A novel bile salt hydrolase-producing Ligilactobacillus salivarius prevents diet-induced obesity via regulation of bile acid metabolism and glucagon-like peptide 1 restoration

Obesity poses a major global health challenge, necessitating safe and effective therapeutic strategies. Using high-throughput genomic screening for bile salt hydrolase (BSH)-producing strains, we identified Ligilactobacillus salivarius (L. salivarius) XA1416, a strain isolated from the feces of healthy individuals, which exhibits high BSH activity, strong acid resistance, and efficient colonization in the gastrointestinal tract. Oral administration of L. salivarius XA1416 counteracted high-fat diet-induced weight gain in mice, improved glucose homeostasis, and enhanced GLP-1 secretion. The strain modulated the gut microbiota, enriching taxa such as Bacteroides, Alistipes, and Faecalibaculum, and altered bile acid profiles, notably increasing ursodeoxycholic acid (UDCA). Mendelian randomization analysis leveraging large-scale human GWAS data and two cross-sectional cohorts' data, complemented by in vitro fecal microbiota fermentation experiments, collectively supports a key role of UDCA in weight control. The oral administration of UDCA recapitulated the anti-obesity effects and metabolic benefits of XA1416, functioning as an intestinal Farnesoid X receptor antagonist and Takeda G-protein-coupled receptor 5 agonist to stimulate GLP-1 secretion. This mechanism likely involves modulation of the hepatic FXR/SHP/SREBP-1c pathway and concurrent activation of the GLP-1 Receptor, contributing to improved metabolic homeostasis. Additionally, we gavaged the mice fed with normal chow or a high-fat diet with GR-7, a specific inhibitor of microbial BSHs, leading to a reduction in UDCA level and GLP-1 production. Using HepG2 cell models and molecular dynamics simulations, we further demonstrated that UDCA directly activates the GLP-1 Receptor. Taken together, our findings position L. salivarius XA1416 as a promising anti-obesity probiotic, with UDCA serving as a key Microbial Metabolite that mediates its beneficial metabolic effects.