Intestinal Epithelial Bmal1 Contributes to High-Fat Diet–Induced Hepatic Lipid Dysmetabolism through Microbiota-Associated Bile Acid Remodeling

Abstract High-fat diet (HFD)-induced hepatic lipid dysmetabolism is closely associated with gut microbiota and bile acid remodeling, but the contribution of intestinal epithelial Bmal1 remains unclear. Here, intestinal epithelial Bmal1 deletion in HFD-fed mice reduced weight gain, improved glucose and lipid homeostasis, and attenuated hepatic steatosis. These changes were accompanied by coordinated regulation of hepatic lipid metabolic pathways, altered bile acid-related signaling along the gut–liver axis, and selective remodeling of the HFD-associated gut microbiota. Targeted analysis further revealed distinct shifts in circulating and fecal bile acid profiles. Fecal microbiota transplantation from HFD-fed Bmal1-deficient donors was associated with similar hepatic metabolic and bile acid-related changes in HFD-fed recipients. Together, these findings support a model in which intestinal epithelial Bmal1 contributes to HFD-induced hepatic lipid dysmetabolism in association with microbiota-associated bile acid remodeling.