2. Academic Validation
  3. Formation of secondary allo-bile acids by novel enzymes from gut Firmicutes

Formation of secondary allo-bile acids by novel enzymes from gut Firmicutes

  • Gut Microbes. 2022 Jan-Dec;14(1):2132903. doi: 10.1080/19490976.2022.2132903.
Jae Won Lee 1 2,  Elise S Cowley 3 4,  Patricia G Wolf 1 2 5 6,  Heidi L Doden 1 2,  Tsuyoshi Murai 7,  Kelly Yovani Olivos Caicedo 8,  Lindsey K Ly 1 9,  Furong Sun 10,  Hajime Takei 11,  Hiroshi Nittono 11,  Steven L Daniel 12,  Isaac Cann 1 2 9 13,  H Rex Gaskins 1 2 9 14,  Karthik Anantharaman 3,  João M P Alves 8,  Jason M Ridlon 1 2 9 14 15 16
Affiliations

Affiliations

  • 1 Carl R. Woese Institute for Genomic Biology, University of Illinois Urbana-Champaign, Urbana, IL, USA.
  • 2 Department of Animal Sciences, University of Illinois Urbana-Champaign, Urbana, IL, USA.
  • 3 Department of Bacteriology, University of Wisconsin-Madison, Madison, WI, USA.
  • 4 Microbiology Doctoral Training Program, University of Wisconsin-Madison, Madison, WI, USA.
  • 5 Institute for Health Research and Policy, University of Illinois Chicago, Chicago, IL, USA.
  • 6 University of Illinois Cancer Center, University of Illinois Chicago, Chicago, IL, USA.
  • 7 School of Pharmaceutical Sciences, Health Sciences University of Hokkaido, Hokkaido, Japan.
  • 8 Department of Parasitology, Institute of Biomedical Sciences, University of São Paulo, São Paulo, Brazil.
  • 9 Division of Nutritional Sciences, University of Illinois Urbana-Champaign, Urbana, IL, USA.
  • 10 Mass Spectrometry Laboratory, School of Chemical Sciences, University of Illinois Urbana-Champaign, IL, USA.
  • 11 Junshin Clinic Bile Acid Institute, Tokyo, Japan.
  • 12 Department of Biological Sciences, Eastern Illinois University, Charleston, IL, USA.
  • 13 Department of Microbiology, University of Illinois Urbana-Champaign, Urbana, IL, USA.
  • 14 Cancer Center at Illinois, Urbana, IL, USA.
  • 15 Center for Advanced Study, University of Illinois Urbana-Champaign, Urbana, IL, USA.
  • 16 Department of Microbiology and Immunology, Virginia Commonwealth University, Richmond, VA, USA.
PMID: 36343662 DOI: 10.1080/19490976.2022.2132903
Abstract

The gut microbiome of vertebrates is capable of numerous biotransformations of bile acids, which are responsible for intestinal lipid digestion and function as key nutrient-signaling molecules. The human liver produces bile acids from Cholesterol predominantly in the A/B-cis orientation in which the sterol rings are "kinked", as well as small quantities of A/B-trans oriented "flat" stereoisomers known as "primary allo-bile acids". While the complex multi-step bile acid 7α-dehydroxylation pathway has been well-studied for conversion of "kinked" primary bile acids such as cholic acid (CA) and chenodeoxycholic acid (CDCA) to deoxycholic acid (DCA) and lithocholic acid (LCA), respectively, the enzymatic basis for the formation of "flat" stereoisomers allo-deoxycholic acid (allo-DCA) and allo-lithocholic acid (allo-LCA) by Firmicutes has remained unsolved for three decades. Here, we present a novel mechanism by which Firmicutes generate the "flat" bile acids allo-DCA and allo-LCA. The BaiA1 was shown to catalyze the final reduction from 3-oxo-allo-DCA to allo-DCA and 3-oxo-allo-LCA to allo-LCA. Phylogenetic and metagenomic analyses of human stool samples indicate that BaiP and BaiJ are encoded only in Firmicutes and differ from membrane-associated bile acid 5α-reductases recently reported in Bacteroidetes that indirectly generate allo-LCA from 3-oxo-Δ4-LCA. We further map the distribution of baiP and baiJ among Firmicutes in human metagenomes, demonstrating an increased abundance of the two genes in colorectal Cancer (CRC) patients relative to healthy individuals.

Keywords

Firmicutes; Secondary allo-bile acids; bile acid 5α-reductases; bile acid dehydroxylation; colorectal cancer.

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