A Synthesis-Based Reverse Metabolomics Approach for the Discovery of Chemical Structures from Humans and Animals.
Open accessPreprint — published as 10.1038/s41586-023-06906-8 · Paper page
Abstract
Identification of metabolites in humans remains challenging. Here, we present synthesis-based reverse metabolomics as a strategy for structure elucidation that aims to also find phenotypic associations. In this approach, MS/MS spectra are acquired from newly synthesized compounds, and searched against public metabolomics data to uncover their phenotypic associations. To demonstrate the concept, we used combinatorial amide coupling reactions to synthesize an array of amino acid conjugated bile acids. A total of 16,587 spectral matches were found for 145 amidates synthesized, representing the single largest expansion of structures in the 170+ year history of bile acids. Furthermore, some new bile acids were associated with health-related phenotypes such as inflammatory bowel diseases and obesity. Using independent human cohorts for validation revealed that some cholic and chenodeoxycholic acid conjugates were elevated in Crohn’s disease, of which some were also potent PXR agonists. Bacteria belonging to bifidobacterium, clostridium, and enterococci genera were the main producers of these new conjugated bile acids. Because searching repositories with MS/MS spectra has only recently become possible, this synthesis-based reverse metabolomics approach can now be employed as a general strategy to elucidate structures and discover other new molecules from human and animal ecosystems.
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Recent studies demonstrated that bacteria have bile acid amine N-acyltransferase activity, with dozens of bacterially conjugated amino acid amidates identified.
“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 [3]
The ‘Microbial production of bile amides’ section (page not provided) reports that bacterial cultures produced cholic- and deoxycholic-acid amidates for 15 amino acids, supporting bacterial production of dozens of amino-acid bile amidates. It does not identify or measure bacterial bile acid amine N-acyltransferase activity specifically; it establishes conjugation from the products detected in culture. (LLM, conf=0.83)
Experimental — accuracy not yet measuredSome BBAAs activate host bile acid nuclear receptors like FXR and PXR.
“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 [3]
The 'Validation of the IBD association' section reports that several conjugated bile acids act as PXR agonists and that two increased PXR activation in intestinal organoids. Our copy does not report that BBAAs activate FXR; FXR appears only in the title of a cited reference, not as a finding of this paper. (LLM, conf=0.88)
Experimental — accuracy not yet measuredBSH enzymes can catalyse reconjugation to generate MCBAs capable of activating host ligand-activated receptors.
“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 [33]
The ‘Microbial production of bile amides’ section reports that bacteria produce amino-acid-conjugated bile acids, and ‘Validation of the IBD association’ reports that several conjugates activate the host receptor PXR (page numbers unavailable). The paper does not identify BSH enzymes as catalysing that conjugation, so the enzyme-specific part of the claim is unsupported. (LLM, conf=0.87)
Experimental — accuracy not yet measuredCharacterization data for Glu-CDCA, Ile-CA, Leu-CA, Phe-CA, Trp-CDCA and Tyr-CA are consistent with reported data.
“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 [33]
The Methods section (‘Synthesis of the top 15 most abundant bile acids in the iHMP2 IBD cohort’; page unavailable) says the synthesis was adapted from a previously described method and describes purification over silica gel. The copy discusses synthesized standards for the named bile-acid conjugates, but does not state that their characterization data agree with previously reported data. (LLM, conf=0.78)
Experimental — accuracy not yet measuredBBAAs are abundant in the gastrointestinal tract and have been associated with human inflammatory bowel disease.
“Furthermore, bacterial bile acid amidates (BBAAs) are abundant in the gastrointestinal tract18 and have been associated with human inflammatory bowel disease3.”
From Bile Acids Are Substrates for Amine N-Acyl Transferase Activity by Bile Salt Hydrolase (2022) · cites this paper as [3]
Bacteria in the gastrointestinal tract produce amino acid bile acid amidates that can affect host-mediated metabolic processes.
“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 [3]
The bacterial enzymes responsible for producing amino acid bile acid amidates are unknown.
“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 [3]
The “Microbial production of bile amides” section (page unavailable) identifies bacteria that produce amino-acid-conjugated bile acids, but does not say whether the enzymes responsible are known. Searches for “enzymes,” “unknown enzymatic mechanism,” and genes encoding conjugation enzymes found no passage addressing enzyme identity. (LLM, conf=0.72)
Experimental — accuracy not yet measuredBSHs may be instrumental in fine tuning different pathways that promote health or disease.
“As there are hundreds of different BSHs found in microbiota that synthesize different BBAAs3, BSHs may be instrumental in fine tuning different pathways that promote health or disease.”
From Bile Acids Are Substrates for Amine N-Acyl Transferase Activity by Bile Salt Hydrolase (2022) · cites this paper as [3]
The Microbial production of bile amides section reports that bacteria produce some conjugated bile acids, and Validation of the IBD association reports immune activity for several conjugates. But the copy does not say that BSHs synthesize different BBAAs or fine-tune health- or disease-related pathways; searches for “BSH” and “bile salt hydrolase” found only a reference-list entry. (LLM, conf=0.73)
Experimental — accuracy not yet measuredCharacterization data for all MCBAs are consistent with reported data.
“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 [33]
The Methods section on synthesis of the top 15 bile acids describes purification and says the synthesis was adapted from a previously described method, but it does not compare characterization data with reported data. Searches for MCBA characterization and agreement with reported data found no passage establishing the claim for all MCBAs; page numbers were unavailable in our copy. (LLM, conf=0.76)
Experimental — accuracy not yet measured
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Patterson, A., Rimal, B., Collins, S., Granda, M., Koo, I., Solanka, S., Hoque, N., Gentry, E., Yan, T., Bisanz, J., et al. (2022) · doi:10.21203/rs.3.rs-2050120/v1 · Cited by 245 · see citing works
Self-citationMicrobiota in inflammatory bowel disease: mechanisms of disease and therapeutic opportunities
Iliev, I. D., Ananthakrishnan, A. N., & Guo, C.-J. (2025) · Nature Reviews Microbiology · doi:10.1038/s41579-025-01163-0 · Cited by 249 · see citing works
Self-citationFoley, M. H., Walker, M. E., Stewart, A. K., O’Flaherty, S., Gentry, E. C., Patel, S., Beaty, V. V., Allen, G., Pan, M., Simpson, J. B., et al. (2023) · Nature Microbiology · doi:10.1038/s41564-023-01337-7 · Cited by 181 · see citing works
Self-citationBile salt hydrolase/aminoacyltransferase shapes the microbiome
Guzior, D., Okros, M., Hernandez, C. M., Shivel, M., Armwald, B., Hausinger, R., & Quinn, R. (2022) · doi:10.21203/rs.3.rs-2050406/v1 · Cited by 187 · see citing works
The Gut Microbial Bile Acid Modulation and Its Relevance to Digestive Health and Diseases
Fogelson, K. A., Dorrestein, P. C., Zarrinpar, A., & Knight, R. (2023) · Gastroenterology · doi:10.1053/j.gastro.2023.02.022 · Cited by 177 · see citing works
Self-citationHow bile acids and the microbiota interact to shape host immunity
Lee, M. H., Nuccio, S.-P., Mohanty, I., Hagey, L. R., Dorrestein, P. C., Chu, H., & Raffatellu, M. (2024) · Nature Reviews Immunology · doi:10.1038/s41577-024-01057-x · Cited by 143 · see citing works
Self-citation
- Authors
- Dorrestein, P., Gentry, E., Collins, S., Panitchpakdi, M., Belda-Ferre, P., Stewart, A., Wang, M., Jarmusch, A., Avila-Pacheco, J., Plichta, D., Aron, A., Vlamakis, H., Ananthakrishnan, A., Clish, C., Xavier, R., Baker, E., Patterson, A., Knight, R., & Siegel, D.
- Affiliations
- University of California San Diego (US)
- Pennsylvania State University (US)
- University of California San Diego
- North Carolina State University (US)
- National Institutes of Health (US)
- Broad Institute of Massachusetts Institute of Technology and Harvard
- Broad Institute (US)
- Massachusetts General Hospital (US)
- University of North Carolina at Chapel Hill (US)
- University of California, San Diego
- Corresponding author
- Dorrestein, Pieter
- ORCID
- Venue
- Nature
- Published
- 2021-08-30
- Volume
- 626
- Issue
- 7998
- Pages
- 419-426
- ISSN
- 0028-0836 (ISSN-L)
- PMC
- PMC10849969
- OpenAlex
- W4389333849
- Cited by
- 197
- References
- 63
- Citations by year
- 2026: 60 · 2025: 67 · 2024: 58 · 2023: 6 · 2022: 6
- FWCI
- 17.02
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Locations
- Nature (publishedVersion, cc-by)
- Research Square (acceptedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- eScholarship (California Digital Library) (submittedVersion, cc-by)
- RePEc: Research Papers in Economics (submittedVersion)
- Funders
- U.S. Environmental Protection Agency (STAR RD 84003201, RD 84003201, P42 ES027704)
- Pennsylvania Department of Health
- National Institutes of Health (1r03ca211211-01, ES025128, ES027704, GM103484)
- National Cancer Institute (R03 CA211211)
- National Institute of General Medical Sciences (P41GM103484, R01GM107550, R01GM141277, RM1GM145416)
- National Institute of Allergy and Infectious Diseases (R01AI167860)
- National Institute of Diabetes and Digestive and Kidney Diseases (R00DK110534, U01DK119702, K23DK123406, T32DK007202, R01DK136117, U24DK133658, P30DK043351, P30DK040561)
- National Institute of Environmental Health Sciences (P42ES031009, ES027704, ES025128, P42ES027704, P30ES025128)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolomics and Mass Spectrometry Studies
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Gut microbiota and health
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Inflammatory Bowel Disease
- Keywords
- untargeted metabolomics, bile acid conjugates, inflammatory bowel disease, Crohn's disease, fatty acid esters of hydroxy fatty acids, Bifidobacterium, Clostridium, Enterococcus, interferon-gamma, pregnane X receptor
- MeSH terms
- Pregnane X Receptor, Amides, Animals, Bifidobacterium, Bile Acids and Salts, Clostridium, Crohn Disease, Esters, Fatty Acids, Humans, Interferon-gamma, Phenotype, Reproducibility of Results, Inflammatory Bowel Diseases, Cohort Studies, CD4-Positive T-Lymphocytes, Enterococcus, Ecosystem, Tandem Mass Spectrometry, Metabolomics
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