Objective Conjugated bile acids are metabolised by upper small intestinal microbiota, and serum levels of taurine-conjugated bile acids are elevated and correlated with insulin resistance in people with type 2 diabetes. However, whether changes in taurine-conjugated bile acids are necessary for small intestinal microbiome to alter insulin action remain unknown.
Design We evaluated circulating and specifically brain insulin action using the pancreatic-euglycaemic clamps in high-fat (HF) versus chow fed rats with or without upper small intestinal healthy microbiome transplant. Chemical and molecular gain/loss-of-function experiments targeting specific taurine-conjugated bile acid-induced changes of farnesoid X receptor (FXR) in the brain were performed in parallel.
Results We found that short-term HF feeding increased the levels of taurochenodeoxycholic acid (TCDCA, an FXR ligand) in the upper small intestine, ileum, plasma and dorsal vagal complex (DVC) of the brain. Transplantation of upper small intestinal healthy microbiome into the upper small intestine of HF rats not only reversed the rise of TCDCA in all reported tissues but also enhanced the ability of either circulating hyperinsulinaemia or DVC insulin action to lower glucose production. Further, DVC infusion of TCDCA or FXR agonist negated the enhancement of insulin action, while genetic knockdown or chemical inhibition of FXR in the DVC of HF rats reversed insulin resistance.
Conclusion Our findings indicate that FXR in the DVC is sufficient and necessary for upper small intestinal microbiome-mediated changes of TCDCA to alter insulin action in rats, and highlight a previously unappreciated TCDCA-FXR axis linking gut microbiome and host insulin action.
- glucose metabolism
- bile acid metabolism
- small intestine
Data availability statement
Data are available upon reasonable request. All data relevant to the study are included in the article or uploaded as supplementary information. N/A.
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S-YZ and RJWL contributed equally.
Contributors S-YZ and RJWL conducted and designed the experiments, performed the data analyses and wrote the manuscript. Y-ML, BB and TMZW assisted with experiments. HL conducted and analysed the bile acid measurements. TKTL supervised the project, designed the experiments and wrote the manuscript.
Funding This study was partly supported by a Canadian Institutes of Health Research (CIHR) Foundation Grant to TKTL (FDN-143204) and by the Toronto General and Western Hospital Foundation.
Competing interests S-YZ is supported by a Banting and Best Diabetes Centre (BBDC) post-doctoral fellowship. RJWL is supported by a BBDC graduate scholarship. Y-ML is supported by a BBDC-Kangbuk Samsung post-doctoral fellowship. TMZW is supported by a Diabetes Canada post-doctoral fellowship. TKTL holds the John Kitson McIvor (1915-1942) Endowed Chair in Diabetes Research and the Tier 1 Canada Research Chair in Diabetes and Obesity at the Toronto General Hospital Research Institute and the University of Toronto.
Provenance and peer review Not commissioned; externally peer reviewed.
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