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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.

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Microbiome Metabolic Engineering Theme, Carl R. Woese Institute for Genomic Biology, Urbana, Illinois, USA.
Department of Animal Sciences, University of Illinois at Urbana-Champaign, Urbana, Illinois, USA.
Department of Biological Sciences, Eastern Illinois University, Charleston, Illinois, USA.
Division of Nutritional Sciences, University of Illinois at Urbana-Champaign, Urbana, Illinois, USA.
Department of Parasitology, Institute of Biomedical Sciences, University of São Paulo, São Paulo, Brazil.
Microbiome Metabolic Engineering Theme, Carl R. Woese Institute for Genomic Biology, Urbana, Illinois, USA
Cancer Center of Illinois, University of Illinois at Urbana-Champaign, Urbana, Illinois, USA.
Department of Microbiology and Immunology, School of Medicine, Virginia Commonwealth University, Richmond, Virginia, USA.
Contributed equally


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.


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

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