Cholesterol-Lowering Mechanism of <em>Lactobacillus</em> Bile Salt Hydrolase through Regulation of <em>Bifidobacterium pseudolongum</em> in the Gut Microbiota

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) derived from lactic acid bacteria reduces cholesterol levels by modulating the growth of Bifidobacterium pseudolongum. Oral administration of a recombinant BSH-producing bacterium, YB334, can significantly lower serum cholesterol levels in hypercholesterolemic mice. Furthermore, metagenomic sequencing revealed a considerable enrichment of B. pseudolongum in the intestines of mice following YB334 administration. In vitro investigations demonstrated that crude extract of YB334-BSH, when supplemented with an inducer, selectively enhanced the growth of B. pseudolongum in a concentration-dependent manner, with strain BPL-4 showing the most pronounced proliferation. This effect is intricately linked to its enhanced tolerance to the BSH catalytic product cholic acid (CA). Subsequent animal studies indicated that isolated B. pseudolongum BPL-4 exhibited substantial BSH activity, modified the bile acid profile, regulated the farnesoid X receptor (FXR) signalling system, markedly decreased serum cholesterol levels in hypercholesterolemic mice, and ameliorated hepatic steatosis. This study elucidated a novel mechanism by which BSH reduces cholesterol by modulating the gut flora, thereby offering a theoretical foundation for the formulation of probiotic-based interventions against CVDs.