proteome-wide thermal stability studies identify 3-mercaptopyruvate sulfurtransferase (MPST) as a direct molecular target of EGT; EGT binds to and activates MPST, thereby boosting mitochondrial respiration and exercise training performance in mice. Together, these data identify the first physiologically relevant EGT target and establish the EGT-MPST axis as a molecular mechanism for regulating mitochondrial function and exercise performance.
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Affiliation(s)
- Hans-Georg Sprenger
- Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA, USA; Department of Cell Biology, Harvard Medical School, Boston, MA, USA; Whitehead Institute for Biomedical Research, Cambridge, MA, USA; Department of Biology, Massachusetts Institute of Technology, Cambridge, MA, USA.
| | - Melanie J Mittenbühler
- Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA, USA; Department of Cell Biology, Harvard Medical School, Boston, MA, USA
| | - Yizhi Sun
- Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA, USA; Department of Cell Biology, Harvard Medical School, Boston, MA, USA
| | | | - Sebastian Schindler
- Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA, USA; Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA, USA
| | - Abhilash Jayaraj
- Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA, USA; Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA, USA
| | - Sumeet A Khetarpal
- Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA, USA; Department of Cell Biology, Harvard Medical School, Boston, MA, USA
| | - Amanda L Smythers
- Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA, USA; Department of Cell Biology, Harvard Medical School, Boston, MA, USA
| | - Ariana Vargas-Castillo
- Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA, USA; Department of Cell Biology, Harvard Medical School, Boston, MA, USA
| | - Anna M Puszynska
- Whitehead Institute for Biomedical Research, Cambridge, MA, USA; Department of Biology, Massachusetts Institute of Technology, Cambridge, MA, USA
| | - Jessica B Spinelli
- Whitehead Institute for Biomedical Research, Cambridge, MA, USA; Department of Biology, Massachusetts Institute of Technology, Cambridge, MA, USA
| | - Andrea Armani
- Whitehead Institute for Biomedical Research, Cambridge, MA, USA; Department of Biology, Massachusetts Institute of Technology, Cambridge, MA, USA
| | - Tenzin Kunchok
- Whitehead Institute for Biomedical Research, Cambridge, MA, USA
| | - Birgitta Ryback
- Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA, USA
| | - Hyuk-Soo Seo
- Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA, USA; Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA, USA
| | - Kijun Song
- Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA, USA
| | - Luke Sebastian
- Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA, USA
| | - Coby O'Young
- Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA, USA
| | | | - Sirano Dhe-Paganon
- Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA, USA; Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA, USA
| | - Nils Burger
- Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA, USA; Department of Cell Biology, Harvard Medical School, Boston, MA, USA
| | - Evanna L Mills
- Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA, USA; Department of Cell Biology, Harvard Medical School, Boston, MA, USA
| | - Steven P Gygi
- Department of Cell Biology, Harvard Medical School, Boston, MA, USA
| | - Joao A Paulo
- Department of Cell Biology, Harvard Medical School, Boston, MA, USA
| | - Haribabu Arthanari
- Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA, USA; Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA, USA
| | - Edward T Chouchani
- Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA, USA; Department of Cell Biology, Harvard Medical School, Boston, MA, USA
| | - David M Sabatini
- Institute of Organic Chemistry and Biochemistry, Prague, Czech Republic
| | - Bruce M Spiegelman
- Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA, USA; Department of Cell Biology, Harvard Medical School, Boston, MA, USA.
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Sharma V, Fernando V, Zheng X, Choi ES, Sweef O, Thomas V, Szpendyk J, Furuta S. Immunogenic shift of arginine metabolism triggers systemic metabolic and immunological reprogramming to suppress HER2 + breast cancer. Cancer Metab 2025; 13:15. [PMID: 40114277 PMCID: PMC11927160 DOI: 10.1186/s40170-025-00384-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2024] [Accepted: 03/07/2025] [Indexed: 03/22/2025] Open
Abstract
BACKGROUND Arginine metabolism in tumors is often shunted into the pathway producing pro-tumor and immune suppressive polyamines (PAs), while downmodulating the alternative nitric oxide (NO) synthesis pathway. Aiming to correct arginine metabolism in tumors, arginine deprivation therapy and inhibitors of PA synthesis have been developed. Despite some therapeutic advantages, these approaches have often yielded severe side effects, making it necessary to explore an alternative strategy. We previously reported that supplementing sepiapterin (SEP), the endogenous precursor of tetrahydrobiopterin (BH4, the essential NO synthase cofactor), could correct arginine metabolism in tumor cells and tumor-associated macrophages (TAMs) and induce their metabolic and phenotypic reprogramming. We saw that oral SEP treatment effectively suppressed the growth of HER2-positive mammary tumors in animals. SEP also has no reported dose-dependent toxicity in clinical trials for metabolic disorders. In the present study, we tested our hypothesis that a long-term administration of SEP to individuals susceptible to HER2-positive mammary tumor would protect them against tumor occurrence. METHODS We administered SEP, in comparison to control DMSO, to MMTV-neu mice susceptible to HER2-positive mammary tumors for 8 months starting at their pre-pubertal stage. We monitored tumor onsets to determine the rate of tumor-free survival. After 8 months of treatment, we grouped animals into DMSO treatment with or without tumors and SEP treatment with or without tumors. We analyzed blood metabolites, PBMC, and bone marrow of DMSO vs. SEP treated animals. RESULTS We found that a long-term use of SEP in animals susceptible to HER2-positive mammary tumors effectively suppressed tumor occurrence. These SEP-treated animals had undergone reprogramming of the systemic metabolism and immunity, elevating total T cell counts in the circulation and bone marrow. Given that bone marrow-resident T cells are mostly memory T cells, it is plausible that chronic SEP treatment promoted memory T cell formation, leading to a potent tumor prevention. CONCLUSIONS These findings suggest the possible roles of the SEP/BH4/NO axis in promoting memory T cell formation and its potential therapeutic utility for preventing HER2-positive breast cancer.
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Affiliation(s)
- Vandana Sharma
- Department of Cell & Cancer Biology, College of Medicine and Life Sciences, University of Toledo Health Science Campus, 3000 Arlington Ave., Toledo, OH, 43614, USA
- Department of Zoology and Physiology, University of Wyoming, 1000 E. University Ave, Biological Science Building, Room 319F, Laramie, WY, 82071, USA
| | - Veani Fernando
- Department of Cell & Cancer Biology, College of Medicine and Life Sciences, University of Toledo Health Science Campus, 3000 Arlington Ave., Toledo, OH, 43614, USA
- Division of Rheumatology, University of Colorado, Anschutz Medical Campus Barbara Davis Center, Mail Stop B115, 1775 Aurora Court, Aurora, CO, 80045, USA
| | - Xunzhen Zheng
- Department of Cell & Cancer Biology, College of Medicine and Life Sciences, University of Toledo Health Science Campus, 3000 Arlington Ave., Toledo, OH, 43614, USA
| | - Eun-Seok Choi
- MetroHealth Medical Center, Case Western Reserve University School of Medicine, Case Comprehensive Cancer Center, 2500 MetroHealth Drive, Cleveland, OH, 44109, USA
| | - Osama Sweef
- MetroHealth Medical Center, Case Western Reserve University School of Medicine, Case Comprehensive Cancer Center, 2500 MetroHealth Drive, Cleveland, OH, 44109, USA
| | - Venetia Thomas
- MetroHealth Medical Center, Case Western Reserve University School of Medicine, Case Comprehensive Cancer Center, 2500 MetroHealth Drive, Cleveland, OH, 44109, USA
| | - Justin Szpendyk
- MetroHealth Medical Center, Case Western Reserve University School of Medicine, Case Comprehensive Cancer Center, 2500 MetroHealth Drive, Cleveland, OH, 44109, USA
| | - Saori Furuta
- Department of Cell & Cancer Biology, College of Medicine and Life Sciences, University of Toledo Health Science Campus, 3000 Arlington Ave., Toledo, OH, 43614, USA.
- MetroHealth Medical Center, Case Western Reserve University School of Medicine, Case Comprehensive Cancer Center, 2500 MetroHealth Drive, Cleveland, OH, 44109, USA.
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15
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Guggeis MA, Harris DM, Welz L, Rosenstiel P, Aden K. Microbiota-derived metabolites in inflammatory bowel disease. Semin Immunopathol 2025; 47:19. [PMID: 40032666 PMCID: PMC11876236 DOI: 10.1007/s00281-025-01046-9] [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: 10/02/2024] [Accepted: 01/25/2025] [Indexed: 03/05/2025]
Abstract
Understanding the role of the gut microbiota in the pathogenesis of inflammatory bowel diseases (IBD) has been an area of intense research over the past decades. Patients with IBD exhibit alterations in their microbial composition compared to healthy controls. However, studies focusing solely on taxonomic analyses have struggled to deliver replicable findings across cohorts regarding which microbial species drive the distinct patterns in IBD. The focus of research has therefore shifted to studying the functionality of gut microbes, especially by investigating their effector molecules involved in the immunomodulatory functions of the microbiota, namely metabolites. Metabolic profiles are altered in IBD, and several metabolites have been shown to play a causative role in shaping immune functions in animal models. Therefore, understanding the complex communication between the microbiota, metabolites, and the host bears great potential to unlock new biomarkers for diagnosis, disease course and therapy response as well as novel therapeutic options in the treatment of IBD. In this review, we primarily focus on promising classes of metabolites which are thought to exert beneficial effects and are generally decreased in IBD. Though results from human trials are promising, they have not so far provided a large-scale break-through in IBD-therapy improvement. We therefore propose tailored personalized supplementation of microbiota and metabolites based on multi-omics analysis which accounts for the individual microbial and metabolic profiles in IBD patients rather than one-size-fits-all approaches.
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Affiliation(s)
- Martina A Guggeis
- Institute of Clinical Molecular Biology, Kiel University and University Medical Center Schleswig-Holstein, Rosalind Franklin Straße 11, Campus Kiel, 24105, Kiel, Germany
- Department of Internal Medicine I, Kiel University and University Medical Center Schleswig-Holstein, Rosalind Franklin Straße 11, Campus Kiel, 24105, Kiel, Germany
| | - Danielle Mm Harris
- Institute of Clinical Molecular Biology, Kiel University and University Medical Center Schleswig-Holstein, Rosalind Franklin Straße 11, Campus Kiel, 24105, Kiel, Germany
- Department of Internal Medicine I, Kiel University and University Medical Center Schleswig-Holstein, Rosalind Franklin Straße 11, Campus Kiel, 24105, Kiel, Germany
- Division Nutriinformatics, Institute for Human Nutrition and Food Science, Kiel University, Kiel, Germany
| | - Lina Welz
- Institute of Clinical Molecular Biology, Kiel University and University Medical Center Schleswig-Holstein, Rosalind Franklin Straße 11, Campus Kiel, 24105, Kiel, Germany
- Department of Internal Medicine I, Kiel University and University Medical Center Schleswig-Holstein, Rosalind Franklin Straße 11, Campus Kiel, 24105, Kiel, Germany
| | - Philip Rosenstiel
- Institute of Clinical Molecular Biology, Kiel University and University Medical Center Schleswig-Holstein, Rosalind Franklin Straße 11, Campus Kiel, 24105, Kiel, Germany
| | - Konrad Aden
- Institute of Clinical Molecular Biology, Kiel University and University Medical Center Schleswig-Holstein, Rosalind Franklin Straße 11, Campus Kiel, 24105, Kiel, Germany.
- Department of Internal Medicine I, Kiel University and University Medical Center Schleswig-Holstein, Rosalind Franklin Straße 11, Campus Kiel, 24105, Kiel, Germany.
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16
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Diener C, Holscher HD, Filek K, Corbin KD, Moissl-Eichinger C, Gibbons SM. Metagenomic estimation of dietary intake from human stool. Nat Metab 2025; 7:617-630. [PMID: 39966520 PMCID: PMC11949708 DOI: 10.1038/s42255-025-01220-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/14/2024] [Accepted: 01/16/2025] [Indexed: 02/20/2025]
Abstract
Dietary intake is tightly coupled to gut microbiota composition, human metabolism and the incidence of virtually all major chronic diseases. Dietary and nutrient intake are usually assessed using self-reporting methods, including dietary questionnaires and food records, which suffer from reporting biases and require strong compliance from study participants. Here, we present Metagenomic Estimation of Dietary Intake (MEDI): a method for quantifying food-derived DNA in human faecal metagenomes. We show that DNA-containing food components can be reliably detected in stool-derived metagenomic data, even when present at low abundances (more than ten reads). We show how MEDI dietary intake profiles can be converted into detailed metabolic representations of nutrient intake. MEDI identifies the onset of solid food consumption in infants, shows significant agreement with food frequency questionnaire responses in an adult population and shows agreement with food and nutrient intake in two controlled-feeding studies. Finally, we identify specific dietary features associated with metabolic syndrome in a large clinical cohort without dietary records, providing a proof-of-concept for detailed tracking of individual-specific, health-relevant dietary patterns without the need for questionnaires.
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Affiliation(s)
- Christian Diener
- Diagnostic and Research Institute of Hygiene, Microbiology and Environmental Medicine, Medical University of Graz, Graz, Austria.
- Institute for Systems Biology, Seattle, WA, USA.
| | - Hannah D Holscher
- Department of Food Science and Human Nutrition, University of Illinois Urbana-Champaign, Urbana, IL, USA
| | - Klara Filek
- Diagnostic and Research Institute of Hygiene, Microbiology and Environmental Medicine, Medical University of Graz, Graz, Austria
| | - Karen D Corbin
- AdventHealth Translational Research Institute, Orlando, FL, USA
| | - Christine Moissl-Eichinger
- Diagnostic and Research Institute of Hygiene, Microbiology and Environmental Medicine, Medical University of Graz, Graz, Austria
- BioTechMed Graz, Graz, Austria
| | - Sean M Gibbons
- Institute for Systems Biology, Seattle, WA, USA.
- Department of Bioengineering, University of Washington, Seattle, WA, USA.
- Department of Genome Sciences, University of Washington, Seattle, WA, USA.
- eScience Institute, University of Washington, Seattle, WA, USA.
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17
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Dasinger JH, Abais-Battad JM, McCrorey MK, Van Beusecum JP. Recent advances on immunity and hypertension: the new cells on the kidney block. Am J Physiol Renal Physiol 2025; 328:F301-F315. [PMID: 39853324 DOI: 10.1152/ajprenal.00309.2024] [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: 10/30/2024] [Revised: 11/26/2024] [Accepted: 01/20/2025] [Indexed: 01/26/2025] Open
Abstract
Over the past 50 years, the contribution of the immune system has been identified in the development of hypertension and renal injury. Both human and experimental animal models of hypertension have demonstrated that innate and adaptive immune cells, along with their cytokines and chemokines, modulate blood pressure fluctuations and end organ renal damage. Numerous cell types of the innate immune system, specifically monocytes, macrophages, and dendritic cells, present antigenic peptides to T cells, promoting inflammation and the elevation of blood pressure. These T cells and other adaptive immune cells migrate to vascular and tubular cells of the kidney and promote end-organ fibrosis, damage, and ultimately hypertensive injury. Through the development of high-throughput screening, novel renal and immune cell subsets have been identified as possible contributors and regulators of renal injury and hypertension. In this review, we will consider classical immunological cells and their contribution to renal inflammation, and novel cell subsets, including renal stromal cells, that could potentially shed new light on renal injury and hypertension. Finally, we will discuss how interorgan inflammation contributes to the development of hypertension and hypertension-related multiorgan damage, and explore the clinical implications of the immunological components of renal injury and hypertension.
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Affiliation(s)
- John Henry Dasinger
- Department of Physiology, School of Medicine, Tulane University, New Orleans, Louisiana, United States
| | - Justine M Abais-Battad
- Department of Physiology, Medical College of Georgia, August University, Augusta, Georgia, United States
| | - Marice K McCrorey
- Division of Nephrology, Department of Medicine, Medical University of South Carolina, Charleston, South Carolina, United States
| | - Justin P Van Beusecum
- Division of Nephrology, Department of Medicine, Medical University of South Carolina, Charleston, South Carolina, United States
- Department of Research and Development, Ralph H. Johnson VA Healthcare System, Charleston, South Carolina, United States
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18
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Sakaguchi M, Miyai N, Zhang Y, Sakamoto Y, Terada K, Utsumi M, Takeshita T, Arita M. The gut microbiota genus Blautia is associated with skeletal muscle mass reduction in community-dwelling older Japanese adults: the Wakayama Study. Eur Geriatr Med 2025; 16:23-32. [PMID: 39661255 DOI: 10.1007/s41999-024-01109-4] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2024] [Accepted: 11/05/2024] [Indexed: 12/12/2024]
Abstract
PURPOSE This cross-sectional study examined the gut microbiota species associated with skeletal muscle mass reduction in a community-based sample of older Japanese adults. METHODS The study included 744 participants (320 men and 424 women) aged 65-89 years (mean age: 73 years) with no history of treatment for colorectal, chronic kidney, or liver diseases. Bioelectrical impedance analysis was performed to estimate the appendicular skeletal muscle mass (ASM) of each participant. The gut microbiota composition was assessed using next-generation sequencing targeting the V3-V4 regions of the prokaryotic 16S rRNA genes. A self-administered questionnaire was used to evaluate daily living habits, including food intake associated with maintaining the gut microbiota. RESULTS Among the participants, those with reduced muscle mass (defined as an ASM index of less than 4.4 kg/m2 for men and 3.7 kg/m2 for women) had significantly higher levels of the genus Blautia when compared with those with normal muscle mass (P = 0.009). Logistic regression analysis revealed that the association between the genus Blautia and skeletal muscle mass remained significant even after adjusting for multiple confounding factors (P = 0.012). Additionally, an increase in the genus Blautia was positively associated with excessive alcohol consumption (≥ 20 g/day, β = 0.125, P = 0.002) and negatively associated with regular yogurt intake (≥ 1 time/week, β = -0.101, P = 0.010), independent of other lifestyle and dietary factors. CONCLUSION Elevated levels of the genus Blautia were associated with reduced skeletal muscle mass in older Japanese adults, suggesting that improving the gut microbiota may be a potential approach to preserving muscle mass among this population.
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Affiliation(s)
- Masato Sakaguchi
- Graduate School of Health and Nursing Science, Wakayama Medical University, 580 Mikazura, P.O. Box 641-0011, Wakayama, Japan
- Department of Cardiology, Sumiya Rehabilitation Hospital, Wakayama, Japan
| | - Nobuyuki Miyai
- Graduate School of Health and Nursing Science, Wakayama Medical University, 580 Mikazura, P.O. Box 641-0011, Wakayama, Japan.
| | - Yan Zhang
- Graduate School of Health and Nursing Science, Wakayama Medical University, 580 Mikazura, P.O. Box 641-0011, Wakayama, Japan
| | - Yukiko Sakamoto
- Graduate School of Health and Nursing Science, Wakayama Medical University, 580 Mikazura, P.O. Box 641-0011, Wakayama, Japan
| | - Kazufumi Terada
- Faculty of Budo and Sport Studies, Tenri University, Nara, Japan
| | - Miyoko Utsumi
- Wakayama Faculty of Nersing, Tokyo Healthcare University, Wakayama, Japan
| | | | - Mikio Arita
- Department of Cardiology, Sumiya Rehabilitation Hospital, Wakayama, Japan
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19
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Suba JK, Keo LS, Sirich TL. Depletion by Hemodialysis of the Antioxidant Ergothioneine. KIDNEY360 2025; 6:265-271. [PMID: 39869777 PMCID: PMC11882260 DOI: 10.34067/kid.0000000645] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/30/2024] [Accepted: 11/08/2024] [Indexed: 01/29/2025]
Abstract
Key Points Hemodialysis may excessively remove valuable solutes. Ergothioneine, a potentially valuable antioxidant, is markedly depleted in the erythrocytes and plasma of people receiving hemodialysis. These findings motivate further investigation into the consequences of ergothioneine depletion in people with kidney disease. Background Hemodialysis may excessively remove valuable solutes. Untargeted metabolomics data from a prior study suggested that ergothioneine (Ergo) was depleted in the plasma of hemodialysis participants. Ergo is a dietary-derived solute with antioxidant properties. The presence of a highly specific Ergo uptake transporter suggests that it is valuable. Ergo levels are high in tissues susceptible to oxidative stress, particularly erythrocytes. We compared erythrocyte and plasma Ergo levels in participants receiving hemodialysis with those in participants with advanced CKD and participants without known kidney disease (controls). We further examined the extent to which indiscriminate removal by hemodialysis could contribute to Ergo depletion. Methods Liquid chromatography tandem mass spectrometry with stable isotope dilution was used to measure the erythrocyte and plasma levels of Ergo in 12 control, 12 CKD, and 11 hemodialysis participants. We also measured the urinary excretion of Ergo in control and participants with CKD and the dialytic removal of Ergo in hemodialysis participants. Results Erythrocyte Ergo levels were markedly reduced in CKD and hemodialysis participants. Erythrocyte levels in CKD participants were on average 24% of the levels in control participants and were even lower in hemodialysis participants, averaging 8% of control participants. Plasma Ergo levels were also reduced in CKD and hemodialysis participants, but to a lesser extent than the erythrocyte levels. Kidney tubular reabsorption of Ergo was avid. By contrast, hemodialysis cleared Ergo at a rate of 146±36 ml/min so that removal of Ergo by hemodialysis greatly exceeded the amount excreted in the urine in both CKD and control participants. Conclusions Ergo, a potentially valuable antioxidant, is severely depleted in people maintained on hemodialysis. Future studies are required to assess the consequences of Ergo depletion.
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Affiliation(s)
- Josef K Suba
- The Departments of Medicine, Veterans Affairs Palo Alto Healthcare System and Stanford University, Palo Alto, California
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20
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Ryan MJ, Raby E, Masuda R, Lodge S, Nitschke P, Maker GL, Wist J, Fear MW, Holmes E, Nicholson JK, Gray N, Whiley L, Wood FM. Clinical prediction of wound re-epithelisation outcomes in non-severe burn injury using the plasma lipidome. Burns 2025; 51:107282. [PMID: 39566342 DOI: 10.1016/j.burns.2024.10.003] [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: 08/11/2024] [Revised: 09/22/2024] [Accepted: 10/05/2024] [Indexed: 11/22/2024]
Abstract
Whilst wound repair in severe burns has received substantial research attention, non-severe burns (<20 % total body surface area) remain relatively understudied, despite causing considerable physiological impact and constituting most of the hospital admissions for burns. Early prediction of healing outcomes would decrease financial and patient burden, and aid in preventing long-term complications from poor wound healing. Lipids have been implicated in inflammation and tissue repair and may play essential roles in burn wound healing. In this study, plasma samples were collected from 20 non-severe burn patients over six weeks from admission, including surgery, and analysed by liquid chromatography-tandem mass spectrometry and nuclear magnetic resonance spectroscopy to identify 850 lipids and 112 lipoproteins. Orthogonal projections to latent structures-discriminant analysis was performed to identify changes associated with re-epithelialisation and delayed re-epithelisation. We demonstrated that the lipid and lipoprotein profiles at admission could predict re-epithelisation outcomes at two weeks post-surgery, and that these discriminatory profiles were maintained up to six weeks post-surgery. Inflammatory markers GlycB and C-reactive protein indicated divergent systemic responses to the burn injury at admission. Triacylglycerols, diacylglycerols and low-density lipoprotein subfractions were associated with re-epithelisation (p-value <0.02, Cliff's delta >0.7), whilst high-density lipoprotein subfractions, phosphatidylinositols, phosphatidylcholines, and phosphatidylserines were associated with delayed wound closure at two weeks post-surgery (p-value <0.01, Cliff's delta <-0.7). Further model validation will potentially lead to personalised intervention strategies to reduce the risk of chronic complications post-burn injury.
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Affiliation(s)
- Monique J Ryan
- Australian National Phenome Centre, Health Futures Institute, Harry Perkins Institute, Murdoch University, 5 Robin Warren Drive, Perth, WA 6150, Australia; Centre for Computational and Systems Medicine, Health Futures Institute, Harry Perkins Institute, Murdoch University, 5 Robin Warren Drive, Perth, WA 6150, Australia
| | - Edward Raby
- Burns Service of Western Australia, WA Department of Health, Perth, WA 6150, Australia; Department of Microbiology, PathWest Laboratory Medicine, Perth, WA 6009, Australia; Department of Infectious Diseases, Fiona Stanley Hospital, Perth, WA 6150, Australia
| | - Reika Masuda
- Australian National Phenome Centre, Health Futures Institute, Harry Perkins Institute, Murdoch University, 5 Robin Warren Drive, Perth, WA 6150, Australia
| | - Samantha Lodge
- Australian National Phenome Centre, Health Futures Institute, Harry Perkins Institute, Murdoch University, 5 Robin Warren Drive, Perth, WA 6150, Australia; Centre for Computational and Systems Medicine, Health Futures Institute, Harry Perkins Institute, Murdoch University, 5 Robin Warren Drive, Perth, WA 6150, Australia
| | - Philipp Nitschke
- Australian National Phenome Centre, Health Futures Institute, Harry Perkins Institute, Murdoch University, 5 Robin Warren Drive, Perth, WA 6150, Australia
| | - Garth L Maker
- Australian National Phenome Centre, Health Futures Institute, Harry Perkins Institute, Murdoch University, 5 Robin Warren Drive, Perth, WA 6150, Australia
| | - Julien Wist
- Australian National Phenome Centre, Health Futures Institute, Harry Perkins Institute, Murdoch University, 5 Robin Warren Drive, Perth, WA 6150, Australia; Centre for Computational and Systems Medicine, Health Futures Institute, Harry Perkins Institute, Murdoch University, 5 Robin Warren Drive, Perth, WA 6150, Australia; Chemistry Department, Universidad del Valle, Cali 76001, Colombia
| | - Mark W Fear
- Burn Injury Research Unit, School of Biomedical Sciences, University of Western Australia, Perth, WA 6009, Australia; Fiona Wood Foundation, Perth, WA 6150, Australia
| | - Elaine Holmes
- Centre for Computational and Systems Medicine, Health Futures Institute, Harry Perkins Institute, Murdoch University, 5 Robin Warren Drive, Perth, WA 6150, Australia; Department of Metabolism Digestion and Reproduction, Faculty of Medicine, Imperial College London, London SW7 2AZ, UK
| | - Jeremy K Nicholson
- Australian National Phenome Centre, Health Futures Institute, Harry Perkins Institute, Murdoch University, 5 Robin Warren Drive, Perth, WA 6150, Australia; Institute of Global Health Innovation, Imperial College London, London SW7 2AZ, UK
| | - Nicola Gray
- Australian National Phenome Centre, Health Futures Institute, Harry Perkins Institute, Murdoch University, 5 Robin Warren Drive, Perth, WA 6150, Australia; Centre for Computational and Systems Medicine, Health Futures Institute, Harry Perkins Institute, Murdoch University, 5 Robin Warren Drive, Perth, WA 6150, Australia
| | - Luke Whiley
- Australian National Phenome Centre, Health Futures Institute, Harry Perkins Institute, Murdoch University, 5 Robin Warren Drive, Perth, WA 6150, Australia; Centre for Computational and Systems Medicine, Health Futures Institute, Harry Perkins Institute, Murdoch University, 5 Robin Warren Drive, Perth, WA 6150, Australia.
| | - Fiona M Wood
- Burns Service of Western Australia, WA Department of Health, Perth, WA 6150, Australia; Burn Injury Research Unit, School of Biomedical Sciences, University of Western Australia, Perth, WA 6009, Australia; Fiona Wood Foundation, Perth, WA 6150, Australia.
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Giakomidi D, Ishola A, Nus M. Targeting gut microbiota to regulate the adaptive immune response in atherosclerosis. Front Cardiovasc Med 2025; 12:1502124. [PMID: 39957996 PMCID: PMC11825770 DOI: 10.3389/fcvm.2025.1502124] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2024] [Accepted: 01/20/2025] [Indexed: 02/18/2025] Open
Abstract
Atherosclerosis, the leading cause of death worldwide, is a chronic inflammatory disease leading to the accumulation of lipid-rich plaques in the intima of large and medium-sized arteries. Accumulating evidence indicates the important regulatory role of the adaptive immune system in atherosclerosis during all stages of the disease. The gut microbiome has also become a key regulator of atherosclerosis and immunomodulation. Whilst existing research extensively explores the impact of the microbiome on the innate immune system, only a handful of studies have explored the regulatory capacity of the microbiome on the adaptive immune system to modulate atherogenesis. Building on these concepts and the pitfalls on the gut microbiota and adaptive immune response interaction, this review explores potential strategies to therapeutically target the microbiome, including the use of prebiotics and vaccinations, which could influence the adaptive immune response and consequently plaque composition and development.
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Affiliation(s)
- Despina Giakomidi
- Cardiovascular Division, Department of Medicine, Heart and Lung Research Institute (HLRI), University of Cambridge, Cambridge, United Kingdom
- British Heart Foundation Centre of Research Excellence, University of Cambridge, Cambridge, United Kingdom
| | - Ayoola Ishola
- Cardiovascular Division, Department of Medicine, Heart and Lung Research Institute (HLRI), University of Cambridge, Cambridge, United Kingdom
| | - Meritxell Nus
- Cardiovascular Division, Department of Medicine, Heart and Lung Research Institute (HLRI), University of Cambridge, Cambridge, United Kingdom
- British Heart Foundation Centre of Research Excellence, University of Cambridge, Cambridge, United Kingdom
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22
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Toivonen E, Sikkinen J, Salonen A, Kärkkäinen O, Koistinen V, Klåvus A, Meuronen T, Heini T, Maltseva A, Niku M, Jääskeläinen T, Laivuori H. Metabolic profiles of meconium in preeclamptic and normotensive pregnancies. Metabolomics 2025; 21:21. [PMID: 39863780 PMCID: PMC11762436 DOI: 10.1007/s11306-025-02224-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/29/2024] [Accepted: 01/16/2025] [Indexed: 01/27/2025]
Abstract
INTRODUCTION Preeclampsia (PE) is a common vascular pregnancy disorder affecting maternal and fetal metabolism with severe immediate and long-term consequences in mothers and infants. During pregnancy, metabolites in the maternal circulation pass through the placenta to the fetus. Meconium, a first stool of the neonate, offers a view to maternal and fetoplacental unit metabolism and could add to knowledge on the effects of PE on the fetus and newborn. OBJECTIVES To compare meconium metabolome of infants from PE and normotensive pregnancies. METHODS A cohort of preeclamptic parturients and normotensive controls were recruited in Tampere University Hospital during 2019-2022. Meconium was sampled and its metabolome analyzed using liquid chromatography- mass spectrometry in 48 subjects in each group. RESULTS Differences in abundances of 1263 compounds, of which 19 could be annotated, were detected between the two groups. Several acylcarnitines, androsterone sulfate, three bile acids, amino acid derivatives (phenylacetylglutamine, epsilon-(gamma-glutamyl)lysine and N-(phenylacetyl)glutamic acid), as well as caffeine and paraxanthine were lower in the PE group compared to the control group. Urea and progesterone were higher in the PE group. CONCLUSION PE is associated with alterations in the meconium metabolome of infants. The differing abundances of several metabolites show alterations in the interaction between the fetoplacental unit and mother in PE, but whether they are a cause or an effect of the disorder remains to be further investigated.
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Affiliation(s)
- Elli Toivonen
- Center for Child, Adolescent and Maternal Health Research, Faculty of Medicine and Health Technology, Tampere University, Tampere, Finland.
- Department of Obstetrics and Gynecology, Tampere University Hospital, The Wellbeing Services County of Pirkanmaa, Tampere, Finland.
| | - Jutta Sikkinen
- Center for Child, Adolescent and Maternal Health Research, Faculty of Medicine and Health Technology, Tampere University, Tampere, Finland
| | - Anne Salonen
- Human Microbiome Research Program, Faculty of Medicine, University of Helsinki, Helsinki, Finland
| | - Olli Kärkkäinen
- Afekta Technologies Ltd., Kuopio, Finland
- School of Pharmacy, University of Eastern Finland, Kuopio, Finland
| | | | | | | | - Tuomas Heini
- Human Microbiome Research Program, Faculty of Medicine, University of Helsinki, Helsinki, Finland
| | - Arina Maltseva
- Department of Veterinary Biosciences, University of Helsinki, Helsinki, Finland
| | - Mikael Niku
- Department of Veterinary Biosciences, University of Helsinki, Helsinki, Finland
| | - Tiina Jääskeläinen
- Medical and Clinical Genetics, University of Helsinki and Helsinki University Hospital, Helsinki, Finland
- Department of Food and Nutrition, University of Helsinki, Helsinki, Finland
| | - Hannele Laivuori
- Center for Child, Adolescent and Maternal Health Research, Faculty of Medicine and Health Technology, Tampere University, Tampere, Finland
- Department of Obstetrics and Gynecology, Tampere University Hospital, The Wellbeing Services County of Pirkanmaa, Tampere, Finland
- Medical and Clinical Genetics, University of Helsinki and Helsinki University Hospital, Helsinki, Finland
- Institute for Molecular Medicine Finland, Helsinki Institute of Life Science, Helsinki, Finland
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23
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Ismail HM, Perera D, Mandal R, DiMeglio LA, Evans-Molina C, Hannon T, Petrosino J, Javornik Cregeen S, Schmidt NW. Gut Microbial Changes Associated With Obesity in Youth With Type 1 Diabetes. J Clin Endocrinol Metab 2025; 110:364-373. [PMID: 39078977 PMCID: PMC11747672 DOI: 10.1210/clinem/dgae529] [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: 01/17/2024] [Revised: 07/11/2024] [Accepted: 07/29/2024] [Indexed: 08/07/2024]
Abstract
CONTEXT Obesity is prevalent in type 1 diabetes (T1D) and is problematic with higher risk for diabetes complications. It is unknown to what extent gut microbiome changes are associated with obesity and T1D. OBJECTIVE This work aimed to describe the gut microbiome and microbial metabolite changes associated with obesity in T1D. We hypothesized statistically significant gut microbial and metabolite differences in lean T1D youth (body mass index [BMI]: 5%-<85%) vs those with obesity (BMI: ≥95%). METHODS We analyzed stool samples for gut microbial (using metagenomic shotgun sequencing) and short-chain fatty acid (SCFA) differences in lean (n = 27) and obese (n = 21) T1D youth in a pilot study. The mean ± SD age was 15.3 ± 2.2 years, glycated hemoglobin A1c 7.8 ± 1.3%, diabetes duration 5.1 ± 4.4 years, 42.0% female, and 94.0% were White. RESULTS Bacterial community composition showed between sample diversity differences (β-diversity) by BMI group (P = .013). There was a higher ratio of Prevotella to Bacteroides in the obese group (P = .0058). There was a differential distribution of significantly abundant taxa in either the lean or obese groups, including increased relative abundance of Prevotella copri, among other taxa in the obese group. Functional profiling showed an upregulation of branched-chain amino acid (BCAA) biosynthesis in the obese group and upregulation of BCAA degradation, tyrosine metabolism, and secondary bile acid biosynthesis in the lean group. Stool SCFAs were higher in the obese vs the lean group (P < .05 for all). CONCLUSION Our findings identify a gut microbiome and microbial metabolite signature associated with obesity in T1D. These findings could help identify gut microbiome-targeted therapies to manage obesity in T1D.
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Affiliation(s)
- Heba M Ismail
- Department of Pediatrics, Indiana University School of Medicine, Indianapolis, IN 46202, USA
| | - Dimuthu Perera
- Department of Molecular Virology and Microbiology, Baylor College of Medicine, Houston, TX 77030, USA
| | - Rabindra Mandal
- Department of Pediatrics, Indiana University School of Medicine, Indianapolis, IN 46202, USA
| | - Linda A DiMeglio
- Department of Pediatrics, Indiana University School of Medicine, Indianapolis, IN 46202, USA
| | - Carmella Evans-Molina
- Department of Pediatrics, Indiana University School of Medicine, Indianapolis, IN 46202, USA
| | - Tamara Hannon
- Department of Pediatrics, Indiana University School of Medicine, Indianapolis, IN 46202, USA
| | - Joseph Petrosino
- Department of Molecular Virology and Microbiology, Baylor College of Medicine, Houston, TX 77030, USA
| | - Sara Javornik Cregeen
- Department of Molecular Virology and Microbiology, Baylor College of Medicine, Houston, TX 77030, USA
| | - Nathan W Schmidt
- Department of Pediatrics, Indiana University School of Medicine, Indianapolis, IN 46202, USA
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24
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Franz K, Markó L, Mähler A, Chakaroun R, Heinitz S, Schlögl H, Sacher J, Steckhan N, Dechend R, Adams N, Andersen M, Glintborg D, Viehweger M, Bahr LS, Forslund-Startceva SK. Sex hormone-dependent host-microbiome interactions and cardiovascular risk (XCVD): design of a longitudinal multi-omics cohort study. BMJ Open 2025; 15:e087982. [PMID: 39788783 PMCID: PMC11751863 DOI: 10.1136/bmjopen-2024-087982] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/24/2024] [Accepted: 12/23/2024] [Indexed: 01/12/2025] Open
Abstract
INTRODUCTION Cardiovascular diseases (CVDs) present differently in women and men, influenced by host-microbiome interactions. The roles of sex hormones in CVD outcomes and gut microbiome in modifying these effects are poorly understood. The XCVD study examines gut microbiome mediation of sex hormone effects on CVD risk markers by observing transgender participants undergoing gender-affirming hormone therapy (GAHT), with findings expected to extrapolate to cisgender populations. METHODS AND ANALYSES This observational, longitudinal cohort study includes baseline, 1- and 2-year follow-ups with transgender participants beginning GAHT. It involves comprehensive phenotyping and microbiome genotyping, integrating computational analyses of high-dimensional data. Microbial diversity will be assessed using gut, skin, and oral samples via 16S rRNA and shotgun metagenomic sequencing of gut samples. Blood measurements will include sex hormones, CVD risk markers, cardiometabolic parameters, cytokines, and immune cell counts. Hair samples will be analysed for cortisol. Participants will complete online questionnaires on physical activity, mental health, stress, quality of life, fatigue, sleep, pain, and gender dysphoria, tracking medication use and diet to control for confounders. Statistical analyses will integrate phenomic, lifestyle, and multi-omic data to model health effects, testing gut microbiome mediation of CVD risk as the endocrine environment shifts between that typical for cisgender men to women and vice versa. ETHICS AND DISSEMINATION The study adheres to Good Clinical Practice and the Declaration of Helsinki. The protocol was approved by the Charité Ethical Committee (EA1/339/21). Signed informed consent will be obtained. Results will be published in peer-reviewed journals and conferences and shared as accessible summaries for participants, community groups, and the public, with participants able to view their data securely after public and patient involvement review for accessibility. TRIAL REGISTRATION NUMBER The XCVD study was registered on ClinicalTrials.gov (NCT05334888) as 'Sex-differential host-microbiome CVD risk - a longitudinal cohort approach (XCVD)" on 4 April 2022. Data set link can be found at https://classic. CLINICALTRIALS gov/ct2/show/NCT05334888.
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Affiliation(s)
- Kristina Franz
- Experimental and Clinical Research Center, Charité - Universitätsmedizin Berlin and Max Delbrück Center for Molecular Medicine, Berlin, Germany
- Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC), Berlin, Germany
- German Centre for Cardiovascular Research (DZHK) partner site Berlin, DZHK, Berlin, Germany
- Deutsches Herzzentrum der Charité - Medical Heart Center of Charité and German Heart Institute Berlin, Department of Cardiology, Angiology and Intensive Care Medicine, Berlin, Germany
- Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany
| | - Lajos Markó
- Experimental and Clinical Research Center, Charité - Universitätsmedizin Berlin and Max Delbrück Center for Molecular Medicine, Berlin, Germany
- Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC), Berlin, Germany
- German Centre for Cardiovascular Research (DZHK) partner site Berlin, DZHK, Berlin, Germany
- Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany
- Berlin Institute of Health (BIH), Berlin, Germany
| | - Anja Mähler
- Experimental and Clinical Research Center, Charité - Universitätsmedizin Berlin and Max Delbrück Center for Molecular Medicine, Berlin, Germany
- Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC), Berlin, Germany
- Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany
| | - Rima Chakaroun
- Medical Department III Endocrinology Nephrology Rheumatology, University of Leipzig Medical Center, Leipzig, Germany
- Sahlgrenska Center for Cardiovascular and Metabolic Research, University of Gothenburg Wallenberg Laboratory for Cardiovascular and Metabolic Research, Goteborg, Sweden
| | - Sascha Heinitz
- Medical Department III Endocrinology Nephrology Rheumatology, University of Leipzig Medical Center, Leipzig, Germany
| | - Haiko Schlögl
- Medical Department III Endocrinology Nephrology Rheumatology, University of Leipzig Medical Center, Leipzig, Germany
- HI-MAG, Helmholtz Institute for Metabolic Obesity and Vascular Research, Leipzig, Germany
| | - Julia Sacher
- Clinic for Cognitive Neurology, University of Leipzig Medical Center, and Department of Neurology, Max Planck Institute for Human Cognitive and Brain Sciences, Max-Planck-Institut fur molekulare Physiologie, Dortmund, Germany
| | - Nico Steckhan
- Digital Health - Connected Healthcare, Hasso Plattner Institute, University of Potsdam, Potsdam, Germany
| | - Ralf Dechend
- Experimental and Clinical Research Center, Charité - Universitätsmedizin Berlin and Max Delbrück Center for Molecular Medicine, Berlin, Germany
- Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC), Berlin, Germany
- German Centre for Cardiovascular Research (DZHK) partner site Berlin, DZHK, Berlin, Germany
- Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany
- Helios Clinic Berlin-Buch, Berlin, Germany
| | - Noah Adams
- University of Toronto, Toronto, Ontario, Canada
- Center for Applied Transgender Studies (CATS), Chicago, Illinois, USA
- Transgender Professional Association for Transgender Health, TPATH, Toronto, Ontario, Canada
| | - Marianne Andersen
- Department of Endocrinology, Odense Universitetshospital, Odense, Denmark
- Institute of Clinical Research, University of Southern Denmark, Odense, Syddanmark, Denmark
| | - Dorte Glintborg
- Institute of Clinical Research, University of Southern Denmark, Odense, Syddanmark, Denmark
- Body Identity Clinic, Odense Universitetshospital Endokrinologisk Afdeling M, Odense, Denmark
| | | | - Lina Samira Bahr
- Experimental and Clinical Research Center, Charité - Universitätsmedizin Berlin and Max Delbrück Center for Molecular Medicine, Berlin, Germany
- Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC), Berlin, Germany
- German Centre for Cardiovascular Research (DZHK) partner site Berlin, DZHK, Berlin, Germany
- Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany
| | - Sofia Kirke Forslund-Startceva
- Experimental and Clinical Research Center, Charité - Universitätsmedizin Berlin and Max Delbrück Center for Molecular Medicine, Berlin, Germany
- Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC), Berlin, Germany
- German Centre for Cardiovascular Research (DZHK) partner site Berlin, DZHK, Berlin, Germany
- Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany
- Transgender Professional Association for Transgender Health, TPATH, Toronto, Ontario, Canada
- European Molecular Biology Laboratory Structural and Computational Biology Unit, Heidelberg, Baden-Württemberg, Germany
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25
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Nishijima S, Stankevic E, Aasmets O, Schmidt TSB, Nagata N, Keller MI, Ferretti P, Juel HB, Fullam A, Robbani SM, Schudoma C, Hansen JK, Holm LA, Israelsen M, Schierwagen R, Torp N, Telzerow A, Hercog R, Kandels S, Hazenbrink DHM, Arumugam M, Bendtsen F, Brøns C, Fonvig CE, Holm JC, Nielsen T, Pedersen JS, Thiele MS, Trebicka J, Org E, Krag A, Hansen T, Kuhn M, Bork P. Fecal microbial load is a major determinant of gut microbiome variation and a confounder for disease associations. Cell 2025; 188:222-236.e15. [PMID: 39541968 DOI: 10.1016/j.cell.2024.10.022] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2024] [Revised: 07/12/2024] [Accepted: 10/14/2024] [Indexed: 11/17/2024]
Abstract
The microbiota in individual habitats differ in both relative composition and absolute abundance. While sequencing approaches determine the relative abundances of taxa and genes, they do not provide information on their absolute abundances. Here, we developed a machine-learning approach to predict fecal microbial loads (microbial cells per gram) solely from relative abundance data. Applying our prediction model to a large-scale metagenomic dataset (n = 34,539), we demonstrated that microbial load is the major determinant of gut microbiome variation and is associated with numerous host factors, including age, diet, and medication. We further found that for several diseases, changes in microbial load, rather than the disease condition itself, more strongly explained alterations in patients' gut microbiome. Adjusting for this effect substantially reduced the statistical significance of the majority of disease-associated species. Our analysis reveals that the fecal microbial load is a major confounder in microbiome studies, highlighting its importance for understanding microbiome variation in health and disease.
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Affiliation(s)
- Suguru Nishijima
- Molecular Systems Biology Unit, European Molecular Biology Laboratory, Heidelberg, Germany
| | - Evelina Stankevic
- Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen, Copenhagen, Denmark
| | - Oliver Aasmets
- Institute of Genomics, University of Tartu, Tartu, Estonia
| | - Thomas S B Schmidt
- Molecular Systems Biology Unit, European Molecular Biology Laboratory, Heidelberg, Germany
| | - Naoyoshi Nagata
- Department of Gastroenterological Endoscopy, Tokyo Medical University, Tokyo, Japan
| | - Marisa Isabell Keller
- Molecular Systems Biology Unit, European Molecular Biology Laboratory, Heidelberg, Germany
| | - Pamela Ferretti
- Molecular Systems Biology Unit, European Molecular Biology Laboratory, Heidelberg, Germany
| | - Helene Bæk Juel
- Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen, Copenhagen, Denmark
| | - Anthony Fullam
- Molecular Systems Biology Unit, European Molecular Biology Laboratory, Heidelberg, Germany
| | | | - Christian Schudoma
- Molecular Systems Biology Unit, European Molecular Biology Laboratory, Heidelberg, Germany
| | - Johanne Kragh Hansen
- Faculty of Health Sciences, University of Southern Denmark, Odense, Denmark; Department of Gastroenterology and Hepatology, Odense University Hospital, Odense, Denmark
| | - Louise Aas Holm
- Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen, Copenhagen, Denmark; The Children's Obesity Clinic, Department of Pediatrics, Copenhagen University Hospital Holbæk, Holbæk, Denmark
| | - Mads Israelsen
- Faculty of Health Sciences, University of Southern Denmark, Odense, Denmark; Department of Gastroenterology and Hepatology, Odense University Hospital, Odense, Denmark
| | - Robert Schierwagen
- Department of Internal Medicine B, University of Münster, Münster, Germany
| | - Nikolaj Torp
- Faculty of Health Sciences, University of Southern Denmark, Odense, Denmark; Department of Gastroenterology and Hepatology, Odense University Hospital, Odense, Denmark
| | - Anja Telzerow
- Molecular Systems Biology Unit, European Molecular Biology Laboratory, Heidelberg, Germany
| | - Rajna Hercog
- Molecular Systems Biology Unit, European Molecular Biology Laboratory, Heidelberg, Germany
| | - Stefanie Kandels
- Molecular Systems Biology Unit, European Molecular Biology Laboratory, Heidelberg, Germany
| | - Diënty H M Hazenbrink
- Molecular Systems Biology Unit, European Molecular Biology Laboratory, Heidelberg, Germany
| | - Manimozhiyan Arumugam
- Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen, Copenhagen, Denmark
| | - Flemming Bendtsen
- Gastrounit, Medical Division, Copenhagen University Hospital Hvidovre, Hvidovre, Denmark
| | - Charlotte Brøns
- Clinical Research, Steno Diabetes Center Copenhagen, Herlev, Denmark
| | - Cilius Esmann Fonvig
- Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen, Copenhagen, Denmark; The Children's Obesity Clinic, Department of Pediatrics, Copenhagen University Hospital Holbæk, Holbæk, Denmark; Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Jens-Christian Holm
- Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen, Copenhagen, Denmark; The Children's Obesity Clinic, Department of Pediatrics, Copenhagen University Hospital Holbæk, Holbæk, Denmark; Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Trine Nielsen
- Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen, Copenhagen, Denmark; Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark; Medical department, University Hospital Zeeland, Køge, Denmark
| | - Julie Steen Pedersen
- Gastrounit, Medical Division, Copenhagen University Hospital Hvidovre, Hvidovre, Denmark
| | - Maja Sofie Thiele
- Faculty of Health Sciences, University of Southern Denmark, Odense, Denmark; Department of Gastroenterology and Hepatology, Odense University Hospital, Odense, Denmark
| | - Jonel Trebicka
- Department of Internal Medicine B, University of Münster, Münster, Germany; European Foundation for the Study of Chronic Liver Failure, EFCLIF, Barcelona, Spain
| | - Elin Org
- Institute of Genomics, University of Tartu, Tartu, Estonia
| | - Aleksander Krag
- Faculty of Health Sciences, University of Southern Denmark, Odense, Denmark; Department of Gastroenterology and Hepatology, Odense University Hospital, Odense, Denmark
| | - Torben Hansen
- Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen, Copenhagen, Denmark
| | - Michael Kuhn
- Molecular Systems Biology Unit, European Molecular Biology Laboratory, Heidelberg, Germany.
| | - Peer Bork
- Molecular Systems Biology Unit, European Molecular Biology Laboratory, Heidelberg, Germany; Max Delbrück Centre for Molecular Medicine, Berlin, Germany; Department of Bioinformatics, Biocenter, University of Würzburg, Würzburg, Germany.
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26
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Tang G, Carr AV, Perez C, Sarmiento KR, Levy L, Lampe JW, Diener C, Gibbons SM. Metagenomic estimation of absolute bacterial biomass in the mammalian gut through host-derived read normalization. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2025:2025.01.07.631807. [PMID: 39829744 PMCID: PMC11741328 DOI: 10.1101/2025.01.07.631807] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/22/2025]
Abstract
Absolute bacterial biomass estimation in the human gut is crucial for understanding microbiome dynamics and host-microbe interactions. Current methods for quantifying bacterial biomass in stool, such as flow cytometry, qPCR, or spike-ins (i.e., adding cells or DNA from an organism not normally found in a sample), can be labor-intensive, costly, and confounded by factors like water content, DNA extraction efficiency, PCR inhibitors, and other technical challenges that add bias and noise. We propose a simple, cost-effective approach that circumvents some of these technical challenges: directly estimating bacterial biomass from metagenomes using bacterial-to-host (B:H) read ratios. We compare B:H ratios to the standard methods outlined above, demonstrating that B:H ratios are useful proxies for bacterial biomass in stool and possibly in other host-associated substrates. We show how B:H ratios can be used to track antibiotic treatment response and recovery in both mice and humans, which showed 403-fold and 45-fold reductions in bacterial biomass during antibiotic treatment, respectively. Our results indicate that host and bacterial metagenomic DNA fractions in human stool fluctuate longitudinally around a stable mean in healthy individuals, and the average host read fraction varies across healthy individuals by < 8-9 fold. B:H ratios offer a convenient alternative to other absolute biomass quantification methods, without the need for additional measurements, experimental design considerations, or machine learning algorithms, enabling retrospective absolute biomass estimates from existing stool metagenomic data.
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Affiliation(s)
- Gechlang Tang
- Institute for Systems Biology, Seattle, WA 98109, USA
- Master of Science Program in Genetic Epidemiology, University of Washington School of Public Health, Seattle, WA 98195, USA
| | - Alex V. Carr
- Institute for Systems Biology, Seattle, WA 98109, USA
| | - Crystal Perez
- Institute for Systems Biology, Seattle, WA 98109, USA
- Molecular Engineering Graduate Program, University of Washington, Seattle, WA 98195, USA
- Medical Scientist Training Program, University of Washington, Seattle, WA 98195, USA
| | | | - Lisa Levy
- Fred Hutchinson Cancer Center, Seattle, WA 98109, USA
| | | | - Christian Diener
- Diagnostic and Research Institute of Hygiene, Microbiology and Environmental Medicine, Medical University of Graz, Graz, Austria
| | - Sean M. Gibbons
- Institute for Systems Biology, Seattle, WA 98109, USA
- Molecular Engineering Graduate Program, University of Washington, Seattle, WA 98195, USA
- Department of Bioengineering, University of Washington, Seattle, WA 98195, USA
- Department of Genome Sciences, University of Washington, Seattle, WA 98195, USA
- eScience Institute, University of Washington, Seattle, WA 98195, USA
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27
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Tsuchida S, Umemura H, Iizuka K, Yamamoto H, Shimazaki I, Shikata E, Nakayama T. Recent findings on metabolomics and the microbiome of oral bacteria involved in dental caries and periodontal disease. World J Microbiol Biotechnol 2024; 41:11. [PMID: 39690257 DOI: 10.1007/s11274-024-04224-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2024] [Accepted: 12/06/2024] [Indexed: 12/19/2024]
Abstract
Periodontal disease is characterized by bacterial toxins within the oral biofilm surrounding the teeth, leading to gingivitis and the gradual dissolution of the alveolar bone, which supports the teeth. Notably, symptoms in the early stages of the disease are often absent. Similarly, dental caries occurs when oral bacteria metabolize dietary sugars, producing acids that dissolve tooth enamel and dentin. These bacteria are commonly present in the oral cavity of most individuals. Metabolomics, a relatively recent addition to the "omics" research landscape, involves the comprehensive analysis of metabolites in vivo to elucidate pathological mechanisms and accelerate drug discovery. Meanwhile, the term "microbiome" refers to the collection of microorganisms within a specific environmental niche or their collective genomes. The human microbiome plays a critical role in health and disease, influencing a wide array of physiological and pathological processes. Recent advances in microbiome research have identified numerous bacteria implicated in dental caries and periodontal disease. Additionally, studies have uncovered various pathogenic factors associated with these microorganisms. This review focuses on recent findings in metabolomics and the microbiome, specifically targeting oral bacteria linked to dental caries and periodontal disease. We acknowledge the limitation of relying exclusively on the MEDLINE database via PubMed, while excluding other sources such as gray literature, conference proceedings, and clinical practice guidelines.
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Affiliation(s)
- Sachio Tsuchida
- Divisions of Laboratory Medicine, Department of Pathology and Microbiology, Nihon University School of Medicine, 30-1 Oyaguchikamicho, Itabashi-ku, Tokyo, Japan
| | - Hiroshi Umemura
- Divisions of Laboratory Medicine, Department of Pathology and Microbiology, Nihon University School of Medicine, 30-1 Oyaguchikamicho, Itabashi-ku, Tokyo, Japan
| | - Kazuhide Iizuka
- Divisions of Laboratory Medicine, Department of Pathology and Microbiology, Nihon University School of Medicine, 30-1 Oyaguchikamicho, Itabashi-ku, Tokyo, Japan
| | - Haruka Yamamoto
- Divisions of Laboratory Medicine, Department of Pathology and Microbiology, Nihon University School of Medicine, 30-1 Oyaguchikamicho, Itabashi-ku, Tokyo, Japan
| | - Isamu Shimazaki
- Divisions of Laboratory Medicine, Department of Pathology and Microbiology, Nihon University School of Medicine, 30-1 Oyaguchikamicho, Itabashi-ku, Tokyo, Japan
| | - Elisa Shikata
- Divisions of Laboratory Medicine, Department of Pathology and Microbiology, Nihon University School of Medicine, 30-1 Oyaguchikamicho, Itabashi-ku, Tokyo, Japan
| | - Tomohiro Nakayama
- Divisions of Laboratory Medicine, Department of Pathology and Microbiology, Nihon University School of Medicine, 30-1 Oyaguchikamicho, Itabashi-ku, Tokyo, Japan.
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Mei Z, Xu L, Huang Q, Lin C, Yu M, Shali S, Wu H, Lu Y, Wu R, Wang Z, Luo L, Sun Z, Sun L, Qian J, Chen G, Tang H, Yao K, Zheng Y, Dai Y, Ge J. Metabonomic Biomarkers of Plaque Burden and Instability in Patients With Coronary Atherosclerotic Disease After Moderate Lipid-Lowering Therapy. J Am Heart Assoc 2024; 13:e036906. [PMID: 39655754 PMCID: PMC11935549 DOI: 10.1161/jaha.124.036906] [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: 06/03/2024] [Accepted: 09/16/2024] [Indexed: 12/18/2024]
Abstract
BACKGROUND Contemporary risk assessment in patients with coronary atherosclerotic disease (CAD) often relies on invasive angiography. However, we aimed to explore the potential of metabolomic biomarkers in reflecting residual risk in patients with CAD after moderate lipid-lowering therapy. METHODS AND RESULTS We analyzed serum metabolomic profile among 2560 patients with newly diagnosed CAD undergoing moderate lipid-lowering therapy, through nuclear magnetic resonance spectroscopy and quantified 175 metabolites, predominantly lipoproteins and their components. CAD severity was evaluated using Gensini score for plaque burden and circulating cardiac troponin T levels for plaque instability. The association of metabolites with CAD severity was examined using multivariate linear regression, and the underlying potential causality was explored using a 2-sample Mendelian randomization approach. Two composite metabolomic indices were constructed to reflect CAD severity using least absolute shrinkage and selection operator linear regression, and their associations with risk of major adverse cardiac events during a median follow-up of 3.8 years were evaluated using Cox models. Our investigation revealed that triglycerides and apolipoprotein B in low-density lipoprotein particles displayed stronger associations with CAD severity compared with the clinically used low-density lipoprotein cholesterol marker. In large high-density lipoprotein, components like cholesterol, cholesterol esters, triglyceride, apolipoprotein A1/A2 showed inverse associations with CAD severity. Certain metabolites, including apolipoprotein B and dihydrothymine, showed a putative causal link with Gensini score. Notably, per standard deviation increase in Gensini score-based metabolomic index was associated with 14.8% higher major adverse cardiac event risk (hazard ratio, 1.148 [95% CI, 1.018-1.295]) independent of demographic factors, medication use, and disease status. CONCLUSIONS Our findings highlight the potential of nuclear magnetic resonance-based metabolomics in identifying novel biomarkers of plaque burden and instability. Metabolites related to plaque burden may facilitate noninvasive assessment of CAD prognosis.
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Affiliation(s)
- Zhendong Mei
- Department of Cardiology, Zhongshan Hospital, Fudan University, Shanghai Institute of Cardiovascular DiseasesNational Clinical Research Center for Interventional MedicineShanghaiChina
- State Key Laboratory of Genetic Engineering, School of Life Sciences and Human Phenome InstituteFudan UniversityShanghaiChina
| | - Lili Xu
- Department of Cardiology, Zhongshan Hospital, Fudan University, Shanghai Institute of Cardiovascular DiseasesNational Clinical Research Center for Interventional MedicineShanghaiChina
- Department of CardiologyShanghai Geriatric Medical CenterShanghaiChina
| | - Qingxia Huang
- State Key Laboratory of Genetic Engineering, School of Life Sciences, Human Phenome Institute, Zhangjiang Fudan International Innovation Center, Metabonomics and Systems Biology Laboratory at Shanghai International Centre for Molecular Phenomics, Zhongshan HospitalFudan UniversityShanghaiChina
| | - Chenhao Lin
- State Key Laboratory of Genetic Engineering, School of Life Sciences and Human Phenome InstituteFudan UniversityShanghaiChina
| | - Mengyao Yu
- Human Phenome Institute, Zhangjiang Fudan International Innovation CenterFudan UniversityShanghaiChina
| | - Shalaimaiti Shali
- Department of Cardiology, Zhongshan Hospital, Fudan University, Shanghai Institute of Cardiovascular DiseasesNational Clinical Research Center for Interventional MedicineShanghaiChina
| | - Hongyi Wu
- Department of Cardiology, Zhongshan Hospital, Fudan University, Shanghai Institute of Cardiovascular DiseasesNational Clinical Research Center for Interventional MedicineShanghaiChina
| | - Yijing Lu
- Department of Cardiology, Zhongshan Hospital, Fudan University, Shanghai Institute of Cardiovascular DiseasesNational Clinical Research Center for Interventional MedicineShanghaiChina
| | - Runda Wu
- Department of Cardiology, Zhongshan Hospital, Fudan University, Shanghai Institute of Cardiovascular DiseasesNational Clinical Research Center for Interventional MedicineShanghaiChina
| | - Zhen Wang
- Department of Cardiology, Zhongshan Hospital, Fudan University, Shanghai Institute of Cardiovascular DiseasesNational Clinical Research Center for Interventional MedicineShanghaiChina
| | - Lingfeng Luo
- State Key Laboratory of Genetic Engineering, School of Life Sciences and Human Phenome InstituteFudan UniversityShanghaiChina
| | - Zhonghan Sun
- State Key Laboratory of Genetic Engineering, School of Life Sciences and Human Phenome InstituteFudan UniversityShanghaiChina
| | - Liang Sun
- Ministry of Education Key Laboratory of Public Health Safety, School of Public Health, Institute of NutritionFudan UniversityShanghaiChina
| | - Juying Qian
- Department of Cardiology, Zhongshan Hospital, Fudan University, Shanghai Institute of Cardiovascular DiseasesNational Clinical Research Center for Interventional MedicineShanghaiChina
| | - Guochong Chen
- Department of Nutrition and Food Hygiene, School of Public HealthSuzhou Medical College of Soochow UniversitySuzhouChina
| | - Huiru Tang
- State Key Laboratory of Genetic Engineering, School of Life Sciences, Human Phenome Institute, Zhangjiang Fudan International Innovation Center, Metabonomics and Systems Biology Laboratory at Shanghai International Centre for Molecular Phenomics, Zhongshan HospitalFudan UniversityShanghaiChina
| | - Kang Yao
- Department of Cardiology, Zhongshan Hospital, Fudan University, Shanghai Institute of Cardiovascular DiseasesNational Clinical Research Center for Interventional MedicineShanghaiChina
| | - Yan Zheng
- Department of Cardiology, Zhongshan Hospital, Fudan University, Shanghai Institute of Cardiovascular DiseasesNational Clinical Research Center for Interventional MedicineShanghaiChina
- State Key Laboratory of Genetic Engineering, School of Life Sciences and Human Phenome InstituteFudan UniversityShanghaiChina
- Ministry of Education Key Laboratory of Public Health Safety, School of Public Health, Institute of NutritionFudan UniversityShanghaiChina
| | - Yuxiang Dai
- Department of Cardiology, Zhongshan Hospital, Fudan University, Shanghai Institute of Cardiovascular DiseasesNational Clinical Research Center for Interventional MedicineShanghaiChina
| | - Junbo Ge
- Department of Cardiology, Zhongshan Hospital, Fudan University, Shanghai Institute of Cardiovascular DiseasesNational Clinical Research Center for Interventional MedicineShanghaiChina
- Department of CardiologyShanghai Geriatric Medical CenterShanghaiChina
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Li J, Li Y, Zhou L, Li H, Wan T, Tang J, Zhou L, Xie H, Wang L. Microbiome analysis reveals the inducing effect of Pseudomonas on prostatic hyperplasia via activating NF-κB signalling. Virulence 2024; 15:2313410. [PMID: 38378443 PMCID: PMC10880505 DOI: 10.1080/21505594.2024.2313410] [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: 08/04/2023] [Accepted: 01/25/2024] [Indexed: 02/22/2024] Open
Abstract
Benign prostatic hyperplasia (BPH) is a prevalent disease among middle-aged and elderly males, but its pathogenesis remains unclear. Dysbiosis of the microbiome is increasingly recognized as a significant factor in various human diseases. Prostate tissue also contains a unique microbiome, and its dysbiosis has been proposed to contribute to prostate diseases. Here, we obtained prostate tissues and preoperative catheterized urine from 24 BPH individuals, and 8 normal prostate samples as controls, which followed strict aseptic measures. Using metagenomic next-generation sequencing (mNGS), we found the disparities in the microbiome composition between normal and BPH tissues, with Pseudomonas significantly enriched in BPH tissues, as confirmed by fluorescence in situ hybridization (FISH). Additionally, we showed that the prostate microbiome differed from the urine microbiome. In vitro experiments revealed that lipopolysaccharide (LPS) of Pseudomonas activated NF-κB signalling, leading to inflammation, proliferation, and EMT processes, while inhibiting apoptosis in prostatic cells. Overall, our research determines the presence of microbiome dysbiosis in BPH, and suggests that Pseudomonas, as the dominant microflora, may promote the progression of BPH through LPS activation of NF-κB signalling.
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Affiliation(s)
- Jiaren Li
- Department of Urology, The Third Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Youyou Li
- Department of Urology, The Third Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Liang Zhou
- Department of Urology, The Third Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Hongming Li
- Movement System Injury and Repair Research Center, Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Tengfei Wan
- Movement System Injury and Repair Research Center, Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Jin Tang
- Department of Urology, The Third Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Lei Zhou
- Department of Urology, The Third Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Hui Xie
- Movement System Injury and Repair Research Center, Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Long Wang
- Department of Urology, The Third Xiangya Hospital, Central South University, Changsha, Hunan, China
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30
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Santana E, Ibrahimi E, Ntalianis E, Cauwenberghs N, Kuznetsova T. Integrating Metabolomics Domain Knowledge with Explainable Machine Learning in Atherosclerotic Cardiovascular Disease Classification. Int J Mol Sci 2024; 25:12905. [PMID: 39684618 DOI: 10.3390/ijms252312905] [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: 10/31/2024] [Revised: 11/19/2024] [Accepted: 11/27/2024] [Indexed: 12/18/2024] Open
Abstract
Metabolomic data often present challenges due to high dimensionality, collinearity, and variability in metabolite concentrations. Machine learning (ML) application in metabolomic analyses is enabling the extraction of meaningful information from complex data. Bringing together domain-specific knowledge from metabolomics with explainable ML methods can refine the predictive performance and interpretability of models used in atherosclerosis research. In this work, we aimed to identify the most impactful metabolites associated with the presence of atherosclerotic cardiovascular disease (ASCVD) in cross-sectional case-control studies using explainable ML methods integrated with metabolomics domain knowledge. For this, a subset from the FLEMENGHO cohort with metabolomic data available was used as the training cohort, including 63 patients with a history of ASCVD and 52 non-smoking controls matched by age, sex, and body mass index from the same population. First, Partial Least Squares Discriminant Analysis (PLS-DA) was applied for dimensionality reduction. The selected metabolites' correlations were analyzed by considering their chemical categorization. Then, eXtreme Gradient Boosting (XGBoost) was used to identify metabolites that characterize ASCVD. Next, the selected metabolites were evaluated in an external cohort to determine their effectiveness in distinguishing between cases and controls. A total of 56 metabolites were selected for ASCVD discrimination using PLS-DA. The primary identified metabolites' superclasses included lipids, organic acids, and organic oxygen compounds. Upon integrating these metabolites with the XGBoost model, the classification yielded a test area under the curve (AUC) of 0.75. SHAP analyses ranked cholesterol, 3-methylhistidine, and glucuronic acid among the most impactful features and showed the diversity of metabolites considered for building the ASCVD discriminator. Also using XGBoost, the selected metabolites achieved an AUC of 0.93 in an independent external validation cohort. In conclusion, the combination of different metabolites has the potential to build classifiers for ASCVD. Integrating metabolite categorization within the SHAP analysis further enhanced the interpretability of the model, offering insights into metabolite-specific contributions to ASCVD risk.
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Affiliation(s)
- Everton Santana
- Research Unit Hypertension and Cardiovascular Epidemiology, KU Leuven Department of Cardiovascular Sciences, University of Leuven, 3000 Leuven, Belgium
| | - Eliana Ibrahimi
- Department of Biology, University of Tirana, 1001 Tirana, Albania
| | - Evangelos Ntalianis
- Research Unit Hypertension and Cardiovascular Epidemiology, KU Leuven Department of Cardiovascular Sciences, University of Leuven, 3000 Leuven, Belgium
| | - Nicholas Cauwenberghs
- Research Unit Hypertension and Cardiovascular Epidemiology, KU Leuven Department of Cardiovascular Sciences, University of Leuven, 3000 Leuven, Belgium
| | - Tatiana Kuznetsova
- Research Unit Hypertension and Cardiovascular Epidemiology, KU Leuven Department of Cardiovascular Sciences, University of Leuven, 3000 Leuven, Belgium
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31
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Warmbrunn MV, Attaye I, Horak A, Banerjee R, Massey WJ, Varadharajan V, Rampanelli E, Hao Y, Dutta S, Nemet I, Aron-Wisnewsky J, Clément K, Koopen A, Wortelboer K, Bergh PO, Davids M, Mohamed N, Kemper EM, Hazen S, Groen AK, van Raalte DH, Herrema H, Backhed F, Brown JM, Nieuwdorp M. Kinetics of imidazole propionate from orally delivered histidine in mice and humans. NPJ Biofilms Microbiomes 2024; 10:118. [PMID: 39496629 PMCID: PMC11535228 DOI: 10.1038/s41522-024-00592-8] [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: 02/25/2024] [Accepted: 10/23/2024] [Indexed: 11/06/2024] Open
Abstract
Imidazole Propionate (ImP), a gut-derived metabolite from histidine, affects insulin signaling in mice and is elevated in type 2 diabetes (T2D). However, the source of histidine and the role of the gut microbiota remain unclear. We conducted an intervention study in mice and humans, comparing ImP kinetics in mice on a high-fat diet with varying histidine levels and antibiotics, and assessed ImP levels in healthy and T2D subjects with histidine supplementation. Results show that dietary histidine is metabolized to ImP, with antibiotic-induced gut microbiota suppression reducing ImP levels in mice. In contrast, oral histidine supplementation resulted in increases in circulating ImP levels in humans, whereas antibiotic treatment increased ImP levels, which was associated with a bloom of several bacterial genera that have been associated with ImP production, such as Lactobacilli. Our findings highlight the gut microbiota's crucial role in regulating ImP and the complexity of translating mouse models to humans.
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Affiliation(s)
- Moritz V Warmbrunn
- Department of Internal and Vascular Medicine, Amsterdam University Medical Centers, Location AMC, Amsterdam, The Netherlands.
- Amsterdam UMC, University of Amsterdam, Gastroenterology and Hepatology, Amsterdam Gastroenterology Endocrinology Metabolism, Amsterdam, Netherlands.
| | - Ilias Attaye
- Department of Internal and Vascular Medicine, Amsterdam University Medical Centers, Location AMC, Amsterdam, The Netherlands
- Department of Cancer Biology, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA
- Department of Cardiovascular and Metabolic Sciences, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA
| | - Anthony Horak
- Department of Cancer Biology, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA
| | - Rakhee Banerjee
- Department of Cancer Biology, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA
| | - William J Massey
- Department of Cancer Biology, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA
| | | | - Elena Rampanelli
- Department of Internal and Vascular Medicine, Amsterdam University Medical Centers, Location AMC, Amsterdam, The Netherlands
| | - Youling Hao
- Department of Internal and Vascular Medicine, Amsterdam University Medical Centers, Location AMC, Amsterdam, The Netherlands
| | - Sumita Dutta
- Department of Cancer Biology, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA
| | - Ina Nemet
- Department of Cardiovascular and Metabolic Sciences, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA
| | - Judith Aron-Wisnewsky
- Sorbonne Université, INSERM, Nutrition and Obesities; Systemic Approaches (NutriOmics), Sorbonne Université, Paris, France
- Assistance Publique Hôpitaux de Paris,Pitie-Salpêtrière Hospital, Nutrition department, CRNH Ile de France, Paris, France
| | - Karine Clément
- Sorbonne Université, INSERM, Nutrition and Obesities; Systemic Approaches (NutriOmics), Sorbonne Université, Paris, France
- Assistance Publique Hôpitaux de Paris,Pitie-Salpêtrière Hospital, Nutrition department, CRNH Ile de France, Paris, France
| | - Annefleur Koopen
- Department of Internal and Vascular Medicine, Amsterdam University Medical Centers, Location AMC, Amsterdam, The Netherlands
| | - Koen Wortelboer
- Department of Internal and Vascular Medicine, Amsterdam University Medical Centers, Location AMC, Amsterdam, The Netherlands
- Amsterdam UMC, University of Amsterdam, Gastroenterology and Hepatology, Amsterdam Gastroenterology Endocrinology Metabolism, Amsterdam, Netherlands
| | - Per-Olof Bergh
- Wallenberg Laboratory and Department of Molecular and Clinical Medicine, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
| | - Mark Davids
- Department of Internal and Vascular Medicine, Amsterdam University Medical Centers, Location AMC, Amsterdam, The Netherlands
| | - Nadia Mohamed
- Department of Internal and Vascular Medicine, Amsterdam University Medical Centers, Location AMC, Amsterdam, The Netherlands
| | - E Marleen Kemper
- Department of Clinical Pharmacology, Amsterdam University Medical Centers, Location AMC, Amsterdam, the Netherlands
| | - Stanley Hazen
- Department of Cancer Biology, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA
| | - Albert K Groen
- Department of Internal and Vascular Medicine, Amsterdam University Medical Centers, Location AMC, Amsterdam, The Netherlands
| | - Daniel H van Raalte
- Department of Internal and Vascular Medicine, Amsterdam University Medical Centers, Location AMC, Amsterdam, The Netherlands
- VU University, Amsterdam Cardiovascular Sciences, Amsterdam, The Netherlands
| | - Hilde Herrema
- Department of Internal and Vascular Medicine, Amsterdam University Medical Centers, Location AMC, Amsterdam, The Netherlands
| | - Fredrik Backhed
- Wallenberg Laboratory and Department of Molecular and Clinical Medicine, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
- Region Västra Götaland, Sahlgrenska University Hospital, Department of Clinical Physiology, Gothenburg, Sweden
| | - J Mark Brown
- Department of Cancer Biology, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA
| | - Max Nieuwdorp
- Department of Internal and Vascular Medicine, Amsterdam University Medical Centers, Location AMC, Amsterdam, The Netherlands
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32
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Oravilahti A, Vangipurapu J, Laakso M, Fernandes Silva L. Metabolomics-Based Machine Learning for Predicting Mortality: Unveiling Multisystem Impacts on Health. Int J Mol Sci 2024; 25:11636. [PMID: 39519188 PMCID: PMC11546733 DOI: 10.3390/ijms252111636] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/03/2024] [Revised: 10/22/2024] [Accepted: 10/29/2024] [Indexed: 11/16/2024] Open
Abstract
Reliable predictors of long-term all-cause mortality are needed for middle-aged and older populations. Previous metabolomics mortality studies have limitations: a low number of participants and metabolites measured, measurements mainly using nuclear magnetic spectroscopy, and the use only of conventional statistical methods. To overcome these challenges, we applied liquid chromatography-tandem mass spectrometry and measured >1000 metabolites in the METSIM study including 10,197 men. We applied the machine learning approach together with conventional statistical methods to identify metabolites associated with all-cause mortality. The three independent machine learning methods (logistic regression, XGBoost, and Welch's t-test) identified 32 metabolites having the most impactful associations with all-cause mortality (25 increasing and 7 decreasing the risk). From these metabolites, 20 were novel and encompassed various metabolic pathways, impacting the cardiovascular, renal, respiratory, endocrine, and central nervous systems. In the Cox regression analyses (hazard ratios and their 95% confidence intervals), clinical and laboratory risk factors increased the risk of all-cause mortality by 1.76 (1.60-1.94), the 25 metabolites by 1.89 (1.68-2.12), and clinical and laboratory risk factors combined with the 25 metabolites by 2.00 (1.81-2.22). In our study, the main causes of death were cancers (28%) and cardiovascular diseases (25%). We did not identify any metabolites associated with cancer but found 13 metabolites associated with an increased risk of cardiovascular diseases. Our study reports several novel metabolites associated with an increased risk of mortality and shows that these 25 metabolites improved the prediction of all-cause mortality beyond and above clinical and laboratory measurements.
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Affiliation(s)
- Anniina Oravilahti
- Institute of Clinical Medicine, Internal Medicine, University of Eastern Finland, 70210 Kuopio, Finland; (A.O.); (J.V.); (M.L.)
| | - Jagadish Vangipurapu
- Institute of Clinical Medicine, Internal Medicine, University of Eastern Finland, 70210 Kuopio, Finland; (A.O.); (J.V.); (M.L.)
| | - Markku Laakso
- Institute of Clinical Medicine, Internal Medicine, University of Eastern Finland, 70210 Kuopio, Finland; (A.O.); (J.V.); (M.L.)
- Department of Medicine, Kuopio University Hospital, 70200 Kuopio, Finland
| | - Lilian Fernandes Silva
- Institute of Clinical Medicine, Internal Medicine, University of Eastern Finland, 70210 Kuopio, Finland; (A.O.); (J.V.); (M.L.)
- Department of Medicine, Division of Cardiology, David Geffen School of Medicine, University of California, Los Angeles, CA 90095, USA
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Sharma V, Fernando V, Zheng X, Sweef O, Choi ES, Thomas V, Furuta S. Immunogenic shift of arginine metabolism triggers systemic metabolic and immunological reprogramming to prevent HER2+ breast cancer. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2024:2024.10.23.619827. [PMID: 39484369 PMCID: PMC11527010 DOI: 10.1101/2024.10.23.619827] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/03/2024]
Abstract
Arginine metabolism in tumors is often shunted into the pathway producing pro-tumor and immune suppressive polyamines (PAs), while downmodulating the alternative nitric oxide (NO) synthesis pathway. Aiming to correct arginine metabolism in tumors, arginine deprivation therapy and inhibitors of PA synthesis have been developed. Despite some therapeutic advantages, these approaches have often yielded severe side effects, making it necessary to explore an alternative strategy. We previously reported that supplementing SEP, the endogenous precursor of BH4 (the essential NO synthase cofactor), could correct arginine metabolism in tumor cells and tumor-associated macrophages (TAMs) and induce their metabolic and phenotypic reprogramming. We saw that oral SEP treatment effectively suppressed the growth of HER2-positive mammary tumors in animals. SEP also has no reported dose-dependent toxicity in clinical trials for metabolic disorders. In the present study, we report that a long-term use of SEP in animals susceptible to HER2-positive mammary tumors effectively prevented tumor occurrence. These SEP-treated animals had undergone reprogramming of the systemic metabolism and immunity, elevating total T cell counts in the circulation and bone marrow. Given that bone marrow-resident T cells are mostly memory T cells, it is plausible that chronic SEP treatment promoted memory T cell formation, leading to a potent tumor prevention. These findings suggest the possible roles of the SEP/BH4/NO axis in promoting memory T cell formation and its potential therapeutic utility for preventing HER2-positive breast cancer.
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Affiliation(s)
- Vandana Sharma
- Department of Cell & Cancer Biology, College of Medicine and Life Sciences, University of Toledo Health Science Campus, 3000 Arlington Ave. Toledo, OH 43614, USA
- Department of Zoology and Physiology, University of Wyoming, 1000 E. University Ave, Biological Science Building, Room 319F, Laramie, WY 82071
| | - Veani Fernando
- Department of Cell & Cancer Biology, College of Medicine and Life Sciences, University of Toledo Health Science Campus, 3000 Arlington Ave. Toledo, OH 43614, USA
- Division of Rheumatology, University of Colorado, Anschutz Medical Campus Barbara Davis Center, Mail Stop B115, 1775 Aurora Court, Aurora, Colorado 80045
| | - Xunzhen Zheng
- Department of Cell & Cancer Biology, College of Medicine and Life Sciences, University of Toledo Health Science Campus, 3000 Arlington Ave. Toledo, OH 43614, USA
| | - Osama Sweef
- MetroHealth Medical Center, Case Western Reserve University School of Medicine, Case Comprehensive Cancer Center, 2500 MetroHealth Drive, Cleveland, OH 44109
- Department of Zoology, Faculty of Science, Tanta University, Tanta 31527, Egypt
| | - Eun-Seok Choi
- MetroHealth Medical Center, Case Western Reserve University School of Medicine, Case Comprehensive Cancer Center, 2500 MetroHealth Drive, Cleveland, OH 44109
| | - Venetia Thomas
- MetroHealth Medical Center, Case Western Reserve University School of Medicine, Case Comprehensive Cancer Center, 2500 MetroHealth Drive, Cleveland, OH 44109
| | - Saori Furuta
- Department of Cell & Cancer Biology, College of Medicine and Life Sciences, University of Toledo Health Science Campus, 3000 Arlington Ave. Toledo, OH 43614, USA
- MetroHealth Medical Center, Case Western Reserve University School of Medicine, Case Comprehensive Cancer Center, 2500 MetroHealth Drive, Cleveland, OH 44109
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Jaagura M, Kronberg J, Reigo A, Aasmets O, Nikopensius T, Võsa U, Bomba L, Estrada K, Wuster A, Esko T, Org E. Comorbidities confound metabolomics studies of human disease. Sci Rep 2024; 14:24810. [PMID: 39438584 PMCID: PMC11496539 DOI: 10.1038/s41598-024-75556-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2024] [Accepted: 10/07/2024] [Indexed: 10/25/2024] Open
Abstract
The co-occurrence of multiple chronic conditions, termed multimorbidity, presents an expanding global health challenge, demanding effective diagnostics and treatment strategies. Chronic ailments such as obesity, diabetes, and cardiovascular diseases have been linked to metabolites interacting between the host and microbiota. In this study, we investigated the impact of co-existing conditions on risk estimations for 1375 plasma metabolites in 919 individuals from population-based Estonian Biobank cohort using liquid chromatography mass spectrometry (LC-MS) method. We leveraged annually linked national electronic health records (EHRs) data to delineate comorbidities in incident cases and controls for the 14 common chronic conditions. Among the 254 associations observed across 13 chronic conditions, we primarily identified disease-specific risk factors (92%, 217/235), with most predictors (93%, 219/235) found to be related to the gut microbiome upon cross-referencing recent literature data. Accounting for comorbidities led to a reduction of common metabolite predictors across various conditions. In conclusion, our study underscores the potential of utilizing biobank-linked retrospective and prospective EHRs for the disease-specific profiling of diverse multifactorial chronic conditions.
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Affiliation(s)
- Madis Jaagura
- Institute of Genomics, Estonian Genome Centre, University of Tartu, Tartu, Estonia
| | - Jaanika Kronberg
- Institute of Genomics, Estonian Genome Centre, University of Tartu, Tartu, Estonia
| | - Anu Reigo
- Institute of Genomics, Estonian Genome Centre, University of Tartu, Tartu, Estonia
| | - Oliver Aasmets
- Institute of Genomics, Estonian Genome Centre, University of Tartu, Tartu, Estonia
| | - Tiit Nikopensius
- Institute of Genomics, Estonian Genome Centre, University of Tartu, Tartu, Estonia
| | - Urmo Võsa
- Institute of Genomics, Estonian Genome Centre, University of Tartu, Tartu, Estonia
| | | | | | | | - Tõnu Esko
- Institute of Genomics, Estonian Genome Centre, University of Tartu, Tartu, Estonia
| | - Elin Org
- Institute of Genomics, Estonian Genome Centre, University of Tartu, Tartu, Estonia.
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35
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Wirbel J, Essex M, Forslund SK, Zeller G. A realistic benchmark for differential abundance testing and confounder adjustment in human microbiome studies. Genome Biol 2024; 25:247. [PMID: 39322959 PMCID: PMC11423519 DOI: 10.1186/s13059-024-03390-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2023] [Accepted: 09/06/2024] [Indexed: 09/27/2024] Open
Abstract
BACKGROUND In microbiome disease association studies, it is a fundamental task to test which microbes differ in their abundance between groups. Yet, consensus on suitable or optimal statistical methods for differential abundance testing is lacking, and it remains unexplored how these cope with confounding. Previous differential abundance benchmarks relying on simulated datasets did not quantitatively evaluate the similarity to real data, which undermines their recommendations. RESULTS Our simulation framework implants calibrated signals into real taxonomic profiles, including signals mimicking confounders. Using several whole meta-genome and 16S rRNA gene amplicon datasets, we validate that our simulated data resembles real data from disease association studies much more than in previous benchmarks. With extensively parametrized simulations, we benchmark the performance of nineteen differential abundance methods and further evaluate the best ones on confounded simulations. Only classic statistical methods (linear models, the Wilcoxon test, t-test), limma, and fastANCOM properly control false discoveries at relatively high sensitivity. When additionally considering confounders, these issues are exacerbated, but we find that adjusted differential abundance testing can effectively mitigate them. In a large cardiometabolic disease dataset, we showcase that failure to account for covariates such as medication causes spurious association in real-world applications. CONCLUSIONS Tight error control is critical for microbiome association studies. The unsatisfactory performance of many differential abundance methods and the persistent danger of unchecked confounding suggest these contribute to a lack of reproducibility among such studies. We have open-sourced our simulation and benchmarking software to foster a much-needed consolidation of statistical methodology for microbiome research.
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Affiliation(s)
- Jakob Wirbel
- Structural and Computational Biology Unit (SCB), European Molecular Biology Laboratory (EMBL), Heidelberg, Germany
| | - Morgan Essex
- Experimental and Clinical Research Center (ECRC), a cooperation of the Max-Delbrück Center and Charité-Universitätsmedizin, Berlin, Germany
- Max-Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC), Berlin, Germany
- Charité-Universitätsmedizin Berlin (a corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin), Berlin, Germany
| | - Sofia Kirke Forslund
- Structural and Computational Biology Unit (SCB), European Molecular Biology Laboratory (EMBL), Heidelberg, Germany.
- Experimental and Clinical Research Center (ECRC), a cooperation of the Max-Delbrück Center and Charité-Universitätsmedizin, Berlin, Germany.
- Max-Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC), Berlin, Germany.
- Charité-Universitätsmedizin Berlin (a corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin), Berlin, Germany.
- German Center for Cardiovascular Research (DZHK), Partner Site Berlin, Berlin, Germany.
| | - Georg Zeller
- Structural and Computational Biology Unit (SCB), European Molecular Biology Laboratory (EMBL), Heidelberg, Germany.
- Center for Infectious Diseases (LUCID), Leiden University, Leiden University Medical Center (LUMC), Leiden, Netherlands.
- Center for Microbiome Analyses and Therapeutics (CMAT), Leiden University Medical Center, Leiden, Netherlands.
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36
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Byndloss M, Devkota S, Duca F, Hendrik Niess J, Nieuwdorp M, Orho-Melander M, Sanz Y, Tremaroli V, Zhao L. The Gut Microbiota and Diabetes: Research, Translation, and Clinical Applications-2023 Diabetes, Diabetes Care, and Diabetologia Expert Forum. Diabetes Care 2024; 47:1491-1508. [PMID: 38996003 PMCID: PMC11362125 DOI: 10.2337/dci24-0052] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/26/2024] [Accepted: 05/23/2024] [Indexed: 07/14/2024]
Abstract
This article summarizes the state of the science on the role of the gut microbiota (GM) in diabetes from a recent international expert forum organized by Diabetes, Diabetes Care, and Diabetologia, which was held at the European Association for the Study of Diabetes 2023 Annual Meeting in Hamburg, Germany. Forum participants included clinicians and basic scientists who are leading investigators in the field of the intestinal microbiome and metabolism. Their conclusions were as follows: 1) the GM may be involved in the pathophysiology of type 2 diabetes, as microbially produced metabolites associate both positively and negatively with the disease, and mechanistic links of GM functions (e.g., genes for butyrate production) with glucose metabolism have recently emerged through the use of Mendelian randomization in humans; 2) the highly individualized nature of the GM poses a major research obstacle, and large cohorts and a deep-sequencing metagenomic approach are required for robust assessments of associations and causation; 3) because single-time point sampling misses intraindividual GM dynamics, future studies with repeated measures within individuals are needed; and 4) much future research will be required to determine the applicability of this expanding knowledge to diabetes diagnosis and treatment, and novel technologies and improved computational tools will be important to achieve this goal.
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Affiliation(s)
- Mariana Byndloss
- Vanderbilt University Medical Center, Nashville, TN
- Howard Hughes Medical Institute, Vanderbilt University Medical Center, Nashville, TN
| | - Suzanne Devkota
- Human Microbiome Research Institute, Cedars-Sinai Medical Center, Los Angeles, CA
| | | | - Jan Hendrik Niess
- Department of Biomedicine, University of Basel, Basel, Switzerland
- Department of Gastroenterology and Hepatology, University Digestive Healthcare Center, Clarunis, Basel, Switzerland
| | - Max Nieuwdorp
- Department of Internal and Vascular Medicine, Amsterdam University Medical Centers, Amsterdam, the Netherlands
- Amsterdam Diabeter Center, Amsterdam University Medical Centers, Amsterdam, the Netherlands
| | - Marju Orho-Melander
- Department of Clinical Sciences in Malmö, Lund University Diabetes Centre, Lund University, Malmö, Sweden
| | - Yolanda Sanz
- Institute of Agrochemistry and Food Technology, Spanish National Research Council (IATA-CSIC), Valencia, Spain
| | - Valentina Tremaroli
- Wallenberg Laboratory, Department of Molecular and Clinical Medicine, Institute of Medicine, University of Gothenburg, Gothenburg, Sweden
| | - Liping Zhao
- Department of Biochemistry and Microbiology, School of Environmental and Biological Sciences, Rutgers University, New Brunswick, NJ
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37
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Lichtenegger AS, Posadas-Cantera S, Badr MT, Häcker G. Comparison of the diversity of anaerobic-cultured gut bacterial communities on different culture media using 16S rDNA sequencing. J Microbiol Methods 2024; 224:106988. [PMID: 38977080 DOI: 10.1016/j.mimet.2024.106988] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/16/2024] [Revised: 07/03/2024] [Accepted: 07/03/2024] [Indexed: 07/10/2024]
Abstract
The gut microbiome is a dense and diverse community of different microorganisms that deeply influence human physiology and that have important interactions with pathogens. For the correct antibiotic treatment of infections, with its twin goals of effective inhibition of the pathogen and limitation of collateral damage to the microbiome, the identification of infectious organisms is key. Microbiological culturing is still the mainstay of pathogen identification, and anaerobic species are among the most demanding bacterial communities to culture. This study aimed to evaluate the impact of growth media on the culture of an-aerobic bacteria from human stool samples. Stool samples from eight human subjects were cultured each on a yeast extract cysteine blood agar (HCB) and a modified peptone-yeast extract-glucose (MPYG) plate and subjected to Illumina NGS analysis after DNA extraction and amplification. The results showed tight clustering of sequencing samples belonging to the same human subject. Various differences in bacterial richness and evenness could be observed between the two media, with HCB plates supporting the growth of a more diverse microbial community, and MPYG plates improving the growth rates of certain taxa. No statistical significance was observed between the groups. This study highlights the importance of choosing the appropriate growth media for anaerobic bacterial culture and adjusting culture conditions to target specific pathological conditions. HCB plates are suitable for standard microbiological diagnostics, while MPYG plates may be more appropriate for targeting specific conditions. This work emphasizes the role of next-generation sequencing in supporting future research in clinical microbiology.
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Affiliation(s)
- Anne Sophie Lichtenegger
- Institute of Medical Microbiology and Hygiene, Medical Center-University of Freiburg, Faculty of Medicine, University of Freiburg, 79104 Freiburg, Germany.
| | - Sara Posadas-Cantera
- Institute of Medical Microbiology and Hygiene, Medical Center-University of Freiburg, Faculty of Medicine, University of Freiburg, 79104 Freiburg, Germany
| | - Mohamed Tarek Badr
- Institute of Medical Microbiology and Hygiene, Medical Center-University of Freiburg, Faculty of Medicine, University of Freiburg, 79104 Freiburg, Germany
| | - Georg Häcker
- Institute of Medical Microbiology and Hygiene, Medical Center-University of Freiburg, Faculty of Medicine, University of Freiburg, 79104 Freiburg, Germany; BIOSS Centre for Biological Signaling Studies, University of Freiburg, 79104 Freiburg, Germany
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38
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Li Z, Xu Q, Huangfu N, Cui H. The effect and mechanism of inulin on atherosclerosis is mediated by the characteristic intestinal flora and metabolites. Coron Artery Dis 2024; 35:498-508. [PMID: 38767579 DOI: 10.1097/mca.0000000000001377] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 05/22/2024]
Abstract
BACKGROUND Inflammation and hyperlipidemia can cause atherosclerosis. Prebiotic inulin has been proven to effectively reduce inflammation and blood lipid levels. Utilizing a mouse model induced by a high-fat diet, this study aimed to explore whether the characteristic intestinal flora and its metabolites mediate the effects of inulin intervention on atherosclerosis and to clarify the specific mechanism. METHODS Thirty apolipoprotein E-deficient (ApoE-/-) mice were randomly divided into three groups. They were fed with a normal diet, a high-fat diet or an inulin+high-fat diet for 16 weeks. The total cholesterol (TC), triglyceride (TG), low-density lipoprotein cholesterol (LDL-C) and high-density lipoprotein cholesterol (HDL-C) in the three groups were compared. The gross aorta and aortic sinus of mice were stained with oil red O, and the area of atherosclerotic plaque was observed and compared. The diversity and structure of the mouse fecal flora were detected by sequencing the V3-V4 region of the 16S rRNA gene, and the levels of metabolites in mouse feces were assessed by gas chromatography-mass spectrometry. The plasma lipopolysaccharide (LPS) levels and aortic inflammatory factors were measured by multi-index flow cytometry (CBA). RESULTS ApoE-/- mice fed with the high-fat diet exhibited an increase of approximately 46% in the area of atherosclerotic lesions, and the levels of TC, TG and LDL-C were significantly increased ( P < 0.05) compared with levels in the normal diet group. After inulin was added to the high-fat group, the area of atherosclerotic lesions, the level of serum LPS and aortic inflammation were reduced, and the levels of TC, TG and LDL-C were decreased ( P < 0.05). Based on 16S rRNA gene detection, we found that the composition of the intestinal microbiota, such as Prevotella, and metabolites, such as L-arginine, changed significantly due to hyperlipidemia, and the dietary inulin intervention partially reversed the relevant changes. CONCLUSION Inulin can inhibit the formation of atherosclerotic plaques, which may be related to the changes in lipid metabolism, the composition of the intestinal microbial community and its metabolites, and the inhibition of the expression of related inflammatory factors. Our study identified the relationships among the characteristic intestinal microbiota, metabolites and atherosclerosis, aiming to provide a new direction for future research to delay or treat atherosclerosis by changing the composition and function of the host intestinal microbiota and metabolites.
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Affiliation(s)
| | - Qingqing Xu
- Department of Nephrology, The First Affiliated Hospital of Ningbo University, Ningbo, China
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39
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Byndloss M, Devkota S, Duca F, Niess JH, Nieuwdorp M, Orho-Melander M, Sanz Y, Tremaroli V, Zhao L. The gut microbiota and diabetes: research, translation, and clinical applications - 2023 Diabetes, Diabetes Care, and Diabetologia Expert Forum. Diabetologia 2024; 67:1760-1782. [PMID: 38910152 PMCID: PMC11410996 DOI: 10.1007/s00125-024-06198-1] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/26/2024] [Accepted: 05/23/2024] [Indexed: 06/25/2024]
Abstract
This article summarises the state of the science on the role of the gut microbiota (GM) in diabetes from a recent international expert forum organised by Diabetes, Diabetes Care, and Diabetologia, which was held at the European Association for the Study of Diabetes 2023 Annual Meeting in Hamburg, Germany. Forum participants included clinicians and basic scientists who are leading investigators in the field of the intestinal microbiome and metabolism. Their conclusions were as follows: (1) the GM may be involved in the pathophysiology of type 2 diabetes, as microbially produced metabolites associate both positively and negatively with the disease, and mechanistic links of GM functions (e.g. genes for butyrate production) with glucose metabolism have recently emerged through the use of Mendelian randomisation in humans; (2) the highly individualised nature of the GM poses a major research obstacle, and large cohorts and a deep-sequencing metagenomic approach are required for robust assessments of associations and causation; (3) because single time point sampling misses intraindividual GM dynamics, future studies with repeated measures within individuals are needed; and (4) much future research will be required to determine the applicability of this expanding knowledge to diabetes diagnosis and treatment, and novel technologies and improved computational tools will be important to achieve this goal.
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Affiliation(s)
- Mariana Byndloss
- Vanderbilt University Medical Center, Nashville, TN, USA
- Howard Hughes Medical Institute, Vanderbilt University Medical Center, Nashville, TN, USA
| | - Suzanne Devkota
- Cedars-Sinai Medical Center, Human Microbiome Research Institute, Los Angeles, CA, USA
| | | | - Jan Hendrik Niess
- Department of Biomedicine, University of Basel, Basel, Switzerland
- Department of Gastroenterology and Hepatology, University Digestive Healthcare Center, Clarunis, Basel, Switzerland
| | - Max Nieuwdorp
- Department of Internal and Vascular Medicine, Amsterdam University Medical Centers, Amsterdam, the Netherlands
- Amsterdam Diabeter Center, Amsterdam University Medical Centers, Amsterdam, the Netherlands
| | - Marju Orho-Melander
- Department of Clinical Sciences in Malmö, Lund University Diabetes Centre, Lund University, Malmö, Sweden
| | - Yolanda Sanz
- Institute of Agrochemistry and Food Technology, Spanish National Research Council (IATA-CSIC), Valencia, Spain.
| | - Valentina Tremaroli
- Wallenberg Laboratory, Department of Molecular and Clinical Medicine, Institute of Medicine, University of Gothenburg, Gothenburg, Sweden
| | - Liping Zhao
- Department of Biochemistry and Microbiology, School of Environmental and Biological Sciences, Rutgers University, New Brunswick, NJ, USA
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40
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Byndloss M, Devkota S, Duca F, Niess JH, Nieuwdorp M, Orho-Melander M, Sanz Y, Tremaroli V, Zhao L. The Gut Microbiota and Diabetes: Research, Translation, and Clinical Applications-2023 Diabetes, Diabetes Care, and Diabetologia Expert Forum. Diabetes 2024; 73:1391-1410. [PMID: 38912690 PMCID: PMC11333376 DOI: 10.2337/dbi24-0028] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/26/2024] [Accepted: 05/23/2024] [Indexed: 06/25/2024]
Abstract
This article summarizes the state of the science on the role of the gut microbiota (GM) in diabetes from a recent international expert forum organized by Diabetes, Diabetes Care, and Diabetologia, which was held at the European Association for the Study of Diabetes 2023 Annual Meeting in Hamburg, Germany. Forum participants included clinicians and basic scientists who are leading investigators in the field of the intestinal microbiome and metabolism. Their conclusions were as follows: 1) the GM may be involved in the pathophysiology of type 2 diabetes, as microbially produced metabolites associate both positively and negatively with the disease, and mechanistic links of GM functions (e.g., genes for butyrate production) with glucose metabolism have recently emerged through the use of Mendelian randomization in humans; 2) the highly individualized nature of the GM poses a major research obstacle, and large cohorts and a deep-sequencing metagenomic approach are required for robust assessments of associations and causation; 3) because single-time point sampling misses intraindividual GM dynamics, future studies with repeated measures within individuals are needed; and 4) much future research will be required to determine the applicability of this expanding knowledge to diabetes diagnosis and treatment, and novel technologies and improved computational tools will be important to achieve this goal.
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Affiliation(s)
- Mariana Byndloss
- Vanderbilt University Medical Center, Nashville, TN
- Howard Hughes Medical Institute, Vanderbilt University Medical Center, Nashville, TN
| | - Suzanne Devkota
- Human Microbiome Research Institute, Cedars-Sinai Medical Center, Los Angeles, CA
| | | | - Jan Hendrik Niess
- Department of Biomedicine, University of Basel, Basel, Switzerland
- Department of Gastroenterology and Hepatology, University Digestive Healthcare Center, Clarunis, Basel, Switzerland
| | - Max Nieuwdorp
- Department of Internal and Vascular Medicine, Amsterdam University Medical Centers, Amsterdam, the Netherlands
- Amsterdam Diabeter Center, Amsterdam University Medical Centers, Amsterdam, the Netherlands
| | - Marju Orho-Melander
- Department of Clinical Sciences in Malmö, Lund University Diabetes Centre, Lund University, Malmö, Sweden
| | - Yolanda Sanz
- Institute of Agrochemistry and Food Technology, Spanish National Research Council (IATA-CSIC), Valencia, Spain
| | - Valentina Tremaroli
- Wallenberg Laboratory, Department of Molecular and Clinical Medicine, Institute of Medicine, University of Gothenburg, Gothenburg, Sweden
| | - Liping Zhao
- Department of Biochemistry and Microbiology, School of Environmental and Biological Sciences, Rutgers University, New Brunswick, NJ
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41
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Balanche J, Lahaye E, Bremard L, Thomas B, Fetissov SO. Comparison of Glucose Metabolizing Properties of Enterobacterial Probiotic Strains In Vitro. Nutrients 2024; 16:2677. [PMID: 39203813 PMCID: PMC11357327 DOI: 10.3390/nu16162677] [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: 07/13/2024] [Revised: 07/27/2024] [Accepted: 08/08/2024] [Indexed: 09/03/2024] Open
Abstract
Before the absorption in the intestine, glucose encounters gut bacteria, which may serve as a barrier against hyperglycemia by metabolizing glucose. In the present study, we compared the capacity of enterobacterial strains to lower glucose levels in an in vitro model of nutrient-induced bacterial growth. Two probiotic strains, Hafnia alvei HA4597 (H. alvei) and Escherichia coli (E. coli) Nissle 1917, as well as E. coli K12, were studied. To mimic bacterial growth in the gut, a planktonic culture was supplemented twice daily by the Luria Bertani milieu with or without 0.5% glucose. Repeated nutrient provision resulted in the incremental growth of bacteria. However, in the presence of glucose, the maximal growth of both strains of E. coli but not of H. alvei was inhibited. When glucose was added to the culture medium, a continuous decrease in its concentration was observed during each feeding phase. At its highest density, H. alvei displayed more efficient glucose consumption accompanied by a more pronounced downregulation of glucose transporters' expression than E. coli K12. Thus, the study reveals that the probiotic strain H. alvei HA4597 is more resilient to maintain its growth than E. coli in the presence of 0.5% glucose accompanied by more efficient glucose consumption. This experimental approach offers a new strategy for the identification of probiotics with increased glucose metabolizing capacities potentially useful for the prevention and co-treatment of type 2 diabetes.
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Affiliation(s)
| | | | | | | | - Sergueï O. Fetissov
- Regulatory Peptides-Energy Metabolism and Motivated Behavior Team, Neuroendocrine, Endocrine and Germinal Differentiation and Communication Laboratory, Inserm UMR1239, University of Rouen Normandie, 76000 Rouen, France; (J.B.); (E.L.); (L.B.); (B.T.)
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42
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Jung YH, Chae CW, Han HJ. The potential role of gut microbiota-derived metabolites as regulators of metabolic syndrome-associated mitochondrial and endolysosomal dysfunction in Alzheimer's disease. Exp Mol Med 2024; 56:1691-1702. [PMID: 39085351 PMCID: PMC11372123 DOI: 10.1038/s12276-024-01282-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/12/2024] [Revised: 04/20/2024] [Accepted: 05/10/2024] [Indexed: 08/02/2024] Open
Abstract
Although the role of gut microbiota (GMB)-derived metabolites in mitochondrial and endolysosomal dysfunction in Alzheimer's disease (AD) under metabolic syndrome remains unclear, deciphering these host-metabolite interactions represents a major public health challenge. Dysfunction of mitochondria and endolysosomal networks (ELNs) plays a crucial role in metabolic syndrome and can exacerbate AD progression, highlighting the need to study their reciprocal regulation for a better understanding of how AD is linked to metabolic syndrome. Concurrently, metabolic disorders are associated with alterations in the composition of the GMB. Recent evidence suggests that changes in the composition of the GMB and its metabolites may be involved in AD pathology. This review highlights the mechanisms of metabolic syndrome-mediated AD development, focusing on the interconnected roles of mitochondrial dysfunction, ELN abnormalities, and changes in the GMB and its metabolites. We also discuss the pathophysiological role of GMB-derived metabolites, including amino acids, fatty acids, other metabolites, and extracellular vesicles, in mediating their effects on mitochondrial and ELN dysfunction. Finally, this review proposes therapeutic strategies for AD by directly modulating mitochondrial and ELN functions through targeting GMB metabolites under metabolic syndrome.
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Affiliation(s)
- Young Hyun Jung
- Department of Physiology, College of Medicine, Soonchunhyang University, Cheonan, 31151, Korea
| | - Chang Woo Chae
- Department of Veterinary Physiology, College of Veterinary Medicine, Research Institute for Veterinary Science, and BK21 FOUR Future Veterinary Medicine Leading Education & Research Center, Seoul National University, Seoul, South Korea
| | - Ho Jae Han
- Department of Veterinary Physiology, College of Veterinary Medicine, Research Institute for Veterinary Science, and BK21 FOUR Future Veterinary Medicine Leading Education & Research Center, Seoul National University, Seoul, South Korea.
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43
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Mei Z, Wang F, Bhosle A, Dong D, Mehta R, Ghazi A, Zhang Y, Liu Y, Rinott E, Ma S, Rimm EB, Daviglus M, Willett WC, Knight R, Hu FB, Qi Q, Chan AT, Burk RD, Stampfer MJ, Shai I, Kaplan RC, Huttenhower C, Wang DD. Strain-specific gut microbial signatures in type 2 diabetes identified in a cross-cohort analysis of 8,117 metagenomes. Nat Med 2024; 30:2265-2276. [PMID: 38918632 PMCID: PMC11620793 DOI: 10.1038/s41591-024-03067-7] [Citation(s) in RCA: 22] [Impact Index Per Article: 22.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2023] [Accepted: 05/14/2024] [Indexed: 06/27/2024]
Abstract
The association of gut microbial features with type 2 diabetes (T2D) has been inconsistent due in part to the complexity of this disease and variation in study design. Even in cases in which individual microbial species have been associated with T2D, mechanisms have been unable to be attributed to these associations based on specific microbial strains. We conducted a comprehensive study of the T2D microbiome, analyzing 8,117 shotgun metagenomes from 10 cohorts of individuals with T2D, prediabetes, and normoglycemic status in the United States, Europe, Israel and China. Dysbiosis in 19 phylogenetically diverse species was associated with T2D (false discovery rate < 0.10), for example, enriched Clostridium bolteae and depleted Butyrivibrio crossotus. These microorganisms also contributed to community-level functional changes potentially underlying T2D pathogenesis, for example, perturbations in glucose metabolism. Our study identifies within-species phylogenetic diversity for strains of 27 species that explain inter-individual differences in T2D risk, such as Eubacterium rectale. In some cases, these were explained by strain-specific gene carriage, including loci involved in various mechanisms of horizontal gene transfer and novel biological processes underlying metabolic risk, for example, quorum sensing. In summary, our study provides robust cross-cohort microbial signatures in a strain-resolved manner and offers new mechanistic insights into T2D.
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Affiliation(s)
- Zhendong Mei
- Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA
- Broad Institute of MIT and Harvard, Cambridge, MA, USA
| | - Fenglei Wang
- Broad Institute of MIT and Harvard, Cambridge, MA, USA
- Department of Nutrition, Harvard T.H. Chan School of Public Health, Boston, MA, USA
| | - Amrisha Bhosle
- Broad Institute of MIT and Harvard, Cambridge, MA, USA
- Department of Biostatistics, Harvard T.H. Chan School of Public Health, Boston, MA, USA
| | - Danyue Dong
- Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA
- Broad Institute of MIT and Harvard, Cambridge, MA, USA
| | - Raaj Mehta
- Broad Institute of MIT and Harvard, Cambridge, MA, USA
- Division of Gastroenterology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA
- Clinical and Translational Epidemiology Unit, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA
- Department of Chemistry and Chemical Biology, Harvard University, Cambridge, MA, USA
| | - Andrew Ghazi
- Broad Institute of MIT and Harvard, Cambridge, MA, USA
- Department of Biostatistics, Harvard T.H. Chan School of Public Health, Boston, MA, USA
| | - Yancong Zhang
- Broad Institute of MIT and Harvard, Cambridge, MA, USA
- Department of Biostatistics, Harvard T.H. Chan School of Public Health, Boston, MA, USA
| | - Yuxi Liu
- Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA
- Broad Institute of MIT and Harvard, Cambridge, MA, USA
- Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, USA
| | - Ehud Rinott
- Department of Medicine, Hebrew University and Hadassah Medical Center, Jerusalem, Israel
| | - Siyuan Ma
- Department of Biostatistics, Vanderbilt University Medical Center, Nashville, TN, USA
| | - Eric B Rimm
- Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA
- Department of Nutrition, Harvard T.H. Chan School of Public Health, Boston, MA, USA
- Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, USA
| | - Martha Daviglus
- Institute for Minority Health Research, University of Illinois Chicago, Chicago, IL, USA
| | - Walter C Willett
- Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA
- Department of Nutrition, Harvard T.H. Chan School of Public Health, Boston, MA, USA
- Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, USA
| | - Rob Knight
- Center for Microbiome Innovation, Jacobs School of Engineering, University of California San Diego, La Jolla, CA, USA
- Department of Pediatrics, School of Medicine, University of California San Diego, La Jolla, CA, USA
- Department of Computer Science and Engineering, University of California San Diego, La Jolla, CA, USA
| | - Frank B Hu
- Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA
- Department of Nutrition, Harvard T.H. Chan School of Public Health, Boston, MA, USA
- Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, USA
| | - Qibin Qi
- Department of Nutrition, Harvard T.H. Chan School of Public Health, Boston, MA, USA
- Department of Epidemiology and Population Health, Albert Einstein College of Medicine, Bronx, NY, USA
| | - Andrew T Chan
- Broad Institute of MIT and Harvard, Cambridge, MA, USA
- Division of Gastroenterology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA
- Clinical and Translational Epidemiology Unit, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA
| | - Robert D Burk
- Department of Epidemiology and Population Health, Albert Einstein College of Medicine, Bronx, NY, USA
- Department of Pediatrics, Albert Einstein College of Medicine, Bronx, NY, USA
- Department of Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, NY, USA
- Department of Obstetrics, Gynecology and Women's Health, Albert Einstein College of Medicine, Bronx, NY, USA
| | - Meir J Stampfer
- Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA
- Department of Nutrition, Harvard T.H. Chan School of Public Health, Boston, MA, USA
- Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, USA
| | - Iris Shai
- Department of Nutrition, Harvard T.H. Chan School of Public Health, Boston, MA, USA
- Faculty of Health Sciences, The Health and Nutrition Innovative International Research Center, Ben-Gurion University of the Negev, Be'er Sheva, Israel
| | - Robert C Kaplan
- Department of Epidemiology and Population Health, Albert Einstein College of Medicine, Bronx, NY, USA
- Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA
| | - Curtis Huttenhower
- Broad Institute of MIT and Harvard, Cambridge, MA, USA.
- Department of Biostatistics, Harvard T.H. Chan School of Public Health, Boston, MA, USA.
- Department of Immunology and Infectious Diseases, Harvard T.H. Chan School of Public Health, Boston, MA, USA.
- Harvard Chan Microbiome in Public Health Center, Harvard T.H. Chan School of Public Health, Boston, MA, USA.
| | - Dong D Wang
- Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.
- Broad Institute of MIT and Harvard, Cambridge, MA, USA.
- Department of Nutrition, Harvard T.H. Chan School of Public Health, Boston, MA, USA.
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44
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Shiroma H, Darzi Y, Terajima E, Nakagawa Z, Tsuchikura H, Tsukuda N, Moriya Y, Okuda S, Goto S, Yamada T. Enteropathway: the metabolic pathway database for the human gut microbiota. Brief Bioinform 2024; 25:bbae419. [PMID: 39222063 PMCID: PMC11367760 DOI: 10.1093/bib/bbae419] [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: 04/10/2024] [Revised: 07/09/2024] [Accepted: 08/08/2024] [Indexed: 09/04/2024] Open
Abstract
The human gut microbiota produces diverse, extensive metabolites that have the potential to affect host physiology. Despite significant efforts to identify metabolic pathways for producing these microbial metabolites, a comprehensive metabolic pathway database for the human gut microbiota is still lacking. Here, we present Enteropathway, a metabolic pathway database that integrates 3269 compounds, 3677 reactions, and 876 modules that were obtained from 1012 manually curated scientific literature. Notably, 698 modules of these modules are new entries and cannot be found in any other databases. The database is accessible from a web application (https://enteropathway.org) that offers a metabolic diagram for graphical visualization of metabolic pathways, a customization interface, and an enrichment analysis feature for highlighting enriched modules on the metabolic diagram. Overall, Enteropathway is a comprehensive reference database that can complement widely used databases, and a tool for visual and statistical analysis in human gut microbiota studies and was designed to help researchers pinpoint new insights into the complex interplay between microbiota and host metabolism.
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Affiliation(s)
- Hirotsugu Shiroma
- School of Life Science and Technology, Tokyo Institute of Technology, 2-12-1 M6-3 Ookayama, Meguro-ku, Tokyo 152-8550, Japan
| | - Youssef Darzi
- School of Life Science and Technology, Tokyo Institute of Technology, 2-12-1 M6-3 Ookayama, Meguro-ku, Tokyo 152-8550, Japan
- Omixer solutions, 4-7-15, Zaimokuza, Kamakura-shi, Kanagawa 248-0013, Japan
| | - Etsuko Terajima
- School of Life Science and Technology, Tokyo Institute of Technology, 2-12-1 M6-3 Ookayama, Meguro-ku, Tokyo 152-8550, Japan
| | - Zenichi Nakagawa
- School of Life Science and Technology, Tokyo Institute of Technology, 2-12-1 M6-3 Ookayama, Meguro-ku, Tokyo 152-8550, Japan
| | - Hirotaka Tsuchikura
- School of Life Science and Technology, Tokyo Institute of Technology, 2-12-1 M6-3 Ookayama, Meguro-ku, Tokyo 152-8550, Japan
| | - Naoki Tsukuda
- School of Life Science and Technology, Tokyo Institute of Technology, 2-12-1 M6-3 Ookayama, Meguro-ku, Tokyo 152-8550, Japan
| | - Yuki Moriya
- Database Center for Life Science, Joint Support-Center for Data Science Research, Research Organization of Information and Systems, 178-4-4 Wakashiba, Kashiwa-shi, Chiba 277-0871, Japan
| | - Shujiro Okuda
- Graduate School of Medical and Dental Sciences, Niigata University, 2-5274, Gakkocho-dori, Chuo-ku, Niigata City, Niigata 951-8514, Japan
| | - Susumu Goto
- Database Center for Life Science, Joint Support-Center for Data Science Research, Research Organization of Information and Systems, 178-4-4 Wakashiba, Kashiwa-shi, Chiba 277-0871, Japan
| | - Takuji Yamada
- School of Life Science and Technology, Tokyo Institute of Technology, 2-12-1 M6-3 Ookayama, Meguro-ku, Tokyo 152-8550, Japan
- Metagen, Inc., 246-2 Mizukami, Kakuganji, Tsuruoka, Yamagata 997-0052, Japan
- Metagen Theurapeutics, Inc., 246-2 Mizukami, Kakuganji, Tsuruoka, Yamagata 997-0052, Japan
- Digzyme, Inc., 2-2-1 Toranomon, Minato-ku, Tokyo 105-0001, Japan
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Zarei I, Eloranta AM, Klåvus A, Väistö J, Lehtonen M, Mikkonen S, Koistinen VM, Sallinen T, Haapala EA, Lintu N, Soininen S, Haikonen R, Atalay M, Schwab U, Auriola S, Kolehmainen M, Hanhineva K, Lakka TA. Eight-year diet and physical activity intervention affects serum metabolites during childhood and adolescence: A nonrandomized controlled trial. iScience 2024; 27:110295. [PMID: 39055945 PMCID: PMC11269805 DOI: 10.1016/j.isci.2024.110295] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2023] [Revised: 04/16/2024] [Accepted: 06/14/2024] [Indexed: 07/28/2024] Open
Abstract
Long-term lifestyle interventions in childhood and adolescence can significantly improve cardiometabolic health, but the underlying molecular mechanisms remain poorly understood. To address this knowledge gap, we conducted an 8-year diet and physical activity intervention in a general population of children. The research revealed that the intervention influenced 80 serum metabolites over two years, with 17 metabolites continuing to be affected after eight years. The intervention primarily impacted fatty amides, including palmitic amide, linoleamide, oleamide, and others, as well as unsaturated fatty acids, acylcarnitines, phospholipids, sterols, gut microbiota-derived metabolites, amino acids, and purine metabolites. Particularly noteworthy were the pronounced changes in serum fatty amides. These serum metabolite alterations could represent molecular mechanisms responsible for the observed benefits of long-term lifestyle interventions on cardiometabolic and overall health since childhood. Understanding these metabolic changes may provide valuable insights into the prevention of cardiometabolic and other non-communicable diseases since childhood.
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Affiliation(s)
- Iman Zarei
- Institute of Public Health and Clinical Nutrition, School of Medicine, Faculty of Health Sciences, University of Eastern Finland, Kuopio, Finland
- Institute of Biomedicine, School of Medicine, Faculty of Health Sciences, University of Eastern Finland, Kuopio, Finland
| | - Aino-Maija Eloranta
- Institute of Public Health and Clinical Nutrition, School of Medicine, Faculty of Health Sciences, University of Eastern Finland, Kuopio, Finland
- Institute of Biomedicine, School of Medicine, Faculty of Health Sciences, University of Eastern Finland, Kuopio, Finland
- Department of Medicine, Endocrinology and Clinical Nutrition, Kuopio University Hospital, Kuopio, Finland
| | - Anton Klåvus
- Institute of Public Health and Clinical Nutrition, School of Medicine, Faculty of Health Sciences, University of Eastern Finland, Kuopio, Finland
| | - Juuso Väistö
- Institute of Biomedicine, School of Medicine, Faculty of Health Sciences, University of Eastern Finland, Kuopio, Finland
| | - Marko Lehtonen
- School of Pharmacy, Faculty of Health Science, University of Eastern Finland, Kuopio, Finland
- LC-MS Metabolomics Center, Biocenter Kuopio, Kuopio, Finland
| | - Santtu Mikkonen
- Department of Applied Physics, University of Eastern Finland, Kuopio, Finland
- Department of Environmental and Biological Sciences, University of Eastern Finland, Kuopio, Finland
| | - Ville M. Koistinen
- Institute of Public Health and Clinical Nutrition, School of Medicine, Faculty of Health Sciences, University of Eastern Finland, Kuopio, Finland
- Food Chemistry and Food Development Unit, Department of Biochemistry, University of Turku, Turku, Finland
| | - Taisa Sallinen
- Institute of Public Health and Clinical Nutrition, School of Medicine, Faculty of Health Sciences, University of Eastern Finland, Kuopio, Finland
- Institute of Biomedicine, School of Medicine, Faculty of Health Sciences, University of Eastern Finland, Kuopio, Finland
| | - Eero A. Haapala
- Institute of Biomedicine, School of Medicine, Faculty of Health Sciences, University of Eastern Finland, Kuopio, Finland
- Faculty of Sport and Health Sciences, University of Jyväskylä, Jyväskylä, Finland
| | - Niina Lintu
- Institute of Biomedicine, School of Medicine, Faculty of Health Sciences, University of Eastern Finland, Kuopio, Finland
| | - Sonja Soininen
- Institute of Biomedicine, School of Medicine, Faculty of Health Sciences, University of Eastern Finland, Kuopio, Finland
- Physician and Nursing Services, Health and Social Services Centre, Wellbeing Services County of North Savo, Varkaus, Finland
| | - Retu Haikonen
- Institute of Public Health and Clinical Nutrition, School of Medicine, Faculty of Health Sciences, University of Eastern Finland, Kuopio, Finland
| | - Mustafa Atalay
- Institute of Biomedicine, School of Medicine, Faculty of Health Sciences, University of Eastern Finland, Kuopio, Finland
| | - Ursula Schwab
- Institute of Public Health and Clinical Nutrition, School of Medicine, Faculty of Health Sciences, University of Eastern Finland, Kuopio, Finland
- Department of Medicine, Endocrinology and Clinical Nutrition, Kuopio University Hospital, Kuopio, Finland
| | - Seppo Auriola
- School of Pharmacy, Faculty of Health Science, University of Eastern Finland, Kuopio, Finland
| | - Marjukka Kolehmainen
- Institute of Public Health and Clinical Nutrition, School of Medicine, Faculty of Health Sciences, University of Eastern Finland, Kuopio, Finland
| | - Kati Hanhineva
- Institute of Public Health and Clinical Nutrition, School of Medicine, Faculty of Health Sciences, University of Eastern Finland, Kuopio, Finland
- Food Chemistry and Food Development Unit, Department of Biochemistry, University of Turku, Turku, Finland
| | - Timo A. Lakka
- Institute of Biomedicine, School of Medicine, Faculty of Health Sciences, University of Eastern Finland, Kuopio, Finland
- Department of Clinical Physiology and Nuclear Medicine, Kuopio University Hospital, Kuopio, Finland
- Kuopio Research Institute of Exercise Medicine, Kuopio, Finland
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46
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Liu Y, Fachrul M, Inouye M, Méric G. Harnessing human microbiomes for disease prediction. Trends Microbiol 2024; 32:707-719. [PMID: 38246848 DOI: 10.1016/j.tim.2023.12.004] [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: 09/12/2023] [Revised: 12/12/2023] [Accepted: 12/12/2023] [Indexed: 01/23/2024]
Abstract
The human microbiome has been increasingly recognized as having potential use for disease prediction. Predicting the risk, progression, and severity of diseases holds promise to transform clinical practice, empower patient decisions, and reduce the burden of various common diseases, as has been demonstrated for cardiovascular disease or breast cancer. Combining multiple modifiable and non-modifiable risk factors, including high-dimensional genomic data, has been traditionally favored, but few studies have incorporated the human microbiome into models for predicting the prospective risk of disease. Here, we review research into the use of the human microbiome for disease prediction with a particular focus on prospective studies as well as the modulation and engineering of the microbiome as a therapeutic strategy.
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Affiliation(s)
- Yang Liu
- Cambridge Baker Systems Genomics Initiative, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK; Cambridge Baker Systems Genomics Initiative, Baker Heart and Diabetes Institute, Melbourne, Victoria, Australia; Department of Clinical Pathology, Melbourne Medical School, The University of Melbourne, Melbourne, Victoria, Australia; Victor Phillip Dahdaleh Heart and Lung Research Institute, University of Cambridge, Cambridge, UK; British Heart Foundation Cardiovascular Epidemiology Unit, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK
| | - Muhamad Fachrul
- Cambridge Baker Systems Genomics Initiative, Baker Heart and Diabetes Institute, Melbourne, Victoria, Australia; Department of Clinical Pathology, Melbourne Medical School, The University of Melbourne, Melbourne, Victoria, Australia; Human Genomics and Evolution Unit, St Vincent's Institute of Medical Research, Victoria, Australia; Melbourne Integrative Genomics, University of Melbourne, Parkville, Victoria, Australia; School of BioSciences, University of Melbourne, Parkville, Victoria, Australia
| | - Michael Inouye
- Cambridge Baker Systems Genomics Initiative, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK; Cambridge Baker Systems Genomics Initiative, Baker Heart and Diabetes Institute, Melbourne, Victoria, Australia; Victor Phillip Dahdaleh Heart and Lung Research Institute, University of Cambridge, Cambridge, UK; British Heart Foundation Cardiovascular Epidemiology Unit, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK; Health Data Research UK Cambridge, Wellcome Genome Campus and University of Cambridge, Cambridge, UK; British Heart Foundation Cambridge Centre of Research Excellence, School of Clinical Medicine, University of Cambridge, Cambridge, UK
| | - Guillaume Méric
- Cambridge Baker Systems Genomics Initiative, Baker Heart and Diabetes Institute, Melbourne, Victoria, Australia; Department of Cardiometabolic Health, University of Melbourne, Melbourne, Victoria, Australia; Central Clinical School, Monash University, Melbourne, Victoria, Australia; Department of Medical Science, Molecular Epidemiology, Uppsala University, Uppsala, Sweden; Department of Cardiovascular Research, Translation, and Implementation, La Trobe University, Melbourne, Victoria, Australia.
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Kayongo A, Ntayi ML, Olweny G, Kyalo E, Ndawula J, Ssengooba W, Kigozi E, Kalyesubula R, Munana R, Namaganda J, Caroline M, Sekibira R, Bagaya BS, Kateete DP, Joloba ML, Jjingo D, Sande OJ, Mayanja-Kizza H. Airway microbiome signature accurately discriminates Mycobacterium tuberculosis infection status. iScience 2024; 27:110142. [PMID: 38904070 PMCID: PMC11187240 DOI: 10.1016/j.isci.2024.110142] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2024] [Revised: 03/05/2024] [Accepted: 05/27/2024] [Indexed: 06/22/2024] Open
Abstract
Mycobacterium tuberculosis remains one of the deadliest infectious agents globally. Amidst efforts to control TB, long treatment duration, drug toxicity, and resistance underscore the need for novel therapeutic strategies. Despite advances in understanding the interplay between microbiome and disease in humans, the specific role of the microbiome in predicting disease susceptibility and discriminating infection status in tuberculosis still needs to be fully investigated. We investigated the impact of M.tb infection and M.tb-specific IFNγ immune responses on airway microbiome diversity by performing TB GeneXpert and QuantiFERON-GOLD assays during the follow-up phase of a longitudinal HIV-Lung Microbiome cohort of individuals recruited from two large independent cohorts in rural Uganda. M.tb rather than IFNγ immune response mainly drove a significant reduction in airway microbiome diversity. A microbiome signature comprising Streptococcus, Neisseria, Fusobacterium, Prevotella, Schaalia, Actinomyces, Cutibacterium, Brevibacillus, Microbacterium, and Beijerinckiacea accurately discriminated active TB from Latent TB and M.tb-uninfected individuals.
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Affiliation(s)
- Alex Kayongo
- Department of Immunology and Molecular Biology, Makerere University, College of Health Sciences, Kampala 256, Uganda
- Lung Institute, Makerere University College of Health Sciences, Kampala 256, Uganda
| | - Moses Levi Ntayi
- Department of Immunology and Molecular Biology, Makerere University, College of Health Sciences, Kampala 256, Uganda
- Lung Institute, Makerere University College of Health Sciences, Kampala 256, Uganda
| | - Geoffrey Olweny
- Department of Immunology and Molecular Biology, Makerere University, College of Health Sciences, Kampala 256, Uganda
| | - Edward Kyalo
- Department of Immunology and Molecular Biology, Makerere University, College of Health Sciences, Kampala 256, Uganda
- Lung Institute, Makerere University College of Health Sciences, Kampala 256, Uganda
| | - Josephine Ndawula
- Department of Immunology and Molecular Biology, Makerere University, College of Health Sciences, Kampala 256, Uganda
- Lung Institute, Makerere University College of Health Sciences, Kampala 256, Uganda
| | - Willy Ssengooba
- Department of Immunology and Molecular Biology, Makerere University, College of Health Sciences, Kampala 256, Uganda
- Lung Institute, Makerere University College of Health Sciences, Kampala 256, Uganda
| | - Edgar Kigozi
- Department of Immunology and Molecular Biology, Makerere University, College of Health Sciences, Kampala 256, Uganda
| | - Robert Kalyesubula
- Department of Research, African Community Center for Social Sustainability (ACCESS), Nakaseke 256, Uganda
- Department of Medicine, Makerere University, College of Health Sciences, Kampala 256, Uganda
| | - Richard Munana
- Department of Research, African Community Center for Social Sustainability (ACCESS), Nakaseke 256, Uganda
| | - Jesca Namaganda
- Department of Immunology and Molecular Biology, Makerere University, College of Health Sciences, Kampala 256, Uganda
- Lung Institute, Makerere University College of Health Sciences, Kampala 256, Uganda
| | - Musiime Caroline
- Department of Immunology and Molecular Biology, Makerere University, College of Health Sciences, Kampala 256, Uganda
| | - Rogers Sekibira
- Department of Immunology and Molecular Biology, Makerere University, College of Health Sciences, Kampala 256, Uganda
| | - Bernard Sentalo Bagaya
- Department of Immunology and Molecular Biology, Makerere University, College of Health Sciences, Kampala 256, Uganda
| | - David Patrick Kateete
- Department of Immunology and Molecular Biology, Makerere University, College of Health Sciences, Kampala 256, Uganda
| | - Moses Lutaakome Joloba
- Department of Immunology and Molecular Biology, Makerere University, College of Health Sciences, Kampala 256, Uganda
| | - Daudi Jjingo
- College of Computing and Information Sciences, Computer Science, Makerere University, Kampala 256, Uganda
- African Center of Excellence in Bioinformatics and Data Science, Infectious Diseases Institute, Kampala 256, Uganda
| | - Obondo James Sande
- Department of Immunology and Molecular Biology, Makerere University, College of Health Sciences, Kampala 256, Uganda
| | - Harriet Mayanja-Kizza
- Department of Medicine, Makerere University, College of Health Sciences, Kampala 256, Uganda
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48
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Trøseid M, Nielsen SD, Vujkovic-Cvijin I. Gut microbiome and cardiometabolic comorbidities in people living with HIV. MICROBIOME 2024; 12:106. [PMID: 38877521 PMCID: PMC11177534 DOI: 10.1186/s40168-024-01815-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/20/2023] [Accepted: 04/12/2024] [Indexed: 06/16/2024]
Abstract
BACKGROUND Despite modern antiretroviral therapy (ART), people living with HIV (PLWH) have increased relative risk of inflammatory-driven comorbidities, including cardiovascular disease (CVD). The gut microbiome could be one of several driving factors, along with traditional risk factors and HIV-related risk factors such as coinfections, ART toxicity, and past immunodeficiency. RESULTS PLWH have an altered gut microbiome, even after adjustment for known confounding factors including sexual preference. The HIV-related microbiome has been associated with cardiometabolic comorbidities, and shares features with CVD-related microbiota profiles, in particular reduced capacity for short-chain fatty acid (SCFA) generation. Substantial inter-individual variation has so far been an obstacle for applying microbiota profiles for risk stratification. This review covers updated knowledge and recent advances in our understanding of the gut microbiome and comorbidities in PLWH, with specific focus on cardiometabolic comorbidities and inflammation. It covers a comprehensive overview of HIV-related and comorbidity-related dysbiosis, microbial translocation, and microbiota-derived metabolites. It also contains recent data from studies in PLWH on circulating metabolites related to comorbidities and underlying gut microbiota alterations, including circulating levels of the SCFA propionate, the histidine-analogue imidazole propionate, and the protective metabolite indole-3-propionic acid. CONCLUSIONS Despite recent advances, the gut microbiome and related metabolites are not yet established as biomarkers or therapeutic targets. The review gives directions for future research needed to advance the field into clinical practice, including promises and pitfalls for precision medicine. Video Abstract.
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Affiliation(s)
- Marius Trøseid
- Research Institute of Internal Medicine, Oslo University Hospital Rikshospitalet, Oslo, Norway.
- Section for Clinical Immunology and Infectious Diseases, Oslo University Hospital Rikshospitalet, Oslo, Norway.
- Institute of Clinical Medicine, University of Oslo, Oslo, Norway.
| | - Susanne Dam Nielsen
- Department of Infectious Diseases, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark
- Department of Clinical Medicine, University of Copenhagen, Blegdamsvej 3B, Copenhagen, 2200, Denmark
- Department of Surgical Gastroenterology and Transplantation, Rigshospitalet, University of Copenhagen, Blegdamsvej 9, Copenhagen Oe, 2100, Denmark
| | - Ivan Vujkovic-Cvijin
- Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, CA, USA
- Karsh Division of Gastroenterology & Hepatology, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, CA, USA
- F. Widjaja Inflammatory Bowel Disease Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA
- Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA
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49
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Ross PA, Xu W, Jalomo-Khayrova E, Bange G, Gumerov VM, Bradley PH, Sourjik V, Zhulin IB. Framework for exploring the sensory repertoire of the human gut microbiota. mBio 2024; 15:e0103924. [PMID: 38757952 PMCID: PMC11237719 DOI: 10.1128/mbio.01039-24] [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: 04/09/2024] [Accepted: 04/17/2024] [Indexed: 05/18/2024] Open
Abstract
Bacteria sense changes in their environment and transduce signals to adjust their cellular functions accordingly. For this purpose, bacteria employ various sensors feeding into multiple signal transduction pathways. Signal recognition by bacterial sensors is studied mainly in a few model organisms, but advances in genome sequencing and analysis offer new ways of exploring the sensory repertoire of many understudied organisms. The human gut is a natural target of this line of study: it is a nutrient-rich and dynamic environment and is home to thousands of bacterial species whose activities impact human health. Many gut commensals are also poorly studied compared to model organisms and are mainly known through their genome sequences. To begin exploring the signals human gut commensals sense and respond to, we have designed a framework that enables the identification of sensory domains, prediction of signals that they recognize, and experimental verification of these predictions. We validate this framework's functionality by systematically identifying amino acid sensors in selected bacterial genomes and metagenomes, characterizing their amino acid binding properties, and demonstrating their signal transduction potential.IMPORTANCESignal transduction is a central process governing how bacteria sense and respond to their environment. The human gut is a complex environment with many living organisms and fluctuating streams of nutrients. One gut inhabitant, Escherichia coli, is a model organism for studying signal transduction. However, E. coli is not representative of most gut microbes, and signaling pathways in the thousands of other organisms comprising the human gut microbiota remain poorly understood. This work provides a foundation for how to explore signals recognized by these organisms.
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Affiliation(s)
- Patricia A. Ross
- Department of Microbiology, The Ohio State University, Columbus, Ohio, USA
- Translational Data Analytics Institute, The Ohio State University, Columbus, Ohio, USA
| | - Wenhao Xu
- Max Planck Institute for Terrestrial Microbiology, Marburg, Germany
- Center for Synthetic Microbiology (SYNMIKRO), Marburg, Germany
| | - Ekaterina Jalomo-Khayrova
- Max Planck Institute for Terrestrial Microbiology, Marburg, Germany
- Center for Synthetic Microbiology (SYNMIKRO), Marburg, Germany
- Department of Chemistry, Philipps-University Marburg, Marburg, Germany
| | - Gert Bange
- Max Planck Institute for Terrestrial Microbiology, Marburg, Germany
- Center for Synthetic Microbiology (SYNMIKRO), Marburg, Germany
- Department of Chemistry, Philipps-University Marburg, Marburg, Germany
| | - Vadim M. Gumerov
- Department of Microbiology, The Ohio State University, Columbus, Ohio, USA
- Translational Data Analytics Institute, The Ohio State University, Columbus, Ohio, USA
| | - Patrick H. Bradley
- Department of Microbiology, The Ohio State University, Columbus, Ohio, USA
- Infectious Diseases Institute, The Ohio State University, Columbus, Ohio, USA
| | - Victor Sourjik
- Max Planck Institute for Terrestrial Microbiology, Marburg, Germany
- Center for Synthetic Microbiology (SYNMIKRO), Marburg, Germany
| | - Igor B. Zhulin
- Department of Microbiology, The Ohio State University, Columbus, Ohio, USA
- Translational Data Analytics Institute, The Ohio State University, Columbus, Ohio, USA
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50
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Liu J, Zhang X, Lin T, Chen R, Zhong Y, Chen T, Wu T, Liu C, Huang A, Nguyen TT, Lee EE, Jeste DV, Tu XM. A New Paradigm for High-dimensional Data: Distance-Based Semiparametric Feature Aggregation Framework via Between-Subject Attributes. Scand Stat Theory Appl 2024; 51:672-696. [PMID: 39101047 PMCID: PMC11296665 DOI: 10.1111/sjos.12695] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2023] [Accepted: 10/11/2023] [Indexed: 08/06/2024]
Abstract
This article proposes a distance-based framework incentivized by the paradigm shift towards feature aggregation for high-dimensional data, which does not rely on the sparse-feature assumption or the permutation-based inference. Focusing on distance-based outcomes that preserve information without truncating any features, a class of semiparametric regression has been developed, which encapsulates multiple sources of high-dimensional variables using pairwise outcomes of between-subject attributes. Further, we propose a strategy to address the interlocking correlations among pairs via the U-statistics-based estimating equations (UGEE), which correspond to their unique efficient influence function (EIF). Hence, the resulting semiparametric estimators are robust to distributional misspecification while enjoying root-n consistency and asymptotic optimality to facilitate inference. In essence, the proposed approach not only circumvents information loss due to feature selection but also improves the model's interpretability and computational feasibility. Simulation studies and applications to the human microbiome and wearables data are provided, where the feature dimensions are tens of thousands.
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Affiliation(s)
- Jinyuan Liu
- Department of Biostatistics, Vanderbilt University, Nashville, Tennessee, U.S.A
| | - Xinlian Zhang
- Department of Family Medicine and Public Health, UC San Diego, San Diego, California, U.S.A
| | - Tuo Lin
- Department of Family Medicine and Public Health, UC San Diego, San Diego, California, U.S.A
| | - Ruohui Chen
- Department of Family Medicine and Public Health, UC San Diego, San Diego, California, U.S.A
| | - Yuan Zhong
- Department of Biostatistics, University of Michigan, Ann Arbor, Michigan, U.S.A
| | - Tian Chen
- Takeda Pharmaceuticals Cambridge, Massachusetts, U.S.A
| | - Tsungchin Wu
- Department of Family Medicine and Public Health, UC San Diego, San Diego, California, U.S.A
| | - Chenyu Liu
- Department of Family Medicine and Public Health, UC San Diego, San Diego, California, U.S.A
| | - Anna Huang
- Department of Psychiatry, Vanderbilt University, Nashville, Tennessee, U.S.A
| | - Tanya T. Nguyen
- Veterans Affairs San Diego Healthcare System, La Jolla, California, U.S.A
- Center for Microbiome Innovation, UC San Diego, San Diego, California, U.S.A
| | - Ellen E. Lee
- Veterans Affairs San Diego Healthcare System, La Jolla, California, U.S.A
- Department of Psychiatry, UC San Diego, San Diego, California, U.S.A
| | - Dilip V. Jeste
- Stein Institute for Research on Aging, UC San Diego, San Diego, California, U.S.A
| | - Xin M. Tu
- Department of Family Medicine and Public Health, UC San Diego, San Diego, California, U.S.A
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