The role of gut microbes and microbial derived metabolites in the development of type 2 diabetes in humans

PROJECT SUMMARY Mounting evidence links the gut microbiome – the modifiable “second genome” consisting of trillions of diverse microbes that inhabit the human gut – with type 2 diabetes mellitus (T2DM) in humans. Studies using fecal transplant in mice have raised the central hypothesis that changes of the gut microbiome and the biochemical by-products originated from these microbes may be key modulators of development of T2DM. To date, however, knowledge of the specific microbial species that drive the development of T2DM in humans remain very limited. Human studies of the gut microbiome in T2DM have largely been cross-sectional and confounded by reverse causality. Indeed, many of the gut microbiome changes observed in human T2DM have been found to be a consequence of the disease or treatments, including the medication metformin, rather than a cause of T2DM. In addition, the circulating metabolites derived from the gut microbes that contribute to the development of T2DM remain to be discovered. In this Early Stage Investigator NIH R01 application, we propose the largest prospective study of the role of gut microbiome in T2DM using a Finnish cohort of 6921 individuals with fecal and plasma samples collected in 2002 and over 15 years of subsequent clinical follow up. This proposed study brings together a diverse team with deep expertise in the human microbiome, mass-spectrometry based metabolomics, computational biology, statistical epidemiology, and diabetes pathobiology, to specifically address the key biological and clinical questions regarding the role of gut microbes and microbial derived metabolites in the development of incident T2DM in humans.