Reverse metabolomics for the discovery of chemical structures from humans

Emily C. Gentry, Stephanie L. Collins, Morgan Panitchpakdi, Pedro Belda-Ferre, Allison K. Stewart, Marvic Carrillo Terrazas, Hsueh-han Lu, Simone Zuffa, Tingting Yan, Julian Avila-Pacheco, Damian R. Plichta, Allegra T. Aron, Mingxun Wang, Alan K. Jarmusch, Fuhua Hao, Mashette Syrkin-Nikolau, Hera Vlamakis, Ashwin N. Ananthakrishnan, Brigid S. Boland, Amy Hemperly, Niels Vande Casteele, Frank J. Gonzalez, Clary B. Clish, Ramnik J. Xavier, Hiutung Chu, Erin S. Baker, Andrew D. Patterson, Rob Knight, Dionicio Siegel and Pieter C. Dorrestein ()
Additional contact information
Emily C. Gentry: University of California, San Diego
Stephanie L. Collins: The Pennsylvania State University
Morgan Panitchpakdi: University of California, San Diego
Pedro Belda-Ferre: University of California, San Diego
Allison K. Stewart: North Carolina State University
Marvic Carrillo Terrazas: University of California, San Diego
Hsueh-han Lu: University of California, San Diego
Simone Zuffa: University of California, San Diego
Tingting Yan: National Institutes of Health
Julian Avila-Pacheco: Broad Institute of MIT and Harvard
Damian R. Plichta: Broad Institute of MIT and Harvard
Allegra T. Aron: University of California, San Diego
Mingxun Wang: University of California, San Diego
Alan K. Jarmusch: University of California, San Diego
Fuhua Hao: The Pennsylvania State University
Mashette Syrkin-Nikolau: Rady Children’s Hospital University of California San Diego
Hera Vlamakis: Broad Institute of MIT and Harvard
Ashwin N. Ananthakrishnan: Massachusetts General Hospital
Brigid S. Boland: University of California, San Diego
Amy Hemperly: Rady Children’s Hospital University of California San Diego
Niels Vande Casteele: University of California, San Diego
Frank J. Gonzalez: National Institutes of Health
Clary B. Clish: Broad Institute of MIT and Harvard
Ramnik J. Xavier: Broad Institute of MIT and Harvard
Hiutung Chu: University of California, San Diego
Erin S. Baker: North Carolina State University
Andrew D. Patterson: The Pennsylvania State University
Rob Knight: University of California, San Diego
Dionicio Siegel: University of California, San Diego
Pieter C. Dorrestein: University of California, San Diego

Nature, 2024, vol. 626, issue 7998, 419-426

Abstract: 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.

Date: 2024
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DOI: 10.1038/s41586-023-06906-8

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