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Improved knowledge of microbial metabolites and their immunomodulatory roles is thus necessary for diagnosis and management. Here, we systematically analyzed the chemical, ecological, and epidemiological properties of ~82k metabolic features in 546 Integrative Human Microbiome Project (iHMP\/HMP2) metabolomes, using a newly developed methodology for bioactive compound prioritization from microbial communities. This suggested &gt;1000 metabolic features as potentially bioactive in IBD and associated ~43% of prevalent, unannotated features with at least one well-characterized metabolite, thereby providing initial information for further characterization of a significant portion of the fecal metabolome. Prioritized features included known IBD-linked chemical families such as bile acids and short-chain fatty acids, and less-explored bilirubin, polyamine, and vitamin derivatives, and other microbial products. One of these, nicotinamide riboside, reduced colitis scores in DSS-treated mice. The method, MACARRoN, is generalizable with the potential to improve microbial community characterization and provide therapeutic candidates.<\/jats:p>","DOI":"10.1038\/s44320-024-00027-8","type":"journal-article","created":{"date-parts":[[2024,3,11]],"date-time":"2024-03-11T13:01:28Z","timestamp":1710162088000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":14,"title":["Integrated annotation prioritizes metabolites with bioactivity in inflammatory bowel disease"],"prefix":"10.1038","volume":"20","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8669-4979","authenticated-orcid":false,"given":"Amrisha","family":"Bhosle","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sena","family":"Bae","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2768-2975","authenticated-orcid":false,"given":"Yancong","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7444-7559","authenticated-orcid":false,"given":"Eunyoung","family":"Chun","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9388-3946","authenticated-orcid":false,"given":"Julian","family":"Avila-Pacheco","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ludwig","family":"Geistlinger","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gleb","family":"Pishchany","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0910-2655","authenticated-orcid":false,"given":"Jonathan N","family":"Glickman","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Monia","family":"Michaud","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2725-0694","authenticated-orcid":false,"given":"Levi","family":"Waldron","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8259-9245","authenticated-orcid":false,"given":"Clary B","family":"Clish","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ramnik J","family":"Xavier","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hera","family":"Vlamakis","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8798-7068","authenticated-orcid":false,"given":"Eric A","family":"Franzosa","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5092-0150","authenticated-orcid":false,"given":"Wendy S","family":"Garrett","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1110-0096","authenticated-orcid":false,"given":"Curtis","family":"Huttenhower","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2024,3,11]]},"reference":[{"key":"27_CR1","doi-asserted-by":"publisher","first-page":"1174","DOI":"10.1136\/gutjnl-2020-323071","volume":"70","author":"A Agus","year":"2021","unstructured":"Agus A, Clement K, Sokol H (2021) Gut microbiota-derived metabolites as central regulators in metabolic disorders. 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