Bile salt hydrolases deplete conjugated bile acids and erode gut barrier integrity in non-alcoholic steatohepatitis

Background & AimsWhile altered host-microbe interactions are implicated in non-alcoholic fatty liver disease/non-alcoholic steatohepatitis (NAFLD/NASH), specific contributions of microbially derived metabolites remain obscure. We investigated the impact of altered bile acid (BA) populations on intestinal and hepatic phenotypes in a rodent model of NAFLD/NASH. MethodsWistar rats fed a choline-deficient high-fat diet (CDAHFD) were assessed for altered intestinal permeability after dietary intervention. Cecal and portal venous BA composition were assessed via mass spectrometry. BA-mediated effects on epithelial permeability were assessed using Caco2 epithelial monolayers. Micelle formation was assessed using fluorescent probes and electron microscopy. Bile salt hydrolase (BSH) activity was inhibited with a gut-restricted small molecule in CDAHFD-fed rats and intestinal and hepatic phenotypes were assessed. ResultsIncreased intestinal permeability and reduced intestinal conjugated BAs were early phenotypes of CDAHFD-fed rats preceding hepatic disease development. Similar intestinal BA pool changes were observed in rats and human NAFLD/NASH patients with progressive disease. Conjugated BAs protected epithelial layers from unconjugated BA-induced damage via mixed micelle formation. The decrease in intestinal conjugated BAs was mediated by increased activity of bacterial BSHs and inhibition of BSH activity prevented the development of pathologic intestinal permeability and hepatic inflammation in the NAFLD/NASH model. ConclusionsConjugated BAs are important for the maintenance of intestinal barrier function by sequestering unconjugated BAs in mixed micelles. Increased BSH activity reduces intestinal conjugated BA abundance, in turn increasing intestinal permeability and susceptibility to the development of NAFLD/NASH. These findings suggest that interventions that shift the intestinal bile acid pool toward conjugated BAs could be developed as therapies for NAFLD/NASH. What You Need To KnowO_ST_ABSBACKGROUND AND CONTEXTC_ST_ABSAltered host-microbe interactions are implicated in the development of NAFLD/NASH but the contributions of specific microbially derived metabolites have remained obscure. NEW FINDINGSConjugated BAs protect intestinal epithelium by sequestering unconjugated BAs in mixed micelles. Reduced intestinal conjugated BAs resulting from increased bacterial BSH activity is observed in a rodent model of NAFLD/NASH. BSH inhibition leads to improved intestinal and hepatic phenotypes. LIMITATIONSThis study was performed primarily in rats with supportive human fecal BA data. Additional studies are required to further support the relevance of our findings in human disease. IMPACTConjugated BAs and bacterial BSH activity are important for intestinal barrier function in NAFLD/NASH. Interventions shifting the intestinal BA pool toward conjugated BAs may be developed as therapies for NAFLD/NASH. Short SummaryInhibition of bile salt hydrolase activity and increased intestinal conjugated bile acids protect against early damage to intestinal barrier integrity and hepatic inflammation in a rodent model of non-alcoholic steatohepatitis.