Hyodeoxycholic acid ameliorates tacrolimus-induced diabetes by modulating the FXR-FGF15 axis.

BACKGROUD: Immunosuppressant tacrolimus (TAC) induces glucose metabolism disorder and diabetes mellitus (DM) closely associated with intestinal microbiota dysbiosis and reduced bile acid levels, and this study aimed to explore the ameliorative effect and underlying mechanism of hyodeoxycholic acid (HDCA) on TAC-induced DM in rat models. METHODS: We first verified the critical role of intestinal microbiota and bile acids in the pathogenesis of TAC-induced DM via antibiotic-induced gut microbiota depletion, then orally administered HDCA (100 mg/kg) to TAC-induced diabetic rats to evaluate its protective efficacy, detecting glycolipid metabolism indices, targeted bile acid omics, FXR/TGR5 protein expression, serum and ileal GLP/FGF15 levels, and mRNA levels of key metabolic genes including Cyp7a1, Cyp27a1, Cyp7b1, Cyp8b1, Fgfr4, Creb1 and Ppargc1a. RESULTS: Antibiotic treatment significantly reduced BSH-active gut microbiota such as Bacteroides and Lactobacillus, disrupting the serum bile acid pool and exacerbating diabetic symptoms by altering the gut microbiota-bile acid axis; while HDCA administration markedly improved glucose tolerance and reshaped bile acid profiles in TAC-induced diabetic rats, specifically lowering serum and fecal 12-OH/Non-12-OH BAs ratio via downregulating hepatic Cyp7a1 and upregulating hepatic Cyp8b1 expression. HDCA also suppressed enteroendocrine cell-derived GLP-1 secretion, decreased serum and ileal FGF15 levels, and reduced the expression of ileal FXR as well as hepatic Creb1 and Ppargc1a. CONCLUSIONS: Collectively, HDCA exerts a significant ameliorative effect on TACinduced DM by regulating metabolic enzymes and altering bile acid profiles, with the core mechanism involving inhibited enterohepatic FXR-FGF15 axis, increased GLP-1 secretion and suppressed hepatic gluconeogenesis, all of which play key regulatory roles in this protective process.