Bile salt hydrolase catalyses formation of amine-conjugated bile acids

Abstract

Bacteria in the gastrointestinal tract produce amino acid bile acid amidates that can affect host-mediated metabolic processes1–6; however, the bacterial gene(s) responsible for their production remain unknown. Herein, we report that bile salt hydrolase (BSH) possesses dual functions in bile acid metabolism. Specifically, we identified a previously unknown role for BSH as an amine N-acyltransferase that conjugates amines to bile acids, thus forming bacterial bile acid amidates (BBAAs). To characterize this amine N-acyltransferase BSH activity, we used pharmacological inhibition of BSH, heterologous expression of bsh and mutants in Escherichia coli and bsh knockout and complementation in Bacteroides fragilis to demonstrate that BSH generates BBAAs. We further show in a human infant cohort that BBAA production is positively correlated with the colonization of bsh-expressing bacteria. Lastly, we report that in cell culture models, BBAAs activate host ligand-activated transcription factors including the pregnane X receptor and the aryl hydrocarbon receptor. These findings enhance our understanding of how gut bacteria, through the promiscuous actions of BSH, have a significant role in regulating the bile acid metabolic network.

Microbially conjugated bile salts found in human bile activate the bile salt receptors TGR5 and FXR

“…Previously unrecognized amine N -acyl transferase activity of bsh, a ubiquitous bacterial enzyme that catalyzes deconjugation of host bile salts, appears to be involved in the formation of MBSCs. 33 Additional biosynthetic pathways likely exist, as suggested by MBSC production by bacteria seemingly devoid of bsh . 33 Notwithstanding the advances in basic aspects of MBSCs, insight into their biological function(s) is limited.…”

“… 33 Additional biosynthetic pathways likely exist, as suggested by MBSC production by bacteria seemingly devoid of bsh . 33 Notwithstanding the advances in basic aspects of MBSCs, insight into their biological function(s) is limited. To appreciate a role in host bile salt signaling, we studied the interaction of MBSCs with the key bile salt receptors TGR5 and FXR.…”

Recent developments in the enzymatic modifications of steroid scaffolds

“…185 Recently, Patterson's and Quinn's groups reported that bile salt hydrolase (BSH) not only plays a role in bile acid metabolism but also acts as an amine N -acyltransferase, forming bacterial bile acid amidates (BBAAs). 186,187 BSH belongs to the N-terminal nucleophile superfamily of enzymes and catalyzes the hydrolysis of glycocholic acid ( 142 ) and taurocholic acid ( 143 ) to generate BBAAs (Fig. 25).…”

Novel approaches in IBD therapy: targeting the gut microbiota-bile acid axis

“… 104 These MCBAs can activate PXR receptor and the aryl hydrocarbon receptor. 105 The intrinsic acyltransferase activity of BSH/T greatly diversifies BA chemistry. The physiological effects of amino acid-conjugated BAs, other than those conjugated to glycine or taurine, are not yet fully understood.…”