Completion of the gut microbial epi-bile acid pathway

Abstract

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.

Review: microbial transformations of human bile acids

“…Based on the findings by Edenharder and Pfutzner, C. paraputrificum 12β-HSDH behaves in a similar manner to established 12α-HSDHs, as shown by its pH optimum and molecular weight. The gene encoding the 12β-HSDH in C. paraputrificum was recently identified, allowing for investigation into the diversity of potential 12β-HSDH producers [ 86 ]. Putative 12β-HSDH genes were found across Firmicutes, Actinobacteria, and Alphaproteobacteria.…”

Oral, Tongue-Coating Microbiota, and Metabolic Disorders: A Novel Area of Interactive Research

“…Microbial–host interactions closely influence human health status ( 1 , 2 ). Microorganisms colonizing the human body can participate in the synthesis and metabolism of vitamins, proteins, and lipids, promote immunity, maintain the local ecological balance in organs, degrade nutrients, provide energy to the host ( 1 , 3 , 4 ) and have an important impact on host metabolic processes. In contrast, oral microbiota have gradually gained importance as easily detectable colonizing microorganisms, and research has shifted from oral diseases to a broader perspective, of which tongue-coating microbiota are an important part.…”

Integrated Analysis of the Cecal Microbiome and Plasma Metabolomics to Explore NaoMaiTong and Its Potential Role in Changing the Intestinal Flora and Their Metabolites in Ischemic Stroke

“…Our research indicated that NMT reversed deoxycholic acid (DCA) level that was negatively correlated with ( Clostridium ) _innocuum_group and Faecalitalea , and positively correlated with ( Eubacterium ) _nodatum_group , Candidatus_Saccharimonas , and Lachnospiraceae_UCG-006 ( Figure 6 ). Bile acids (BA) are synthesized from cholesterol in the liver and most secreted into the intestinal lumen, where a substantial mass of toxic-hydrophobic bile acids was transformed, such as DCA ( Nicholson et al, 2012 ; Doden et al, 2021 ). Recently, destruction of the intestinal barrier which correlated with secondary bile acids has been reported ( Pi et al, 2020 ).…”