Simulating the Post-Gastric Bypass Intestinal Microenvironment Uncovers a Barrier-Stabilizing Role for FXR

Summary Regional changes to the intestinal microenvironment brought about by Roux-en-Y gastric bypass (RYGB) surgery may contribute to some of its potent systemic metabolic benefits through favorably regulating various local cellular processes. Here, we show that the intestinal contents of RYGB-operated compared with sham-operated rats region-dependently confer superior glycaemic control to recipient germ-free mice in association with suppression of endotoxemia. Accordingly, they had direct barrier-stabilizing effects on an intestinal epithelial cell line which, for the duodenal and colonic contents, were partly farnesoid X receptor (FXR)-dependent. Further, circulating fibroblast growth factor 19 levels, a read-out of intestinal FXR activation, negatively correlated with endotoxemia severity in RYGB patients. These findings suggest that various host- and/or microbiota-derived intestinal luminal factors region-specifically and synergistically stabilize the intestinal epithelial barrier following RYGB through intestinal FXR signaling, which could potentially be exploited to better treat endotoxemia-induced insulin resistance in obesity in a non-invasive and more targeted manner.