Fig. 3: Interaction of gut microbiota and small intestinal nutrient sensing.

We put forward a working hypothesis for the mechanistic links between small intestinal nutrient-sensing, microbiota, peptide release, and metabolic regulation. (From Left to Right of the Schematic): Bacterial species can directly and/or indirectly impact epithelial GPRs to alter GLP1 expression and release. Bacterial by-products such as LPS can impair lipid and glucose sensing and potentially disrupt ACSL3 and SGLT1 dependent pathways that regulate glucose and energy homeostasis. Bile salt hydrolase of bacteria contributes to the bile acid pool and regulates bile acid metabolism. As a result, changes in bile acids can alter GLP-1 release and metabolic regulation via intestinal FXR and TGR5 signaling. High-fat feeding reduces the abundance of small intestinal Lactobacillus species (e.g., L. gasseri) and consequently inhibits ACSL3 expression and impairs lipid sensing. Lastly, metformin increases the abundance of upper small intestinal Lactobacillus and enhances SGLT1 expression and glucose sensing, while also reducing the abundance of Bacteroides fragilis that results in ileal FXR inhibition and improvement in glucose metabolism. Bariatric surgery enhances small intestinal nutrient sensing mechanisms and consequently lowers glucose levels, while changes in bile acid metabolism and FXR are necessary for the glucose-lowering effect of bariatric surgery.