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

Abstract

Bile acids (BAs) are steroid-derived molecules with important roles in digestion, the maintenance of host metabolism and immunomodulation. Primary BAs are synthesised by the host, while secondary BAs are produced by the gut microbiome through transformation of the former. 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). Here, we demonstrate that the 7-dehydroxylation of CDCA and UDCA by Clostridium scindens is induced by CA suggesting that CA-dependent transcriptional regulation of 7-dehydroxylation is generalisable to CDCA and UDCA. In contrast, the murine isolate Extibacter muris did not respond to CA exposure in vitro, suggesting that bai genes are regulated differently in this strain. However, it could 7-dehydroxylate in vivo and its in vitro activity was promoted by the addition of cecal content. The accessory gene baiJ was only upregulated in the Clostridium 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 as a result of CA-driven induction and suggests distinct bai gene induction mechanisms across bacterial species.