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

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

Pathak Preeti; Xie Cen; Nichols Robert G; Ferrell Jessica M; Boehme Shannon; Krausz Kristopher W; Patterson Andrew D; Gonzalez Frank J; Chiang John Y L

Hepatology (Baltimore, Md.)

2018

2018-10

Bile acids activate farnesoid X receptor (FXR) and G protein-coupled bile acid receptor-1 (aka Takeda G protein-coupled receptor-5 [TGR5]) to regulate bile acid metabolism and glucose and insulin sensitivity. FXR and TGR5 are coexpressed in the enteroendocrine L cells, but their roles in integrated regulation of metabolism are not completely understood. We reported recently that activation of FXR induces TGR5 to stimulate glucagon-like peptide-1 (GLP-1) secretion to improve insulin sensitivity and hepatic metabolism. In this study, we used the intestine-restricted FXR agonist fexaramine (FEX) to study the effect of activation of intestinal FXR on the gut microbiome, bile acid metabolism, and FXR and TGR5 signaling. The current study revealed that FEX markedly increased taurolithocholic acid, increased secretion of fibroblast growth factors 15 and 21 and GLP-1, improved insulin and glucose tolerance, and promoted white adipose tissue browning in mice. Analysis of 16S ribosomal RNA sequences of the gut microbiome identified the FEX-induced and lithocholic acid-producing bacteria Acetatifactor and Bacteroides. Antibiotic treatment completely reversed the

Male; Animals; Mice; Random Allocation; Sensitivity and Specificity; *Signal Transduction; Lipid Metabolism; Bile Acids and Salts/*metabolism; GTP-Binding Proteins/*metabolism; Receptors; Inbred C57BL; Animal; Disease Models; G-Protein-Coupled/*metabolism; Gastrointestinal Microbiome/*drug effects; Glucagon-Like Peptide 1/metabolism; Cytoplasmic and Nuclear/*antagonists & inhibitors/pharmacology

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1574-1588

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