Intestine-restricted farnesoid X receptor agonist shapes the gut microbiota to activate G protein bile acid receptor-1 signaling and improve hepatic metabolism

Bile acids are endogenous ligands that activate farnesoid X receptor (FXR) and G protein- coupled receptor TGR5 to regulate bile acid metabolism and glucose and insulin sensitivity. However, the roles of these bile acid-activated receptors in metabolic diseases and the underlying mechanisms are not completely understood. We reported recently that activation of intestine FXR induces TGR5 to stimulate TGR5-glucagon-like peptide-1 (GLP-1) secretion to improve hepatic metabolism (Pathak, et al. J Biol Chem. 292:11055, 2017). In this study, we used the intestine-restrict FXR agonist fexaramine (FEX) to study the effect and mechanism of activation of intestine FXR on gut microbiome, bile acid metabolism and FXR and TGR5 signaling in hepatic metabolism. The current study revealed that treatment of mice with FEX markedly increased tauro-lithocholic acid (TLCA) in ileum and colon, bile acid hydrophobicity, intestinal fibroblast growth factor 15 (FGF15), but did not affect total bile acid pool size and bile acid synthesis gene expression. FEX stimulated GLP-1 secretion and improved insulin and glucose tolerance, and adipose tissue browning. Analysis of 16S ribosomal RNA sequences of the gut microbiome identified the FEX-induced and LCA-producing bacteria Acetalifactor and Bacteroides in mice. Antibiotic treatment completely reversed the metabolic effects of FEX. FEX treatment effectively improved metabolic disorders in diabetic mice. This study uncovered a novel mechanism in which activation of intestinal FXR signaling shaped the gut microbiota to activate TGR5/GLP-1 signaling to improve hepatic glucose and lipid metabolism and metabolic disorders. The gut microbiota plays a critical role in mediating intestinal FXR signaling to effect hepatic bile acid metabolism and homeostasis.