한빛사 논문
Jae Won Leea,b, Elise S. Cowleyc,d, Patricia G. Wolfa,b,e,f*, Heidi L. Dodena,b, Tsuyoshi Muraig, Kelly Yovani Olivos Caicedoh, Lindsey K. Lya,i, Furong Sunj, Hajime Takeik, Hiroshi Nittonok, Steven L. Daniell, Isaac Canna,b,i,m, H. Rex Gaskinsa,b,i,n, Karthik Anantharamanc, João M. P. Alvesh, and Jason M. Ridlona,b,i,n,o,p
aCarl R. Woese Institute for Genomic Biology, University of Illinois Urbana-Champaign, Urbana, IL, USA; bDepartment of Animal Sciences, University of Illinois Urbana-Champaign, Urbana, IL, USA; cDepartment of Bacteriology, University of Wisconsin-Madison, Madison, WI, USA; dMicrobiology Doctoral Training Program, University of Wisconsin-Madison, Madison, WI, USA; eInstitute for Health Research and Policy, University of Illinois Chicago, Chicago, IL, USA; fUniversity of Illinois Cancer Center, University of Illinois Chicago, Chicago, IL, USA; gSchool of Pharmaceutical Sciences, Health Sciences University of Hokkaido, Hokkaido, Japan; hDepartment of Parasitology, Institute of Biomedical Sciences, University of São Paulo, São Paulo, Brazil; iDivision of Nutritional Sciences, University of Illinois Urbana-Champaign, Urbana, IL, USA; jMass Spectrometry Laboratory, School of Chemical Sciences, University of Illinois Urbana-Champaign, IL, USA; kJunshin Clinic Bile Acid Institute, Tokyo, Japan; lDepartment of Biological Sciences, Eastern Illinois University, Charleston, IL, USA; mDepartment of Microbiology, University of Illinois Urbana-Champaign, Urbana, IL, USA; nCancer Center at Illinois, Urbana, IL, USA; oCenter for Advanced Study, University of Illinois Urbana-Champaign, Urbana, IL, USA; pDepartment of Microbiology and Immunology, Virginia Commonwealth University, Richmond, VA, USA
Correspondence: Jason M. Ridlon
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.
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