Reverse metabolomics for the discovery of chemical structures from humans

  • Nature. 2024 Feb;626(7998):419-426. doi: 10.1038/s41586-023-06906-8.
Emily C Gentry  1  2  3 ,  Stephanie L Collins  4 ,  Morgan Panitchpakdi  1  2 ,  Pedro Belda-Ferre  5  6 ,  Allison K Stewart  7 ,  Marvic Carrillo Terrazas  8 ,  Hsueh-Han Lu  8 ,  Simone Zuffa  1  2 ,  Tingting Yan  9 ,  Julian Avila-Pacheco  10 ,  Damian R Plichta  10 ,  Allegra T Aron  1  2 ,  Mingxun Wang  1  2 ,  Alan K Jarmusch  1  2  11 ,  Fuhua Hao  12 ,  Mashette Syrkin-Nikolau  13 ,  Hera Vlamakis  10  14 ,  Ashwin N Ananthakrishnan  15 ,  Brigid S Boland  16 ,  Amy Hemperly  13 ,  Niels Vande Casteele  16 ,  Frank J Gonzalez  9 ,  Clary B Clish  10 ,  Ramnik J Xavier  10  14  17  18 ,  Hiutung Chu  8  19 ,  Erin S Baker  7  20 ,  Andrew D Patterson  12 ,  Rob Knight  5  6  21  22 ,  Dionicio Siegel  1 ,  Pieter C Dorrestein  23  24
Affiliations
  • 1. Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, San Diego, La Jolla, CA, USA.
  • 2. Collaborative Mass Spectrometry Innovation Center, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, San Diego, La Jolla, CA, USA.
  • 3. Department of Chemistry, Virginia Tech, Blacksburg, VA, USA.
  • 4. Department of Biochemistry and Molecular Biology, The Pennsylvania State University, University Park, PA, USA.
  • 5. Department of Pediatrics, University of California, San Diego, La Jolla, CA, USA.
  • 6. Department of Computer Science and Engineering, Jacobs School of Engineering, University of California, San Diego, San Diego, CA, USA.
  • 7. Department of Chemistry, North Carolina State University, Raleigh, NC, USA.
  • 8. Department of Pathology, University of California, San Diego, La Jolla, CA, USA.
  • 9. Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
  • 10. Broad Institute of MIT and Harvard, Cambridge, MA, USA.
  • 11. Immunity, Inflammation, and Disease Laboratory, Division of Intramural Research, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, NC, USA.
  • 12. Center for Molecular Toxicology and Carcinogenesis, Department of Veterinary and Biomedical Sciences, The Pennsylvania State University, University Park, PA, USA.
  • 13. Division of Gastroenterology, Department of Pediatrics, Rady Children's Hospital University of California San Diego, La Jolla, CA, USA.
  • 14. Center for Microbiome Informatics and Therapeutics, Massachusetts Institute of Technology, Cambridge, MA, USA.
  • 15. Division of Gastroenterology, Massachusetts General Hospital, Boston, MA, USA.
  • 16. Division of Gastroenterology, University of California, San Diego, La Jolla, CA, USA.
  • 17. Center for Computational and Integrative Biology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.
  • 18. Department of Molecular Biology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.
  • 19. CU-UCSD, Center for Mucosal Immunology, Allergy and Vaccine Development, University of California, San Diego, La Jolla, California, USA.
  • 20. Department of Chemistry, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
  • 21. Center for Microbiome Innovation, Jacobs School of Engineering, University of California, San Diego, San Diego, CA, USA.
  • 22. Department of Bioengineering, University of California, San Diego, San Diego, California, USA.
  • 23. Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, San Diego, La Jolla, CA, USA. [email protected].
  • 24. Collaborative Mass Spectrometry Innovation Center, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, San Diego, La Jolla, CA, USA. [email protected].
PMID: 38052229 DOI: 10.1038/s41586-023-06906-8
Abstract

Determining the structure and phenotypic context of molecules detected in untargeted metabolomics experiments remains challenging. Here we present reverse metabolomics as a discovery strategy, whereby tandem mass spectrometry spectra acquired from newly synthesized compounds are searched for in public metabolomics datasets to uncover phenotypic associations. To demonstrate the concept, we broadly synthesized and explored multiple classes of metabolites in humans, including N-acyl amides, fatty acid esters of hydroxy fatty acids, bile acid esters and conjugated bile acids. Using repository-scale analysis1,2, we discovered that some conjugated bile acids are associated with inflammatory bowel disease (IBD). Validation using four distinct human IBD cohorts showed that cholic acids conjugated to Glu, Ile/Leu, Phe, Thr, Trp or Tyr are increased in Crohn's disease. Several of these compounds and related structures affected pathways associated with IBD, such as interferon-γ production in CD4+ T cells3 and agonism of the pregnane X receptor4. Culture of bacteria belonging to the Bifidobacterium, Clostridium and Enterococcus genera produced these bile amidates. Because searching repositories with tandem mass spectrometry spectra has only recently become possible, this reverse metabolomics approach can now be used as a general strategy to discover Other molecules from human and animal ecosystems.

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