Bile salt hydrolase activity as a rational target for MASLD therapy.

Metabolic dysfunction-associated steatotic liver disease (MASLD) is the most prevalent chronic liver disease in the United States, yet therapeutic options remain limited. Emerging evidence implicates the gut‒liver axis and intestinal permeability in disease pathogenesis. Previous studies in animal models and human cell culture indicated that bile salt hydrolases (BSHs), which are gut bacterial enzymes that deconjugate host-derived bile acids, damage intestinal barrier integrity and cause liver damage through the generation of unconjugated bile acids (UBAs). However, the relevance of these findings to MASLD patients is unknown. Here, we demonstrate that BSH activity is elevated in fecal samples from MASLD patients with advanced liver fibrosis and correlates with reduced fecal bile acid levels, which is consistent with a proposed model of increased intestinal permeability during MASLD progression. Through anaerobic culturing and activity-guided screening, we identify diverse BSH-active bacteria from patient fecal samples, suggesting broad microbial contributions to bile acid deconjugation in MASLD patients. Importantly, small-molecule BSH inhibitors suppressed BSH activity in both fecal communities and monocultures from MASLD patients without affecting bacterial viability. These findings indicate that BSH activity is a microbial function associated with MASLD progression and suggest that BSH inhibitors could be developed as a microbiome-targeted strategy for MASLD treatment.