Completion of the gut microbial epi-bile acid pathway

• Published in: Gut microbes Vol. 13; no. 1; pp. 1 - 20
• Main Authors: Doden, Heidi L., Wolf, Patricia G., Gaskins, H. Rex, Anantharaman, Karthik, Alves, João M. P., Ridlon, Jason M.
• Format: Journal Article
• Language: English
• Published: United States Taylor & Francis 01-01-2021; Taylor & Francis Group
• Subjects: 12-oxolithocholic acid; Actinobacteria - genetics; Bacterial Proteins - genetics; Bacterial Proteins - metabolism; Bile acid; Bile Acids and Salts - metabolism; Clostridium - enzymology; Clostridium - genetics; Clostridium - metabolism; Clostridium Infections - microbiology; deoxycholic acid; DNA, Bacterial; epi-bile acid; Gastrointestinal Microbiome; Humans; hydroxysteroid dehydrogenase; Hydroxysteroid Dehydrogenases - genetics; Hydroxysteroid Dehydrogenases - metabolism; iso-bile acid; Lithocholic Acid - metabolism; NADP - metabolism; Phylogeny; Recombinant Proteins - genetics; Recombinant Proteins - metabolism; Research Paper; urso-bile acid; 12-oxolithocholic acid; iso-bile acid; hydroxysteroid dehydrogenase; Bile acid; epi-bile acid; urso-bile acid; deoxycholic acid
• ISSN: 1949-0976; 1949-0984
• DOI: 10.1080/19490976.2021.1907271

Bile acids are detergent molecules that solubilize dietary lipids and lipid-soluble vitamins. Humans synthesize bile acids with α-orientation hydroxyl groups which can be biotransformed by gut microbiota to toxic, hydrophobic bile acids, such as deoxycholic acid (DCA). Gut microbiota can also convert hydroxyl groups from the α-orientation through an oxo-intermediate to the β-orientation, resulting in more hydrophilic, less toxic bile acids. This interconversion is catalyzed by regio- (C-3 vs. C-7) and stereospecific (α vs. β) hydroxysteroid dehydrogenases (HSDHs). So far, genes encoding the urso- (7α-HSDH & 7β-HSDH) and iso- (3α-HSDH & 3β-HSDH) bile acid pathways have been described. Recently, multiple human gut clostridia were reported to encode 12α-HSDH, which interconverts DCA and 12-oxolithocholic acid (12-oxoLCA). 12β-HSDH completes the epi-bile acid pathway by converting 12-oxoLCA to the 12β-bile acid denoted epiDCA; however, a gene(s) encoding this enzyme has yet to be identified. We confirmed 12β-HSDH activity in cultures of Clostridium paraputrificum ATCC 25780. From six candidate C. paraputrificum ATCC 25780 oxidoreductase genes, we discovered the first gene (DR024_RS09610) encoding bile acid 12β-HSDH. Phylogenetic analysis revealed unforeseen diversity for 12β-HSDH, leading to validation of two additional bile acid 12β-HSDHs through a synthetic biology approach. By comparison to a previous phylogenetic analysis of 12α-HSDH, we identified the first potential C-12 epimerizing strains: Collinsella tanakaei YIT 12063 and Collinsella stercoris DSM 13279. A Hidden Markov Model search against human gut metagenomes located putative 12β-HSDH genes in about 30% of subjects within the cohorts analyzed, indicating this gene is relevant in the human gut microbiome.