Balance between bile acid conjugation and hydrolysis activity can alter outcomes of gut inflammation

Conjugated bile acids (BAs) are multi-functional detergents produced in the gastrointestinal (GI) tract by the liver enzyme bile acid:amino acid N-acyltransferase (BAAT) and by the microbiome from acyltransferase activity of the ubiquitous enzyme bile salt hydrolase (BSH). Humans with inflammatory bowel disease (IBD) have an enrichment in both host and microbially conjugated BAs (MCBAs), but their impacts on GI inflammation are not well understood. We investigated the role of host-conjugated BAs in the dextran sodium sulfate (DSS) model of colitis using a BAAT knockout background. Baat ^-/- KO mice have severe phenotypes in the DSS model that were rescued by supplementation with taurocholate (TCA). Gene expression and histological analysis showed that this rescue was likely due to an improved epithelial barrier and goblet cell function. TCA supplementation also increased microbiome diversity, particularly the BA metabolizing Lachnospiraceae . Metabolomics showed that TCA supplementation in the DSS model increased all known forms of conjugated BAs including both host and microbial sources, but also their hydrolysis and metabolism to secondary BAs. The ability of TCA to improve pathology under DSS inflammation despite its ready hydrolysis led us to investigate the BSH activity of diverse gut bacteria on a panel of conjugated BAs in vitro and in vivo . Exposure of 17 gut bacterial isolates to a panel of 10 amino acid conjugated BAs showed broad hydrolytic capacity depending on the bacterium. Host-produced TCA and the MCBAs SerCA and AlaCA were readily hydrolyzed, whereas GluCA, AspCA and ThrCA were more resistant. This hydrolytic variability translated in vivo where mice fed the recalcitrant GluCA had less secondary BAs production in the DSS model compared to TCA. The complexity of microbial dysbiosis and conjugated BA metabolism in an inflamed murine gut led to the exploration of BSHs genes in metagenomic data from human IBD patients. Certain bsh sequences were enriched in the diseased states including that from Ruminococcus gnavus and Enterocloster clostridioformis in people with Crohn’s disease. Collectively, this study shows that the conjugated BAs may provide benefits to those with IBD, but this is dictated by a delicate balance between BA conjugation/deconjugation based on the BSH sequences present.