Exploring the Gut Microbial Action of Metformin: Targeting the Gut Microbiota to Treat Metabolic Disease. (360G-Wellcome-102531_Z_13_Z)

Gut microbiota is a determinant of host health, influencing nutrition-related syndromes such as type-2 diabetes, obesity and ageing, and can be modulated by xenobiotic drugs. Metformin is the most widely prescribed drug to treat type-2 diabetes. However, its therapeutic potential goes far beyond its anti-hyperglycaemic action, also reducing the risk of ageing. Despite significant research into the functions and molecular mechanisms of metformin, little is known about its specific cellular target (s), in particular those underlying the long-term wide-range effects on mammalian health. Our prediction is that metformin alters the function/structure of the microbial communities, which confers long-term health benefits in the host. Objectives to be tested empirically: 1) Does the anti-diabetic drug metformin require gut microbiota to exert beneficial effects on the host? 2) Are the long-term positive effects of metformin mediated by gut microbial changes upon treatment? 3) Can we target gut microbiota with metformin or genetically engineered microbial strains to treat metabolic disease and ageing in the host? To this end, we will utilise germ-free rodent and C. elegans applying high-end metabolomic and transcriptomic techniques. Therefore, this proposal aims to clarify the causality between host-microbe interactions and metabolic disease, and its modulation by the anti-diabetic drug metformin.