Cholesterol-Lowering Mechanism of Lactobacillus Bile Salt Hydrolase Through Regulation of Bifidobacterium pseudolongum in the Gut Microbiota

Background: Cardiovascular diseases (CVDs) represent a major global health burden, and cholesterol reduction is a key strategy for their prevention and management. This study investigated the mechanism by which bile salt hydrolase (BSH) from Lactobacilli reduces cholesterol levels by modulating the growth of Bifidobacterium pseudolongum. Methods: The BSH-recombinant strain YB334 was administered to high-cholesterol-diet mice, and the cholesterol-lowering function of the strain was evaluated by assessing serum cholesterol parameters, including total cholesterol (TC), low-density lipoprotein (LDL) and high-density lipoprotein (HDL). Metagenomic sequencing was used to analyze the gut microbiota, leading to the screening and acquisition of the “responsive” strains affected by BSH. Subsequent investigations were conducted into their cholesterol-lowering effects and mechanisms of action. Results: Oral administration of the BSH-recombinant strain YB334 can effectively reduce serum cholesterol levels in hypercholesterolemic mice while simultaneously leading to a significant increase in the abundance of B. pseudolongum within the gut microbiota. In vitro experiments indicated that this increased abundance might be closely associated with the strain’s high tolerance to CA, the catalytic product of the BSH enzyme. The BPL-4 strain, obtained through screening, demonstrated cholesterol-lowering efficacy. Mechanistically, BPL-4 altered bile acid pool composition and modulated the farnesoid X receptor (FXR) signaling axis: it suppressed ileal FXR-fibroblast growth factor 15 (FGF15) expression, thereby de-repressing hepatic cholesterol 7α-hydroxylase (CYP7A1) and accelerating cholesterol catabolism into bile acids. Conclusions: This study provides the first evidence that BSH from lactobacilli can shape the signature gut microbiota by modulating bile acid metabolism via the FXR-CYP7A1 axis, thereby demonstrating a mechanism for its cholesterol-lowering effects.