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Bile salt hydrolase activity as a rational target for MASLD therapy
Elizabeth V Jones1, Yongtao Wang2, Wenchao Wei3,4
1Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA, USA.
Gut Microbes
|January 2, 2026
Summary
Elevated gut bacteria enzyme activity (bile salt hydrolases) is linked to advanced metabolic dysfunction-associated steatotic liver disease (MASLD). Inhibiting these enzymes may offer a new treatment strategy for MASLD.
Area of Science:
- Gastroenterology and Hepatology
- Microbiome Research
- Drug Discovery
Background:
- Metabolic dysfunction-associated steatotic liver disease (MASLD) is a growing health concern with limited treatments.
- The gut-liver axis and intestinal permeability are implicated in MASLD pathogenesis.
- Gut bacterial bile salt hydrolases (BSHs) may contribute to liver damage via unconjugated bile acids (UBAs).
Purpose of the Study:
- To investigate the role of BSH activity in MASLD patients.
- To identify BSH-producing bacteria in MASLD patients.
- To evaluate the therapeutic potential of BSH inhibitors for MASLD.
Main Methods:
- Analysis of fecal BSH activity and bile acid levels in MASLD patients.
- Anaerobic culturing and activity-guided screening of fecal bacteria.
- Testing small-molecule BSH inhibitors on fecal communities and bacterial monocultures.
Main Results:
- Elevated fecal BSH activity was observed in MASLD patients with advanced fibrosis, correlating with reduced fecal bile acids.
- Diverse BSH-active bacteria were identified in patient samples.
- BSH inhibitors effectively suppressed BSH activity without impacting bacterial viability.
Conclusions:
- BSH activity is a microbial function associated with MASLD progression.
- BSH inhibitors represent a potential microbiome-targeted therapeutic strategy for MASLD.
