Grant: Team Grant: Bariatric Care - Mechanisms underlying bariatric procedures

Morbid obesity(MO) coupled with metabolic syndrome(MSx) increase risks of cardiovascular disease, stroke, fatty liver & sleep apnea, which left unchecked are inevitably fatal and at enormous cost to Canada. The only reliable & effective is a drastic surgical procedure that restricts size of the stomach and bypasses a long segment of intestine- Roux-en-Y gastric bypass (RYGB). RYGB causes massive weight loss in all patients but remarkably improves type 2 diabetes(T2D) & insulin resistance(IR) before the weight loss. The altered surgical anatomy of RYGB causes unforeseen changes in the gut contributing to these beneficial effects. A major change is the fecal bacterial community (intestinal microbiota-IM) & resulting bacterial genes (metagenome), shown in animal models to influence an excess assimilation of nutrients & many organs' responses- brain satiety, liver & fat accumulation, and body inflammatory responses, the latter related to many obesity-related diseases. These findings haven't been translated to human. This presents an opportunity for an entirely new therapeutic platform whereby clever use of the IM post-RYGB by fecal microbiota transplantation(FMT) serves as a 'medical' bypass strategy that can independently improve MSx & induce weight loss, perhaps reducing the need for RYGB. Our aims are: 1. Track changes in IM & metagenome of MO patients undergoing RYGB and determine the independent associations between specific changes & improvement in IR, T2D & weight loss. 2. Determine if FMT of stools from MO patients from Aim 1 vs FMT from lean subjects into a MO mouse model could reduce IR, obesity & other MSx features. We'll determine the specific candidate microbial species or genes that account for the beneficial effects on specific organs (fat, liver, insulin secretion) independent of the RYGB. 3. Test the effect of FMT of lean subjects into MO patients; assessing if the resulting IM is similar to post-RYGB IM to account for the beneficial effect