Reverse metabolomics for the discovery of chemical structures from humans

• 成果类型: Article
• 署名作者: Gentry, Emily C.; Collins, Stephanie L.; Panitchpakdi, Morgan; Belda-Ferre, Pedro; Stewart, Allison K.; Terrazas, Marvic Carrillo; Lu, Hsueh-han; Zuffa, Simone; Yan, Tingting; Avila-Pacheco, Julian; Plichta, Damian R.; Aron, Allegra T.; Wang, Mingxun; Jarmusch, Alan K.; Hao, Fuhua; Syrkin-Nikolau, Mashette; Vlamakis, Hera; Ananthakrishnan, Ashwin N.; Boland, Brigid S.; Hemperly, Amy; Vande Casteele, Niels; Gonzalez, Frank J.; Clish, Clary B.; Xavier, Ramnik J.; Chu, Hiutung; Baker, Erin S.; Patterson, Andrew D.; Knight, Rob; Siegel, Dionicio; Dorrestein, Pieter C.
• 署名单位: University of California System; University of California San Diego; University of California System; University of California San Diego; Virginia Polytechnic Institute & State University; Pennsylvania Commonwealth System of Higher Education (PCSHE); Pennsylvania State University; Pennsylvania State University - University Park; University of California System; University of California San Diego; University of California System; University of California San Diego; North Carolina State University; University of California System; University of California San Diego; National Institutes of Health (NIH) - USA; NIH National Cancer Institute (NCI); Harvard University; Massachusetts Institute of Technology (MIT); Broad Institute; National Institutes of Health (NIH) - USA; NIH National Institute of Environmental Health Sciences (NIEHS); Pennsylvania Commonwealth System of Higher Education (PCSHE); Pennsylvania State University; Pennsylvania State University - University Park; University of California System; University of California San Diego; Rady Childrens Hospital San Diego; Massachusetts Institute of Technology (MIT); Harvard University; Harvard University Medical Affiliates; Massachusetts General Hospital; University of California System; University of California San Diego; Harvard University; Harvard University Medical Affiliates; Massachusetts General Hospital; Harvard University; Harvard Medical School; Harvard University; Harvard University Medical Affiliates; Massachusetts General Hospital; University of California System; University of California San Diego; University of North Carolina; University of North Carolina Chapel Hill; University of California System; University of California San Diego; University of California System; University of California San Diego
• 刊物名称: Nature
• ISSN/ISSBN: 0028-5615
• DOI: 10.1038/s41586-023-06906-8
• 发表日期: 2024-02-08
• 关键词: acid conjugates fabacs; bile-acids; amino-acids; rifaximin; identification; annotation

摘要

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-gamma 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. A new discovery strategy, 'reverse metabolomics', facilitates high-throughput matching of mass spectrometry spectra in public untargeted metabolomics datasets, and a proof-of-concept experiment identified an association between microbial bile amidates and inflammatory bowel disease.