GLUCOFLORAB

The worldwide development of obesity and type 2 diabetes urges the scientific community to seek for a better understanding of the mechanisms of control of food intake and insulin sensitivity. Three novel rationales have emerged during the last 10 years : 1) the role of a novel glucose producing organ (the small intestine), as a signal of control of food intake and insulin sensitivity, involving the brain (Mithieux, Nutrition, 2009) ; 2) the acknowledgement of the rapid and spectacular amelioration of the glucose control in morbidly obese patients undergoing surgeries of obesity of the type « by-pass », which involve a derivation of nutrients directly in the distal gut ; 3) the possible implication of the intestinal bacterial flora in the initiation of inflammatory mechanisms leading to insulin resistance (Cani et al, Diabetes, 2007). A key recent result obtained by the partners of this project has been the demonstration of the causal role of intestinal gluconeogenesis in the initiation of the benefits of gastric bypass in mice (Troy et al, Cell Metab, 2008). In this proposal, we will assess whether the intestinal microflora composition may be a key step between the nutritional modifications introduced by the gastric surgeries of the bypass type and intestinal gluconeogenesis. These modifications relate to the direct delivery of nutrients in the distal jejunum and ileum, and to the derivation of biliary and pancreatic secretions from a part of the intestine. These modifications might notably alter the composition of the bacterial flora. They might also directly alter intestinal gluconeogenesis, because food protein and bile salts have been shown to be regulators of this function. Different models of derivation of bile and pancreas secretions and of gastric surgery (especially gastric bypass and ileal transposition) will be used to estimate the respective roles of the different effectors. In each case, the expression of the genes of intestinal gluconeogenesis and the composition of the intestinal flora will be analyzed. In a second time, the causal role of the flora in the control of intestinal gluconeogenesis will be estimated from axenic mice, which will be colonized with the flora recovered in mice from the differents models of gastric surgery and biliary and pancreatic derivation. This project will provide a better understanding of the control of intestinal gluconeogenesis, a key function in glucose and energy homeostasis, after the remodelling of the gut involved in gastric bypass surgery, and of the role of bacterial flora in these regulations. It should allow us to propose novel therapeutic approaches of diabetic morbid obesity, less invasive than the surgery.