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Global chemical effects of the microbiome include new bile-acid conjugations
Open accessAbstract
A mosaic of cross-phylum chemical interactions occurs between all metazoans and their microbiomes. A number of molecular families that are known to be produced by the microbiome have a marked effect on the balance between health and disease 1-9. Considering the diversity of the human microbiome (which numbers over 40,000 operational taxonomic units 10), the effect of the microbiome on the chemistry of an entire animal remains underexplored. Here we use mass spectrometry informatics and data visualization approaches 11-13 to provide an assessment of the effects of the microbiome on the chemistry of an entire mammal by comparing metabolomics data from germ-free and specific-pathogen-free mice. We found that the microbiota affects the chemistry of all organs. This included the amino acid conjugations of host bile acids that were used to produce phenylalanocholic acid, tyrosocholic acid and leucocholic acid, which have not previously been characterized despite extensive research on bile-acid chemistry 14. These bile-acid conjugates were also found in humans, and were enriched in patients with inflammatory bowel disease or cystic fibrosis. These compounds agonized the farnesoid X receptor in vitro, and mice gavaged with the compounds showed reduced expression of bile-acid synthesis genes in vivo. Further studies are required to confirm whether these compounds have a physiological role in the host, and whether they contribute to gut diseases that are associated with microbiome dysbiosis.
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“Some BBAAs activate host bile acid nuclear receptors like the farnesoid X receptor (FXR) and pregnane X receptor (PXR)1,3, but an assessment of other receptors has not been completed.”
From Bile Acids Are Substrates for Amine N-Acyl Transferase Activity by Bile Salt Hydrolase (2022) · cites this paper as [1]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“Recent studies demonstrated that bacteria, in addition to the host, have bile acid amine N-acyltransferase activity, with dozens of bacterially conjugated amino acid amidates identified1–4,6,17.”
From Bile Acids Are Substrates for Amine N-Acyl Transferase Activity by Bile Salt Hydrolase (2022) · cites this paper as [1]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“The extensive compilation of recently identified MCBAs expands the complexity of the BSH-BA pool and reinforces BSHs as the gatekeepers of bile acid metabolism, capable of reshaping the BA landscape in the gut31,32.”
From Bile salt hydrolases shape the bile acid landscape and restrict Clostridioides difficile growth in the murine gut (2023) · cites this paper as [31]
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In the citing paper
“An array of intestinal bacteria can catalyse the conjugation of BAs to a variety of amino acids through an unknown mechanism”
From Bile salt hydrolases shape the bile acid landscape and restrict Clostridioides difficile growth in the murine gut (2023) · cites this paper as [31]
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In the citing paper
“Furthermore, BSH activity is complicated by the emerging data indicating that these enzymes can catalyse reconjugation to generate MCBAs capable of activating host ligand-activated receptors31,33,46,47.”
From Bile salt hydrolases shape the bile acid landscape and restrict Clostridioides difficile growth in the murine gut (2023) · cites this paper as [31]
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“All MCBAs were purified according to literature precedent and characterization data are consistent with reported data31,33,42,77,78.”
From Bile salt hydrolases shape the bile acid landscape and restrict Clostridioides difficile growth in the murine gut (2023) · cites this paper as [31]
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“Glu-CDCA, Ile-CA, Leu-CA, Phe-CA, Trp-CDCA and Tyr-CA were purified according to literature precedent and characterization data are consistent with reported data31,33.”
From Bile salt hydrolases shape the bile acid landscape and restrict Clostridioides difficile growth in the murine gut (2023) · cites this paper as [31]
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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 [1]
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“The enzymes responsible for these conjugation reactions are unknown.”
From Bile Acids Are Substrates for Amine N-Acyl Transferase Activity by Bile Salt Hydrolase (2022) · cites this paper as [1]
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Metadata
- Authors
- Quinn, R. A., Melnik, A. V., Vrbanac, A., Fu, T., Patras, K. A., Christy, M. P., Bodai, Z., Belda-Ferre, P., Tripathi, A., Chung, L. K., Downes, M., Welch, R. D., Quinn, M., Humphrey, G., Panitchpakdi, M., Weldon, K. C., Aksenov, A., da Silva, R., Avila-Pacheco, J., Clish, C., Bae, S., Mallick, H., Franzosa, E. A., Lloyd-Price, J., Bussell, R., Thron, T., Nelson, A. T., Wang, M., Leszczynski, E., Vargas, F., Gauglitz, J. M., Meehan, M. J., Gentry, E., Arthur, T. D., Komor, A. C., Poulsen, O., Boland, B. S., Chang, J. T., Sandborn, W. J., Lim, M., Garg, N., Lumeng, J. C., Xavier, R. J., Kazmierczak, B. I., Jain, R., Egan, M., Rhee, K. E., Ferguson, D., Raffatellu, M., Vlamakis, H., Haddad, G. G., Siegel, D., Huttenhower, C., Mazmanian, S. K., Evans, R. M., Nizet, V., Knight, R., & Dorrestein, P. C.
- Affiliations
- University of California San Diego (US)
- Salk Institute for Biological Studies (US)
- Michigan State University (US)
- Broad Institute (US)
- Harvard University (US)
- California Institute of Technology (US)
- Georgia Institute of Technology (US)
- University of Michigan (US)
- Yale University (US)
- Corresponding author
- Dorrestein, Pieter C.
- ORCID
- Quinn, Robert A.
- Melnik, Alexey V.
- Vrbanac, Alison
- Patras, Kathryn A.
- Christy, Mitchell P.
- Bodai, Zsolt
- Tripathi, Anupriya
- Downes, Michael
- Quinn, Melissa
- Panitchpakdi, Morgan
- Weldon, Kelly C.
- Aksenov, Alexander
- Clish, Clary
- Mallick, Himel
- Franzosa, Eric A.
- Thron, Taren
- Nelson, Andrew T.
- Wang, Mingxun
- Leszczynski, Eric
- Vargas, Fernando
- Gauglitz, Julia M.
- Meehan, Michael J.
- Gentry, Emily
- Arthur, Timothy D.
- Komor, Alexis C.
- Boland, Brigid S.
- Chang, John T.
- Sandborn, William J.
- Garg, Neha
- Lumeng, Julie C.
- Xavier, Ramnik J.
- Kazmierczak, Barbara I.
- Jain, Ruchi
- Egan, Marie
- Rhee, Kyung E.
- Ferguson, David
- Raffatellu, Manuela
- Vlamakis, Hera
- Haddad, Gabriel G.
- Siegel, Dionicio
- Huttenhower, Curtis
- Mazmanian, Sarkis K.
- Evans, Ronald M.
- Nizet, Victor
- Knight, Rob
- Dorrestein, Pieter C.
- Venue
- Nature
- Published
- 2020-02-26
- Volume
- 579
- Issue
- 7797
- Pages
- 123-129
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- PMC
- PMC7252668
- OpenAlex
- W3007415664
- Cited by
- 579
- References
- 43
- Citations by year
- 2026: 79 · 2025: 99 · 2024: 124 · 2023: 73 · 2022: 99 · 2021: 64 · 2020: 40
- FWCI
- 22.39
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Digital Access to Scholarship at Harvard (DASH) (Harvard University) (acceptedVersion)
- CaltechAUTHORS (California Institute of Technology) (submittedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- Funders
- Howard Hughes Medical Institute
- Crohn's and Colitis Foundation (675191, 815985)
- National Institutes of Health (1s10rr029121-01, 1r03ca211211-01, KL2TR001444, UL1TR001863)
- National Heart, Lung, and Blood Institute (R01HL105278, R01HL116235, P01HL088093)
- National Cancer Institute (CA014195, R03 CA211211, P30CA014195)
- National Institute of General Medical Sciences (R01GM107550)
- National Institute of Allergy and Infectious Diseases (R01AI126277, U01AI124316)
- National Institute of Diabetes and Digestive and Kidney Diseases (R37DK057978, T32DK007494, R01DK057978, R24DK110499, P30DK120515, P30DK043351, P30DK040561)
- National Institute of Environmental Health Sciences (P42ES010337)
- National Institute of Dental and Craniofacial Research (U54DE023798)
- U.S. National Library of Medicine (T15LM011271)
- National Center for Research Resources (S10-RR029121)
- National Center for Advancing Translational Sciences
- National Center for Complementary and Integrative Health (DP1AT010885)
- Eunice Kennedy Shriver National Institute of Child Health and Human Development (R01HD084163)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Gut microbiota and health
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolomics and Mass Spectrometry Studies
- Health Sciences › Medicine › Oncology › Drug Transport and Resistance Mechanisms
- Keywords
- gut microbiota, bile acid conjugation, farnesoid X receptor, germ-free mice, inflammatory bowel disease, cystic fibrosis, bile acid synthesis, dysbiosis, host metabolome
- MeSH terms
- Receptor, Farnesoid X-Activated, Animals, Bile Acids and Salts, Cystic Fibrosis, Germ-Free Life, Humans, Inflammatory Bowel Diseases, Receptors, Cytoplasmic and Nuclear, Cholic Acid, Mice, Metabolomics, Microbiota
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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