Strain-dependent induction of primary bile acid 7-dehydroxylation by cholic acid

Abstract

Background Bile acids (BAs) are steroid-derived molecules with important roles in digestion, the maintenance of host metabolism, and immunomodulation. Primary BAs are synthesized by the host, while secondary BAs are produced by the gut microbiome through transformation of the former. Nevertheless, regulation of microbial production of secondary BAs is not well understood, particularly the production of 7-dehydroxylated BAs, which are the most potent agonists for host BA receptors. The 7-dehydroxylation of cholic acid (CA) is well established and is linked to the expression of a bile acid-inducible (bai) operon responsible for this process. However, little to no 7-dehydroxylation has been reported for other host-derived BAs (e.g., chenodeoxycholic acid, CDCA or ursodeoxycholic acid, UDCA). Results Here, we demonstrate that the 7-dehydroxylation of CDCA and UDCA by human-isolated Clostridium scindens strains is induced by CA suggesting that CA-dependent transcriptional regulation of 7-dehydroxylation is generalisable to CDCA and UDCA. In contrast, in the murine isolate Extibacter muris, bai gene expression did not respond to CA or other primary BAs exposure in vitro. E. muris was found to 7-dehydroxylate in vivo. Conclusions The distinct expression responses amongst strains indicate that bai genes are regulated differently. CA promoted the 7-dehydroxylating activity in C. scindens strains. Conversely, the in vitro activity of E. muriswas promoted only after the addition of cecal content. The accessory gene baiJ was only upregulated in the C. scindens ATCC 35704 strain, implying mechanistic differences amongst isolates. Interestingly, the human-derived C. scindens strains were also capable of 7-dehydroxylating murine bile acids (muricholic acids) to a limited extent. This study shows novel 7-dehydroxylation activity in vitro resulting from the presence of CA and suggests distinct baigene expression across bacterial species.