Presentation Information
[4Ferm-00-KL]Microbiota-Derived Metabolites as Regulators of Metabolic and Inflammatory Diseases: From Mechanistic Discovery to Therapeutic Intervention
〇François Brial 1, François Brial 2, Dominique Gauguier 3, Jun Ogawa 4, Jean-Baptiste Julla 5, Subhalaxmi Moitra 6, Omnya Ebrahim 7, Daniel Auld 8
(1. Université Paris Cité, Inserm U1132 BIOSCAR, Paris, France
2. Université Paris Cité, Paris, France,
3. INSERM Director of Research, CNRS UMR 8251, Université Paris Cité
4. Kyoto University, Kyoto, Japan
5. INSERM U1151, Université Paris Cité, Paris, France
6. Université Paris Cité, Inserm U1132 BIOSCAR, Paris, France,
7. CNRS UMR 8251, Université Paris Cité, Paris, France
8. McGill University, Montreal, Canada)
(1. Université Paris Cité, Inserm U1132 BIOSCAR, Paris, France
2. Université Paris Cité, Paris, France,
3. INSERM Director of Research, CNRS UMR 8251, Université Paris Cité
4. Kyoto University, Kyoto, Japan
5. INSERM U1151, Université Paris Cité, Paris, France
6. Université Paris Cité, Inserm U1132 BIOSCAR, Paris, France,
7. CNRS UMR 8251, Université Paris Cité, Paris, France
8. McGill University, Montreal, Canada)
The gut microbiota is increasingly recognized as a key regulator of host physiology through the production of bioactive metabolites that influence metabolic, immune and inflammatory pathways. While numerous studies have identified associations between microbial signatures and chronic diseases, establishing causal relationships and translating these findings into therapeutic strategies remain major challenges.
Our research program focuses on the identification and functional characterization of microbiota-derived metabolites involved in cardiometabolic and inflammatory diseases. By combining human metabolomics, microbial ecology and physiological investigations in preclinical models, we have developed a translational framework spanning metabolite discovery, mechanistic investigation and therapeutic intervention.
Using integrated metabolomic approaches in human cohorts, several microbiota-derived metabolites were identified as determinants of metabolic health and disease. Functional studies revealed distinct mechanisms through which these metabolites modulate host physiology. 4-cresol, a product of bacterial aromatic amino acid metabolism, was found to be inversely associated with obesity and type 2 diabetes and promotes pancreatic β-cell proliferation and glucose homeostasis through pathways involving the kinase RSK2. Hippurate emerged as both a biomarker and mediator of metabolic health, reflecting host–microbiota interactions associated with metabolic resilience. More recently, we demonstrated that microbial trimethylamine directly inhibits IRAK4 signaling, thereby attenuating metabolic inflammation and improving glycemic control. Together, these studies establish microbiota-derived metabolites as bioactive signaling molecules acting on specific host targets to regulate cardiometabolic homeostasis.
More broadly, these findings support the concept that microbiota-derived metabolites constitute a rich and largely unexplored source of endogenous molecules capable of modulating key physiological pathways in the host. Identifying the metabolic pathways and molecular targets involved in their production and action offers new opportunities to understand disease mechanisms and develop innovative preventive and therapeutic strategies.
Together, these studies illustrate how microbiota-derived metabolites act as mechanistic mediators linking microbial activity to host physiology and represent promising targets for the development of next-generation therapeutic approaches aimed at improving human metabolic and inflammatory health.
Our research program focuses on the identification and functional characterization of microbiota-derived metabolites involved in cardiometabolic and inflammatory diseases. By combining human metabolomics, microbial ecology and physiological investigations in preclinical models, we have developed a translational framework spanning metabolite discovery, mechanistic investigation and therapeutic intervention.
Using integrated metabolomic approaches in human cohorts, several microbiota-derived metabolites were identified as determinants of metabolic health and disease. Functional studies revealed distinct mechanisms through which these metabolites modulate host physiology. 4-cresol, a product of bacterial aromatic amino acid metabolism, was found to be inversely associated with obesity and type 2 diabetes and promotes pancreatic β-cell proliferation and glucose homeostasis through pathways involving the kinase RSK2. Hippurate emerged as both a biomarker and mediator of metabolic health, reflecting host–microbiota interactions associated with metabolic resilience. More recently, we demonstrated that microbial trimethylamine directly inhibits IRAK4 signaling, thereby attenuating metabolic inflammation and improving glycemic control. Together, these studies establish microbiota-derived metabolites as bioactive signaling molecules acting on specific host targets to regulate cardiometabolic homeostasis.
More broadly, these findings support the concept that microbiota-derived metabolites constitute a rich and largely unexplored source of endogenous molecules capable of modulating key physiological pathways in the host. Identifying the metabolic pathways and molecular targets involved in their production and action offers new opportunities to understand disease mechanisms and develop innovative preventive and therapeutic strategies.
Together, these studies illustrate how microbiota-derived metabolites act as mechanistic mediators linking microbial activity to host physiology and represent promising targets for the development of next-generation therapeutic approaches aimed at improving human metabolic and inflammatory health.
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