"Obesity and associated metabolic diseases such as type 2 diabetes are increasing worldwide and are the result of complex gene-environment interactions. Recent studies indicate that socio-demographic and environmental factors are more important for disease development than genetics, and we and others have demonstrated that the gut microbiota can be considered an environmental factor that contributes to obesity. Effective treatment for obesity remains a challenge and bariatric surgery is the only available therapy that is proven to maintain weight loss. Intriguingly, bariatric surgery also improves glucose metabolism, but the underlying molecular mechanisms for this beneficial effect are unclear. An altered gut microbiota has been linked to metabolic diseases and pilot studies indicate that the gut microbiota is also altered upon bariatric surgery; these findings suggest that some of the improved metabolic features following bariatric surgery may be mediated by altered composition of the gut microbiota. The overall goal of this proposal is to integrate clinical research with mechanistic studies in mice to determine if and how the gut microbiota mediates the beneficial effects of bariatric surgery. We will define how bariatric surgery alters the gut metagenome in humans, both at a species and at a functional level. By transferring the fecal microbiota from these patients before and after surgery to germ-free mice, we will determine if an altered gut microbiota directly modulates host metabolism. Finally, we will establish surgical methods in germ-free mice to directly test whether the beneficial effects observed following surgery require a microbiota. Increased understanding of these mechanisms may provide the basis for non-surgical treatments based on supplementation of novel probiotics to treat metabolic diseases. Follow-up work in larger clinical cohorts may also indicate how patients can be stratified to determine who would benefit the most from bariatric surgery."