Dietary phytosterols ameliorate hyperlipidemia by enriching the FXR antagonist taurohyodeoxycholic acid via suppression of microbial bile salt hydrolases_Ileal content 16S full-length sequencing

Dyslipidemia is a major cardiovascular risk factor. While dietary phytosterols are known to lower cholesterol, the mechanisms involving the gut-liver axis are not fully understood. By integrating human clinical trials and mechanistic animal models, we demonstrate that phytosterols improve lipid profiles by modulating the gut microbiota-bile acid-farnesoid X receptor (FXR) axis. Phytosterol supplementation suppresses the abundance of bile salt hydrolase-active bacteria, such as Lactobacillus, leading to reduced intestinal enzymatic activity and the accumulation of conjugated bile acids. These bile acids act as intestinal FXR antagonists, downregulating the ileal fibroblast growth factor 15 (FGF15) signaling pathway. This suppression relieves feedback inhibition on hepatic bile acid synthesis, thereby accelerating cholesterol catabolism. Fecal microbiota transplantation validates that these metabolic benefits are gut microbiota dependent. Together, these findings link dietary phytosterols to host lipid metabolism through gut microbial bile acid regulation, providing a mechanistic framework for individualized, food-based strategies to manage dyslipidemia.