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Appl Environ Microbiol. 2018 May 1;84(10). pii: e00235-18. doi: 10.1128/AEM.00235-18. Print 2018 May 15.

Metabolism of Oxo-Bile Acids and Characterization of Recombinant 12α-Hydroxysteroid Dehydrogenases from Bile Acid 7α-Dehydroxylating Human Gut Bacteria.

Author information

1
Microbiome Metabolic Engineering Theme, Carl R. Woese Institute for Genomic Biology, Urbana, Illinois, USA.
2
Department of Animal Sciences, University of Illinois at Urbana-Champaign, Urbana, Illinois, USA.
3
Department of Biological Sciences, Eastern Illinois University, Charleston, Illinois, USA.
4
Division of Nutritional Sciences, University of Illinois at Urbana-Champaign, Urbana, Illinois, USA.
5
Department of Parasitology, Institute of Biomedical Sciences, University of São Paulo, São Paulo, Brazil.
6
Microbiome Metabolic Engineering Theme, Carl R. Woese Institute for Genomic Biology, Urbana, Illinois, USA jmridlon@illinois.edu.
7
Cancer Center of Illinois, University of Illinois at Urbana-Champaign, Urbana, Illinois, USA.
8
Department of Microbiology and Immunology, School of Medicine, Virginia Commonwealth University, Richmond, Virginia, USA.
#
Contributed equally

Abstract

Bile acids are important cholesterol-derived nutrient signaling hormones, synthesized in the liver, that act as detergents to solubilize dietary lipids. Bile acid 7α-dehydroxylating gut bacteria generate the toxic bile acids deoxycholic acid and lithocholic acid from host bile acids. The ability of these bacteria to remove the 7-hydroxyl group is partially dependent on 7α-hydroxysteroid dehydrogenase (HSDH) activity, which reduces 7-oxo-bile acids generated by other gut bacteria. 3α-HSDH has an important enzymatic activity in the bile acid 7α-dehydroxylation pathway. 12α-HSDH activity has been reported for the low-activity bile acid 7α-dehydroxylating bacterium Clostridium leptum; however, this activity has not been reported for high-activity bile acid 7α-dehydroxylating bacteria, such as Clostridium scindens, Clostridium hylemonae, and Clostridium hiranonis Here, we demonstrate that these strains express bile acid 12α-HSDH. The recombinant enzymes were characterized from each species and shown to preferentially reduce 12-oxolithocholic acid to deoxycholic acid, with low activity against 12-oxochenodeoxycholic acid and reduced activity when bile acids were conjugated to taurine or glycine. Phylogenetic analysis suggests that 12α-HSDH is widespread among Firmicutes, Actinobacteria in the Coriobacteriaceae family, and human gut ArchaeaIMPORTANCE 12α-HSDH activity has been established in the medically important bile acid 7α-dehydroxylating bacteria C. scindens, C. hiranonis, and C. hylemonae Experiments with recombinant 12α-HSDHs from these strains are consistent with culture-based experiments that show a robust preference for 12-oxolithocholic acid over 12-oxochenodeoxycholic acid. Phylogenetic analysis identified novel members of the gut microbiome encoding 12α-HSDH. Future reengineering of 12α-HSDH enzymes to preferentially oxidize cholic acid may provide a means to industrially produce the therapeutic bile acid ursodeoxycholic acid. In addition, a cholic acid-specific 12α-HSDH expressed in the gut may be useful for the reduction in deoxycholic acid concentration, a bile acid implicated in cancers of the gastrointestinal (GI) tract.

KEYWORDS:

12α-hydroxysteroid dehydrogenase; Clostridium hiranonis; Clostridium hylemonae; Clostridium scindens; bile acid 7α-dehydroxylation; cholic acid; deoxycholic acid; human gut bacteria; oxo-bile acids

PMID:
29549099
PMCID:
PMC5930368
DOI:
10.1128/AEM.00235-18
[Indexed for MEDLINE]
Free PMC Article

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