Phytosterol-induced modulation of gut microbial bile salt hydrolases ameliorates hyperlipidemia via taurohyodeoxycholic acid-mediated FXR antagonism.

Dyslipidemia remains a major cardiovascular risk factor. Although dietary phytosterols have established lipid-lowering effects, their interactions with the gut-liver metabolic axis remain incompletely understood. Here, we integrated human observational and intervention studies with mechanistic experiments in hyperlipidemic rats, fecal microbiota transplantation (FMT), and in vitro cellular models to investigate how phytosterols influence lipid homeostasis through gut microbiota-bile acid signaling. Human analyses identified associations between phytosterol exposure, lipid phenotypes, gut microbial features, and circulating bile acid profiles. In rats, phytosterol treatment altered gut microbial composition and the relative abundance of putative bile salt hydrolase (BSH)-producing taxa, accompanied by reduced ileal luminal BSH activity. These changes coincided with bile acid remodeling, including increased concentrations of taurohyodeoxycholic acid (THDCA) in liver tissue and ileal contents. In vitro cellular assays indicated that THDCA antagonized intestinal farnesoid X receptor (FXR) signaling. Consistent with this, phytosterol treatment in vivo attenuated ileal FXR-fibroblast growth factor 15 (FGF15) signaling and decreased hepatic CYP7A1 while increasing CYP7B1 protein expression, a pattern consistent with a shift from the classical toward the alternative bile acid synthesis pathway. Complementary FMT experiments further supported a contributory role of the gut microbiota in the lipid-modulating effects of phytosterols. Collectively, these findings suggest that dietary phytosterols may ameliorate dyslipidemia partly through modulation of the gut microbiota-bile acid-FXR axis, with microbiota-associated BSH-THDCA-FXR signaling representing one plausible contributing pathway. This study provides convergent preclinical mechanistic and exploratory human evidence for a diet-microbe-host pathway relevant to dyslipidemia.