Prominent mediatory role of gut microbiome in the effect of lifestyle on host metabolic phenotypes

Lifestyle factors influence both gut microbiome composition and host metabolism, yet their combined and mediating effects on host phenotypes remain poorly characterized in cardiometabolic populations. In 1,643 participants from the MetaCardis study, we developed a composite lifestyle score (QASD: dietary quality, physical activity, smoking, and diet diversity) that outperformed individual lifestyle variables in explaining microbial gene richness and exhibited a significant impact on the gut microbiome composition. While bidirectional pathways linking the QASD score, host phenotypes, and microbiome composition were assessed, causal inference-based mediation analyses indicated stronger effects when the microbiome was modeled as the mediator variable, particularly in relation to the insulin resistance-associated profile. Microbiome gene richness emerged as a key mediator explaining 27.8% of QASD score's effect on the insulin resistance marker (HOMA-IR), while no significant mediation was observed on BMI. Extended mediation analyses on microbial species and serum metabolomics deconfounded for drug use and clinical profiles identified 47 mediations where microbial taxa mediated more than 20% of the effect of the QASD score on serum metabolites associated with insulin resistance. Notably, several <i>Faecalibacterium</i> lineages enriched in individuals with high QASD score played a significant mediatory role in increasing the serum biomarkers of microbiome diversity (as cinnamoylglycine or 3-phenylpropionate). Conversely, elevated levels of secondary bile acids in individuals with low QASD scores were strongly mediated by high levels of <i>Clostridium bolteae</i>. These findings highlight distinct and clinically relevant microbiome pathways linking lifestyle behaviors to cardiometabolic risks.One sentence summary:The gut microbiome mediates the impact of diet quality and diversity, physical activity and smoking status - combined in a composite lifestyle score - on cardiometabolic phenotypes.

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Journal
Gut Microbes
Published
2025-12-17
DOI
https://doi.org/10.1080/19490976.2025.2599565
Primary Topic
Gut microbiota and health
Type
article
Field-Weighted Citation Impact
0.00

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article

Prominent mediatory role of gut microbiome in the effect of lifestyle on host metabolic phenotypes

Rohia Alili, Philippe Froguel, Hédi Soula, Sara Vieira‐Silva et al.
Gut Microbes
Gut microbiota and health
article

Prominent mediatory role of gut microbiome in the effect of lifestyle on host metabolic phenotypes

Rohia Alili, Philippe Froguel, Hédi Soula, Sara Vieira‐Silva, Jeroen Raes, Marc‐Emmanuel Dumas, Trine Nielsen, Francesc Puig‐Castellví, Sofia Kirke Forslund, Kanta Chechi, Karine Clément, Inés Castro, Edi Prifti, Michael Stümvoll, Eugeni Belda, Jean‐Michel Oppert, Solia Adriouch, Tiphaine Le Roy, Oluf Pedersen, Rima Chakaroun, Gwen Falony, Maria Carlota Dao, Peer Bork, S. Dusko Ehrlich, Judith Aron‐Wisnewsky, Fabrizio Andréelli, Christine Poitou, Joe‐Elie Salem, Jean‐Daniel Zucker, T.D. Swartz, Pierre Bel Lassen, Petros Andrikopoulos, Bridget Holmes, Christine Rouault
article en

Abstract

Lifestyle factors influence both gut microbiome composition and host metabolism, yet their combined and mediating effects on host phenotypes remain poorly characterized in cardiometabolic populations. In 1,643 participants from the MetaCardis study, we developed a composite lifestyle score (QASD: dietary quality, physical activity, smoking, and diet diversity) that outperformed individual lifestyle variables in explaining microbial gene richness and exhibited a significant impact on the gut microbiome composition. While bidirectional pathways linking the QASD score, host phenotypes, and microbiome composition were assessed, causal inference-based mediation analyses indicated stronger effects when the microbiome was modeled as the mediator variable, particularly in relation to the insulin resistance-associated profile. Microbiome gene richness emerged as a key mediator explaining 27.8% of QASD score's effect on the insulin resistance marker (HOMA-IR), while no significant mediation was observed on BMI. Extended mediation analyses on microbial species and serum metabolomics deconfounded for drug use and clinical profiles identified 47 mediations where microbial taxa mediated more than 20% of the effect of the QASD score on serum metabolites associated with insulin resistance. Notably, several <i>Faecalibacterium</i> lineages enriched in individuals with high QASD score played a significant mediatory role in increasing the serum biomarkers of microbiome diversity (as cinnamoylglycine or 3-phenylpropionate). Conversely, elevated levels of secondary bile acids in individuals with low QASD scores were strongly mediated by high levels of <i>Clostridium bolteae</i>. These findings highlight distinct and clinically relevant microbiome pathways linking lifestyle behaviors to cardiometabolic risks.One sentence summary:The gut microbiome mediates the impact of diet quality and diversity, physical activity and smoking status - combined in a composite lifestyle score - on cardiometabolic phenotypes.

Gut MicrobesVol. 17(1)
University of Copenhagen (DK), Centre National de la Recherche Scientifique (FR), Helmholtz Association of German Research Centres (DE), Food and Agriculture Organization of the United Nations (IT), Steno Diabetes Centers (DK), Inserm (FR), University of New Hampshire (US), University of New Hampshire at Manchester (US), Neurosciences Institute (US), Johannes Gutenberg University Mainz (DE), Max Delbrück Center (DE), Université de Lille (FR), Université Paris-Saclay (FR), Institut Pasteur de Lille (FR), Novo Nordisk Foundation (DK), Gentofte Hospital (DK), Victor (Japan) (JP), Humboldt-Universität zu Berlin (DE), Sorbonne Université (FR), Institut National de Recherche pour l'Agriculture, l'Alimentation et l'Environnement (FR), University Medical Center of the Johannes Gutenberg University Mainz (DE), Food and Nutrition Service (US), Nutrition et obésité : approches systémiques (FR), Institute of Molecular Biology (BG), Assistance Publique – Hôpitaux de Paris (FR), VIB-KU Leuven Center for Microbiology (BE), McGill Genome Centre (CA), Pitié-Salpêtrière Hospital (FR), German Centre for Cardiovascular Research (DE), Helmholtz-Institute Ulm (DE), Institute of Medical Microbiology and Hygiene (DE), National Hospital for Neurology and Neurosurgery (GB), Unité de Modélisation Mathématique et Informatique des Systèmes Complexes (FR), Food & Nutrition (NL), Institute of Molecular Biology (DE), Institut de Recherche pour le Développement (FR), European Genomic Institute for Diabetes (FR), University College London (GB), Imperial College London (GB), McGill University (CA), Freie Universität Berlin (DE), Charité - Universitätsmedizin Berlin (DE), University of Gothenburg (SE), Wageningen University & Research (NL)
Wellcome Trust, Deutsches Zentrum für Herz-Kreislaufforschung, UK Research and Innovation, Université de Lille, National Institute for Health and Care Research, Diabetes UK, European Commission, Deutsche Forschungsgemeinschaft, Agence Nationale de la Recherche, Fondation Leducq, Fondation pour la Recherche Médicale, Centre National de la Recherche Scientifique, Conseil Régional Hauts-de-France, HORIZON EUROPE Framework Programme, Medical Research Council, NIHR Imperial Biomedical Research Centre, NUTRIM School of Nutrition and Translational Research in Metabolism, CHIST-ERA
Openalex Percentile: Top 62%
Gut microbiota and health
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