Mechanisms of intestinal epithelial barrier restoration following Roux-en-Y gastric bypass surgery

• Applicants: Dr. Mohammed Khair Hankir, Ph.D.; Professor Dr. Nicolas Schlegel; Dr. Florian Seyfried
• Subject Area: General and Visceral Surgery
• Term: since 2021
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 457029959

Metabolic surgeries, especially Roux-en-Y gastric bypass (RYGB), uniquely cause remission of type 2 diabetes in up to 40% of patients with morbid obesity. This is attributed, in part, to an attenuation of endotoxemia-induced insulin resistance through stabilization of the intestinal epithelial barrier (IEB); however, the underlying mechanisms remain poorly understood. In preliminary experiments, we found that the intestinal contents of RYGB-operated compared with sham-operated, diet-induced obese rats region-specifically improved barrier structure and function in Caco-2 cells in vitro. This was dependent on changes of nuclear bile-acid receptor (FXR) signaling and changes of the gut microbiota. In the present proposal, we will build on these findings and test the hypothesis that the altered composition of intestinal luminal factors following RYGB, including bile acids and microbiota products, directly contribute to IEB stabilization. To this end, we will first comprehensively study regional changes in intestinal barrier structure in RYGB-operated and sham-operated, genetically obese and glucose-intolerant Zucker fatty (fa/fa) rats and the relevant lean (fa/+) and pair-fed controls. We will then perform detailed compositional and microbiota analyses of the intestinal contents of RYGB-operated rats in conjunction with functional and structural analyses on rat-derived enteroids. In a translational approach, similar experiments will be performed on enteroids and feces from healthy and morbidly obese patients before and after RYGB. Based on the findings from these experiments, we will then address the causal role of key signaling pathways in enterocytes that contribute to intestinal barrier stabilization and improved metabolic parameters following RYGB in transgenic mice. The findings from this project will provide much-needed insight into the role of intestinal luminal factors leading to IEB stabilization, attenuated endotoxemia, and improved glycaemic control following RYGB. This may pave way for the development of a new generation of type 2 diabetes treatments that specifically target the gastrointestinal tract.

• DFG Programme: Research Grants
• International Connection: Switzerland