Small intestinal taurochenodeoxycholic acid-FXR axis alters local nutrient-sensing glucoregulatory pathways in rats

• Published in: Molecular metabolism (Germany) Vol. 44; p. 101132
• Main Authors: Waise, T.M. Zaved, Lim, Yu-Mi, Danaei, Zahra, Zhang, Song-Yang, Lam, Tony K.T.
• Format: Journal Article
• Language: English
• Published: Germany Elsevier GmbH 01.02.2021; Elsevier
• Subjects: Bile acids; FXR; Glucose tolerance; Nutrient sensing; Original; Small intestine; Glucose tolerance; FXR; Bile acids; L. gasseri; USI; Nutrient sensing; TCDCA; Small intestine; HF
• ISSN: 2212-8778; 2212-8778
• DOI: 10.1016/j.molmet.2020.101132

The mechanism of nutrient sensing in the upper small intestine (USI) and ileum that regulates glucose homeostasis remains elusive. Short-term high-fat (HF) feeding increases taurochenodeoxycholic acid (TCDCA; an agonist of farnesoid X receptor (FXR)) in the USI and ileum of rats, and the increase of TCDCA is prevented by transplantation of microbiota obtained from the USI of healthy donors into the USI of HF rats. However, whether changes of TCDCA-FXR axis in the USI and ileum alter nutrient sensing remains unknown. Intravenous glucose tolerance test was performed in rats that received USI or ileal infusion of nutrients (i.e., oleic acids or glucose) via catheters placed toward the lumen of USI and/or ileum, while mechanistic gain- and loss-of-function studies targeting the TCDCA-FXR axis or bile salt hydrolase activity in USI and ileum were performed. USI or ileum infusion of nutrients increased glucose tolerance in healthy but not HF rats. Transplantation of healthy microbiome obtained from USI into the USI of HF rats restored nutrient sensing and inhibited FXR via a reduction of TCDCA in the USI and ileum. Further, inhibition of USI and ileal FXR enhanced nutrient sensing in HF rats, while inhibiting USI (but not ileal) bile salt hydrolase of HF rats transplanted with healthy microbiome activated FXR and disrupted nutrient sensing in the USI and ileum. We reveal a TCDCA-FXR axis in both the USI and ileum that is necessary for the upper small intestinal microbiome to govern local nutrient-sensing glucoregulatory pathways in rats. •Upper small intestinal infusion of oleic acid or glucose increases glucose tolerance in healthy but not HF-fed rats.•Ileal infusion of oleic acid or glucose increases glucose tolerance in healthy but not HF-fed rats.•Upper small intestinal healthy microbiome transplant enhances nutrient sensing and inhibits FXR via reduced TCDCA levels.•Inhibition of FXR in the upper small intestine or ileum enhances oleic acid sensing to increase glucose tolerance.•Inhibition of upper small intestinal bile salt hydrolase negates oleic acid sensing and activates FXR in the small intestine.