Review: microbial transformations of human bile acids

Abstract

Bile acids play key roles in gut metabolism, cell signaling, and microbiome composition. While the liver is responsible for the production of primary bile acids, microbes in the gut modify these compounds into myriad forms that greatly increase their diversity and biological function. Since the early 1960s, microbes have been known to transform human bile acids in four distinct ways: deconjugation of the amino acids glycine or taurine, and dehydroxylation, dehydrogenation, and epimerization of the cholesterol core. Alterations in the chemistry of these secondary bile acids have been linked to several diseases, such as cirrhosis, inflammatory bowel disease, and cancer. In addition to the previously known transformations, a recent study has shown that members of our gut microbiota are also able to conjugate amino acids to bile acids, representing a new set of "microbially conjugated bile acids." This new finding greatly influences the diversity of bile acids in the mammalian gut, but the effects on host physiology and microbial dynamics are mostly unknown. This review focuses on recent discoveries investigating microbial mechanisms of human bile acids and explores the chemical diversity that may exist in bile acid structures in light of the new discovery of microbial conjugations. Video Abstract.

Keywords: Bile acid; Cholic acid; Clostridium scindens; Conjugation; Enterocloster bolteae; Gut health; Metabolism; Microbiology; Microbiome.

Conflict of interest statement

The authors declare that they have no competing interests.

Figures

Fig. 1

Diversity of known human bile acids. A All BAs are built off the same sterol backbone with variations in hydroxylated positions, hydroxyl orientation, and the presence of ketones. CA and CDCA, along with GlyCA, GlyCDCA, TaurCA, and TaurCDCA, make up the primary BA pool. Remaining BAs in the list make up secondary and tertiary BA pools as a result of modifications from gut microbes [–7]. Allobile acids, although matching in hydroxyl positions to their standard bile acid counterparts, differ in ring orientation. Standard bile acids have the first ring in the B transorientation, yielding 5β-BAs, while allobile acids have this ring in the C cis-orientation, yielding 5α-BAs

Fig. 2

Deconjugation reactions and enzyme homology present between gut bacteria. Regardless of hydroxylation positions, substitution of water for either A glycine or B taurine yields the same products. C Structural homology between subunits from B. thetaiotaomicron (6UFY, blue), L. salivarius (5HKE, red), B. longum (2HF0, yellow), C. perfringens (2BJF, green), and E. faecalis (4WL3, orange) using Visual Molecular Dynamics (VMD) software [47]. D Structural homology (QH) was measured utilizing VMD with a minimum of 0.5804 and a maximum of 0.8533. E. faecalis and L. salivarius BSHs had the greatest similarity while B. thetaiotaomicron was the most dissimilar to all other organisms. These analyses were created de novo for this review

Fig. 3

Dehydroxylation pathway for primary BAs CA (R: -OH) and CDCA (R: -H). A The pathway to complete 7α-dehydroxylation is a multi-stage process that involves progressive substrate oxidation, likely for molecule stability, prior to dehydroxylation, followed by reduction at each previously oxidized position along the sterol backbone [59]. The enzyme capable of dehydroxylation, BaiE, is highly conserved structurally between C. scindens (red), C. hylemonae (blue), and P. hiranonis (yellow), evident in both B side and C top-down views of BaiE

Fig. 4

Pathways of CA and CDCA epimerization, including corresponding EC identifiers. A CA undergoes three different epimerization pathways leading to the production of iCA (via 3α/β-HSDH), UCA (via 7α/β-HSDH), or 12-ECA (via 12α/β-HSDH) while B CDCA undergoes two distinct epimerization pathways leading to the production of UDCA (via 7α/β-HSDH) or iCDCA (via 3α/β-HSDH). *S. maltophilia transforms CDCA to 7-oxo-CDCA but the enzyme is categorized under EC 1.1.1.159, where the official reaction involves CA 7α-oxidation [70]

Fig. 5

Potential increased diversity of host BA pool as a result of MCBA production. With the current understanding of BA metabolism, A primary BAs CA and CDCA are known to be conjugated in the liver to taurine and glycine to form B GlyCA, TaurCA, GlyCDCA, and TaurCDCA, completing the pool of primary human BAs. In light of recent research, CA is also known to be conjugated by gut microbes to form C PheCA, LeuCA, and TyrCA [5]. Expanding the potential library of microbially conjugated BAs by including the remaining amino acids conjugates for D CA and E CDCA increases the diversity of human BAs over 5-fold for these backbones alone