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Global chemical effects of the microbiome include new bile-acid conjugations

Quinn, Robert A. and Melnik, Alexey V. and Vrbanac, Alison and Fu, Ting and Patras, Kathryn A. and Christy, Mitchell P. and Bodai, Zsolt and Belda-Ferre, Pedro and Tripathi, Anupriya and Chung, Lawton K. and Downes, Michael and Welch, Ryan D. and Quinn, Melissa and Humphrey, Greg and Panitchpakdi, Morgan and Weldon, Kelly C. and Aksenov, Alexander and da Silva, Ricardo and Avila-Pacheco, Julian and Clish, Clary and Bae, Sena and Mallick, Himel and Franzosa, Eric A. and Lloyd-Price, Jason and Bussell, Robert and Thron, Taren and Nelson, Andrew T. and Wang, Mingxun and Leszczynski, Eric and Vargas, Fernando and Gauglitz, Julia M. and Meehan, Michael J. and Gentry, Emily and Arthur, Timothy D. and Komor, Alexis C. and Poulsen, Orit and Boland, Brigid S. and Chang, John T. and Sandborn, William J. and Lim, Meerana and Garg, Neha and Lumeng, Julie C. and Xavier, Ramnik J. and Kazmierczak, Barbara I. and Jain, Ruchi and Egan, Marie and Rhee, Kyung E. and Ferguson, David and Raffatellu, Manuela and Vlamakis, Hera and Haddad, Gabriel G. and Siegel, Dionicio and Huttenhower, Curtis and Mazmanian, Sarkis K. and Evans, Ronald M. and Nizet, Victor and Knight, Rob and Dorrestein, Pieter C. (2020) Global chemical effects of the microbiome include new bile-acid conjugations. Nature, 579 (7797). pp. 123-129. ISSN 0028-0836. doi:10.1038/s41586-020-2047-9.

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[img] Image (JPEG) (Extended Data Fig. 1: Microbiome and metabolome diversity in germ-free and SPF mice) - Supplemental Material
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[img] Image (JPEG) (Extended Data Fig. 2: Microbial metabolism of soyasaponins in metabolomics data from germ-free and SPF mice) - Supplemental Material
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[img] Image (JPEG) (Extended Data Fig. 3: Microbial metabolism of plant isoflavones in metabolomics data from germ-free and SPF mice) - Supplemental Material
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[img] Image (JPEG) (Extended Data Fig. 4: Microbial metabolism of known bile acids in metabolomics data from germ-free and SPF mice) - Supplemental Material
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[img] Image (JPEG) (Extended Data Fig. 7: MASST search results and associations of newly identified conjugated bile acids with high-fat diet) - Supplemental Material
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[img] Image (JPEG) (Extended Data Fig. 8: Synthesis of newly identified conjugated bile acids by Clostridium) - Supplemental Material
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[img] Image (JPEG) (Extended Data Fig. 9: Effect of newly identified bile acids on FXR) - Supplemental Material
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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. Considering the diversity of the human microbiome (which numbers over 40,000 operational taxonomic units), the effect of the microbiome on the chemistry of an entire animal remains underexplored. Here we use mass spectrometry informatics and data visualization approaches 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. 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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Mazmanian, Sarkis K.0000-0003-2713-1513
Additional Information:© 2020 Springer Nature Limited. Received 06 July 2018; Accepted 03 January 2020; Published 26 February 2020. The authors acknowledge funding from the National Institutes of Health (NIH), grants 5U01AI124316-03, 1R03CA211211-01, 1R01HL116235 U54DE023798, R24DK110499, GMS10RR029121, 1 DP1 AT010885, P30 DK120515 and R01HD084163. Additionally, B.S.B. was supported by UCSD KL2 (1KL2TR001444), T.D.A. by the National Library of Medicine Training Grant NIH grant T15LM011271. R.M.E. is an investigator of the Howard Hughes Medical Institute and March of Dimes Chair in Molecular and Developmental Biology at the Salk Institute. R.M.E. was funded by grants from the NIH (DK057978, HL105278, HL088093 and ES010337), and Samuel Waxman Cancer Research Foundation. We acknowledge G. Ackermann for her contributions. This work was also supported in part by Seed Grants from the UC San Diego Center for Microbiome Innovation. This work was funded by grants from the NIH (DK057978, HL105278 and HL088093), National Cancer Institute (CA014195), the Leona M. and Harry B. Helmsley Charitable Trust (2017PG-MED001), SWCRF Investigator Award and Ipsen/Biomeasure. J.L. is supported by grant EIA14660045, an American Heart Association Established Investigator Award. T.F. is supported by a Hewitt Medical Foundation Fellowship, a Salk Alumni Fellowship. T.F., R.K. and P.C.D. acknowledge support from the Crohn’s & Colitis Foundation (CCFA). R.M.E. and M.D. are supported in part by a Stand Up to Cancer (SU2C) - Cancer Research UK-Lustgarten Foundation Pancreatic Cancer Dream Team Research Grant (SU2C-AACR-DT-20-16). SU2C is a programme of the Entertainment Industry Foundation. Research grants are administered by the American Association for Cancer Research, the scientific partner of SU2C. Research reported in this publication was also supported by the National Institute of Environmental Health Sciences of the NIH under Award Number P42ES010337. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH. Data availability: All metabolomics data that support the findings of this study are available at GNPS ( under MassIVE ID numbers: MSV000079949 (original germ-free and SPF mouse data), MSV000082480, MSV000082467, MSV000079134, MSV000082406, MSV000083032, MSV000083004 and MSV000083446. The sequencing data for the germ-free and SPF mouse study are available on the Qiita microbiome data analysis platform at under study ID 10801 and through the European Bioinformatics Institute accession number ERP109688. Source Data for Figs. 1–3, Extended Data Fig. 7 are provided with the paper. Code availability: MASST can be accessed at; the development of MASST is described in ref. 43. The code for MS/MS-based MASST searching is available at Author Contributions: P.C.D., R.K. and R.A.Q. designed the project. P.C.D. and R.A.Q. discovered the bile acids. R.A.Q., A.A., A.V.M., F.V., J.M.G., N.G., A.T., M.P.C., L.K.C., A.T.N., M.J.M., G.H., M.P., C.C., S.B., E.G., K.C.W., P.B.-F., H.M., E.A.F., H.V., J.L.-P., T.D.A., A.C.K., J.A.-P., Z.B., E.L., M.Q., T.F., R.D.W., D.F., G.G.H. and R.B. generated data. R.A.Q., A.V., A.T., Z.B., A.V.M., R.d.S., R.J.X., T.F., R.D.W., M.D., R.M.E. and M.P.C. analysed data. R.A.Q., B.S.B., M.L., O.P., J.T.C., M.L., J.C.L., K.A.P., B.I.K., R.J., M.E., K.E.R., G.H., C.C., W.J.S. and R.B. collected samples. D.S., E.G., M.P.C. and A.T.N. were responsible for chemical synthesis. T.F., R.D.W., M.D. and R.M.E. were responsible for the FXR in vitro and in vivo functional studies and analysis, and edited the paper. P.C.D., R.K., S.K.M., V.N., C.H., R.J.X., A.C.K. and D.S. guided experimental design and analysis. M.W. converted the data in GNPS and developed MASST spectral search. T.T., V.N., M.R. and S.K.M. raised mice and guided experimental design. R.A.Q. and P.C.D. wrote the manuscript. Competing interests: C.H. is on the scientific advisory board of Seres Therapeutics. M.W. is founder of, and A.A. is a consultant for, Ometa Laboratories LLC. P.C.D. and M.W. are consultants for Sirenas Therapeutics. W.J.S. consults for Abbvie, Allergan, Amgen, Arena Pharmaceuticals, Avexegen Therapeutics, BeiGene, Boehringer Ingelheim, Celgene, Celltrion, Conatus, Cosmo, Escalier Biosciences, Ferring, Forbion, Genentech, Gilead Sciences, Gossamer Bio, Incyte, Janssen, Kyowa Kirin Pharmaceutical Research, Landos Biopharma, Lilly, Oppilan Pharma, Otsuka, Pfizer, Progenity, Prometheus Biosciences (merger of Precision IBD and Prometheus Laboratories), Reistone, Ritter Pharmaceuticals, Robarts Clinical Trials (owned by Health Academic Research Trust, HART), Series Therapeutics, Shire, Sienna Biopharmaceuticals, Sigmoid Biotechnologies, Sterna Biologicals, Sublimity Therapeutics, Takeda, Theravance Biopharma, Tigenix, Tillotts Pharma, UCB Pharma, Ventyx Biosciences, Vimalan Biosciences and Vivelix Pharmaceuticals; and holds stock or stock options from BeiGene, Escalier Biosciences, Gossamer Bio, Oppilan Pharma, Prometheus Biosciences (merger of Precision IBD and Prometheus Laboratories), Progenity, Ritter Pharmaceuticals, Ventyx Biosciences and Vimalan Biosciences.
Funding AgencyGrant Number
NIH1 DP1 AT010885
NIHP30 DK120515
University of California, San Diego1KL2TR001444
NIH Predoctoral FellowshipT15LM011271
Howard Hughes Medical Institute (HHMI)UNSPECIFIED
March of Dimes FoundationUNSPECIFIED
Samuel Waxman Cancer Research FoundationUNSPECIFIED
Leona M. and Harry B. Helmsley Charitable Trust2017PG-MED001
American Heart AssociationEIA14660045
Hewitt Medical Foundation FellowshipUNSPECIFIED
Crohn’s and Colitis Foundation of AmericaUNSPECIFIED
Cancer Research UK-Lustgarten FoundationSU2C-AACR-DT-20-16
Entertainment Industry FoundationUNSPECIFIED
American Association for Cancer ResearchUNSPECIFIED
Subject Keywords:Metabolomics; Microbiome
Issue or Number:7797
Record Number:CaltechAUTHORS:20200303-123932684
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Official Citation:Quinn, R.A., Melnik, A.V., Vrbanac, A. et al. Global chemical effects of the microbiome include new bile-acid conjugations. Nature 579, 123–129 (2020).
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:101682
Deposited By: Tony Diaz
Deposited On:03 Mar 2020 21:16
Last Modified:16 Nov 2021 18:04

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