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A metabolic pathway for bile acid dehydroxylation by the gut microbiome
Open accessPublished version of a preprint
Abstract
The gut microbiota synthesize hundreds of molecules, many of which influence host physiology. Among the most abundant metabolites are the secondary bile acids deoxycholic acid (DCA) and lithocholic acid (LCA), which accumulate at concentrations of around 500 μM and are known to block the growth of Clostridium difficile 1, promote hepatocellular carcinoma 2 and modulate host metabolism via the G-protein-coupled receptor TGR5 (ref. 3). More broadly, DCA, LCA and their derivatives are major components of the recirculating pool of bile acids 4; the size and composition of this pool are a target of therapies for primary biliary cholangitis and nonalcoholic steatohepatitis. Nonetheless, despite the clear impact of DCA and LCA on host physiology, an incomplete knowledge of their biosynthetic genes and a lack of genetic tools to enable modification of their native microbial producers limit our ability to modulate secondary bile acid levels in the host. Here we complete the pathway to DCA and LCA by assigning and characterizing enzymes for each of the steps in its reductive arm, revealing a strategy in which the A-B rings of the steroid core are transiently converted into an electron acceptor for two reductive steps carried out by Fe-S flavoenzymes. Using anaerobic in vitro reconstitution, we establish that a set of six enzymes is necessary and sufficient for the eight-step conversion of cholic acid to DCA. We then engineer the pathway into Clostridium sporogenes, conferring production of DCA and LCA on a nonproducing commensal and demonstrating that a microbiome-derived pathway can be expressed and controlled heterologously. These data establish a complete pathway to two central components of the bile acid pool.
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“Bacteria in the gastrointestinal tract produce amino acid bile acid amidates that can affect host-mediated metabolic processes1–6; however, the bacterial gene(s) responsible for their production remain unknown.”
From Bile Acids Are Substrates for Amine N-Acyl Transferase Activity by Bile Salt Hydrolase (2022) · cites this paper as [5]
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Cites
Commensal microbe-derived butyrate induces the differentiation of colonic regulatory T cells
Furusawa, Y., Obata, Y., Fukuda, S., Endo, T. A., Nakato, G., Takahashi, D., Nakanishi, Y., Uetake, C., Kato, K., Kato, T., et al. (2013) · Nature · doi:10.1038/nature12721 · Cited by 5,549
The Microbial Metabolites, Short-Chain Fatty Acids, Regulate Colonic T reg Cell Homeostasis
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Host-gut microbiota metabolic interactions
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Regulation of inflammatory responses by gut microbiota and chemoattractant receptor GPR43
Maslowski, K. M., Vieira, A. T., Ng, A., Kranich, J., Sierro, F., Yu, D., Schilter, H. C., Rolph, M. S., Mackay, F., Artis, D., et al. (2009) · Nature · doi:10.1038/nature08530 · Cited by 3,241
Intestinal Crosstalk between Bile Acids and Microbiota and Its Impact on Host Metabolism
Wahlstrom, A. M., Sayin, S. I., Marschall, H., & Bäckhed, F. (2016) · Cell Metabolism · doi:10.1016/j.cmet.2016.05.005 · Cited by 2,969
Bile salt biotransformations by human intestinal bacteria
Ridlon, J. M., Kang, D.-J., & Hylemon, P. B. (2006) · Journal of Lipid Research · doi:10.1194/jlr.r500013-jlr200 · Cited by 2,829
Obesity-induced gut microbial metabolite promotes liver cancer through senescence secretome
Yoshimoto, S., Loo, T. M., Atarashi, K., Kanda, H., Sato, S., Oyadomari, S., Iwakura, Y., Oshima, K., Morita, H., Hattori, M., et al. (2013) · Nature · doi:10.1038/nature12347 · Cited by 2,219
Precision microbiome reconstitution restores bile acid mediated resistance to Clostridium difficile
Buffie, C. G., Bucci, V., Stein, R. R., McKenney, P. T., Ling, L., Gobourne, A., No, D., Liu, H., Kinnebrew, M., Viale, A., et al. (2015) · Nature · doi:10.1038/nature13828 · Cited by 1,872
Bouatra, S., Aziat, F., Mandal, R., Guo, A. C., Wilson, M. R., Knox, C., Bjorndahl, T. C., Krishnamurthy, R., Saleem, F., Liu, P., et al. (2013) · PLoS ONE · doi:10.1371/journal.pone.0073076 · Cited by 1,457
Bile acid metabolites control TH17 and Treg cell differentiation
Hang, S., Paik, D., Yao, L., Kim, E., Trinath, J., Lu, J., Ha, S., Nelson, B. N., Kelly, S. P., Wu, L., et al. (2019) · Nature · doi:10.1038/s41586-019-1785-z · Cited by 1,457
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Gut microbial metabolites as multi-kingdom intermediates
Krautkramer, K. A., Fan, J., & Bäckhed, F. (2021) · Nature Reviews Microbiology · doi:10.1038/s41579-020-0438-4 · Cited by 1,398
Bile acids and the gut microbiota: metabolic interactions and impacts on disease
Collins, S. L., Stine, J. G., Bisanz, J. E., Okafor, C. D., & Patterson, A. D. (2023) · Nature Reviews Microbiology · doi:10.1038/s41579-022-00805-x · Cited by 1,214
Gut microbiota-derived bile acids in intestinal immunity, inflammation, and tumorigenesis
Cai, J., Sun, L., & Gonzalez, F. J. (2022) · Cell Host & Microbe · doi:10.1016/j.chom.2022.02.004 · Cited by 881
Gut-liver axis: Pathophysiological concepts and clinical implications
Tilg, H., Adolph, T. E., & Trauner, M. (2022) · Cell Metabolism · doi:10.1016/j.cmet.2022.09.017 · Cited by 843
Review: microbial transformations of human bile acids
Guzior, D. V., & Quinn, R. A. (2021) · Microbiome · doi:10.1186/s40168-021-01101-1 · Cited by 788
Metadata
- Authors
- Funabashi, M., Grove, T. L., Wang, M., Varma, Y., McFadden, M. E., Brown, L. C., Guo, C., Higginbottom, S., Almo, S. C., & Fischbach, M. A.
- Affiliations
- Daiichi Sankyo RD Novare (Japan) (JP)
- Albert Einstein College of Medicine (US)
- Stanford University (US)
- Indiana University Bloomington (US)
- Stanford Medicine (US)
- Chan Zuckerberg Biohub San Francisco (US)
- Corresponding author
- Almo, Steven C.
- Fischbach, Michael A.
- ORCID
- Venue
- Nature
- Published
- 2020-06-17
- Volume
- 582
- Issue
- 7813
- Pages
- 566-570
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- PMC
- PMC7319900
- OpenAlex
- W3036012425
- Cited by
- 590
- References
- 46
- Citations by year
- 2026: 125 · 2025: 108 · 2024: 123 · 2023: 89 · 2022: 78 · 2021: 53 · 2020: 13
- FWCI
- 18.90
- Type
- journal article
- Language
- en
- Open access
- green
- doi.org
- Locations
- Nature (publishedVersion)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- Funders
- Howard Hughes Medical Institute
- Price Family Foundation
- National Institutes of Health (1dp2hd101401-01, GM093342, DK113598, DK110174, GM094662)
- National Heart, Lung, and Blood Institute (P01HL147823)
- National Institute of General Medical Sciences (U54GM093342, U54GM094662, P01GM118303)
- National Institute of Diabetes and Digestive and Kidney Diseases (R01DK110174, DP1DK113598, R01DK101674)
- Eunice Kennedy Shriver National Institute of Child Health and Human Development (DP2 HD101401)
- Topics
- Physical Sciences › Chemistry › Organic Chemistry › Steroid Chemistry and Biochemistry
- Life Sciences › Immunology and Microbiology › Applied Microbiology and Biotechnology › Microbial Natural Products and Biosynthesis
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Microbial Metabolic Engineering and Bioproduction
- Keywords
- secondary bile acids, deoxycholic acid, lithocholic acid, gut microbiota, reductive dehydroxylation, cholic acid, Clostridium sporogenes, heterologous pathway expression, germ-free mice, primary biliary cirrhosis, nonalcoholic steatohepatitis, TGR5
- MeSH terms
- Gastrointestinal Microbiome, Animals, Bile Acids and Salts, Clostridium, Deoxycholic Acid, Hydroxylation, Lithocholic Acid, Male, Operon, Symbiosis, Mice, Metabolic Networks and Pathways, Metabolic Engineering
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