{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,22]],"date-time":"2026-09-22T16:14:02Z","timestamp":1790093642491,"version":"4.0.1"},"reference-count":47,"publisher":"American Chemical Society (ACS)","issue":"37","license":[{"start":{"date-parts":[[2026,9,6]],"date-time":"2026-09-06T00:00:00Z","timestamp":1788652800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000054","name":"National Cancer Institute","doi-asserted-by":"publisher","award":["CA014236"],"award-info":[{"award-number":["CA014236"]}],"id":[{"id":"10.13039\/100000054","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000062","name":"National Institute of Diabetes and Digestive and Kidney Diseases","doi-asserted-by":"publisher","award":["DK034987"],"award-info":[{"award-number":["DK034987"]}],"id":[{"id":"10.13039\/100000062","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000062","name":"National Institute of Diabetes and Digestive and Kidney Diseases","doi-asserted-by":"publisher","award":["DK116868"],"award-info":[{"award-number":["DK116868"]}],"id":[{"id":"10.13039\/100000062","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000062","name":"National Institute of Diabetes and Digestive and Kidney Diseases","doi-asserted-by":"publisher","award":["DK137771"],"award-info":[{"award-number":["DK137771"]}],"id":[{"id":"10.13039\/100000062","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000062","name":"National Institute of Diabetes and Digestive and Kidney Diseases","doi-asserted-by":"publisher","award":["K01DK135647"],"award-info":[{"award-number":["K01DK135647"]}],"id":[{"id":"10.13039\/100000062","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000149","name":"Division of Engineering Education and Centers","doi-asserted-by":"publisher","award":["EEC-2133504"],"award-info":[{"award-number":["EEC-2133504"]}],"id":[{"id":"10.13039\/100000149","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100005562","name":"North Carolina Biotechnology Center","doi-asserted-by":"publisher","award":["2021-FLG-3819"],"award-info":[{"award-number":["2021-FLG-3819"]}],"id":[{"id":"10.13039\/100005562","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2026,9,22]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Histone deacetylase (HDAC) is a family of key epigenetic regulator implicated in inflammation, metabolism, and cancer. Microbiome metabolites can modulate host histone acetylation, yet systematic identification of metabolites that target HDAC remains limited. Here we present a computationally driven discovery pipeline that combines training data composition optimization with experimental validation to prioritize microbiome-derived HDAC inhibitors. Starting from a large, public HDAC3 screening data set (314,129 compounds; 485 actives), we developed an automated iterative sampling strategy that balances active and inactive compounds while enriching the inactive class for metabolite-like chemistry. Models trained on the balanced metabolite-enriched subsets achieved substantially higher sensitivity and balanced accuracy than models trained on the full data set. Consensus predictions from multiple optimized runs were applied to a curated microbiome metabolite database to prioritize candidates for testing. Two top candidates, 5-(hydroxymethyl)furoic acid (HMFA) and d-glucuronolactone (DGL), were evaluated using an HDAC3-specific biochemical assay, followed by broader HDAC activity assessment. Both metabolites exhibited mild inhibitory activity overall. Docking simulations suggested that HMFA may interact with the HDAC3 catalytic site. Together, we show that targeted training set composition can improve machine learning-assisted discovery of microbiome-derived small molecule inhibitors and identified HMFA as a microbiome-associated metabolite with measurable in vitro HDAC inhibitory activity.<\/jats:p>","DOI":"10.1021\/acsomega.5c12875","type":"journal-article","created":{"date-parts":[[2026,9,6]],"date-time":"2026-09-06T18:01:20Z","timestamp":1788717680000},"page":"54936-54949","source":"Crossref","is-referenced-by-count":0,"title":["Machine Learning\nGuided Discovery of Microbiome Metabolites\nThat Inhibit HDAC"],"prefix":"10.1021","volume":"11","author":[{"given":"Hong A.","family":"Chung","sequence":"first","affiliation":[{"name":"Duke University , , , ,","place":["Durham, North Carolina, United States, 27708"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Emily M.","family":"Eshleman","sequence":"additional","affiliation":[{"name":"Cincinnati Children\u2019s Hospital Medical Center , , , ,","place":["Cincinnati, Ohio, United States, 45267"]},{"name":"University of Cincinnati College of Medicine , , , ,","place":["Cincinnati, Ohio, United States, 45267"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"James","family":"Carter","sequence":"additional","affiliation":[{"name":"Duke University , , , ,","place":["Durham, North Carolina, United States, 27708"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Theresa","family":"Alenghat","sequence":"additional","affiliation":[{"name":"Cincinnati Children\u2019s Hospital Medical Center , , , ,","place":["Cincinnati, Ohio, United States, 45267"]},{"name":"University of Cincinnati College of Medicine , , , ,","place":["Cincinnati, Ohio, United States, 45267"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4789-7380","authenticated-orcid":true,"given":"Daniel","family":"Reker","sequence":"additional","affiliation":[{"name":"Duke University , , , ,","place":["Durham, North Carolina, United States, 27708"]},{"name":"Duke University , , , ,","place":["Durham, North Carolina, United States, 27708"]},{"name":"Duke University School of Medicine , , , ,","place":["Durham, North Carolina, United States, 27710"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"316","published-online":{"date-parts":[[2026,9,6]]},"reference":[{"key":"2026092210562241000_cit1","doi-asserted-by":"publisher","first-page":"204","DOI":"10.1038\/s12276-020-0382-4","article-title":"A short guide to histone deacetylases including recent progress on\nclass II enzymes","volume":"52","author":"Park","year":"2020","journal-title":"Exp. Mol. Med."},{"issue":"5","key":"2026092210562241000_cit2","doi-asserted-by":"publisher","first-page":"620","DOI":"10.3390\/ph17050620","article-title":"The histone\ndeacetylase\nfamily: Structural features and application of combined computational\nmethods","volume":"17","author":"Curcio","year":"2024","journal-title":"Pharmaceuticals"},{"issue":"4","key":"2026092210562241000_cit3","doi-asserted-by":"publisher","first-page":"a018713","DOI":"10.1101\/cshperspect.a018713","article-title":"Erasers of histone\nacetylation: The histone deacetylase\nenzymes","volume":"6","author":"Seto","year":"2014","journal-title":"Cold Spring Harbor Perspect. Biol."},{"issue":"8","key":"2026092210562241000_cit4","doi-asserted-by":"publisher","first-page":"1588","DOI":"10.1016\/j.ajhg.2024.06.015","article-title":"De novo missense\nvariants in HDAC3 leading to epigenetic machinery dysfunction are\nassociated with a variable neurodevelopmental disorder","volume":"111","author":"Yoon","year":"2024","journal-title":"Am. J. Hum. Genet."},{"issue":"1","key":"2026092210562241000_cit5","doi-asserted-by":"publisher","DOI":"10.1111\/cpr.13731","article-title":"HDAC3 in action: Expanding roles in inflammation and\ninflammatory\ndiseases","volume":"58","author":"He","year":"2025","journal-title":"Cell Proliferation"},{"issue":"8","key":"2026092210562241000_cit6","doi-asserted-by":"publisher","first-page":"9573","DOI":"10.1007\/s12035-025-04866-w","article-title":"HDAC3 as an Emerging Therapeutic\nTarget for Alzheimer\u2019s Disease and other Neurological Disorders","volume":"62","author":"Li","year":"2025","journal-title":"Mol. Neurobiol."},{"key":"2026092210562241000_cit7","doi-asserted-by":"publisher","first-page":"1419685","DOI":"10.3389\/fimmu.2024.1419685","article-title":"The role of\nHDAC3 in inflammation: mechanisms and therapeutic implications","volume":"15","author":"Watson","year":"2024","journal-title":"Front. Immunol."},{"issue":"2","key":"2026092210562241000_cit8","first-page":"166","article-title":"Histone deacetylase\ninhibitors: molecular mechanisms\nof action and clinical trials as anti-cancer drugs","volume":"3","author":"Kim","year":"2010","journal-title":"Am. J. Transl. Res."},{"issue":"12","key":"2026092210562241000_cit9","doi-asserted-by":"publisher","first-page":"4577","DOI":"10.1111\/bcp.14889","article-title":"Recent developments of HDAC inhibitors: Emerging indications\nand novel molecules","volume":"87","author":"Bondarev","year":"2021","journal-title":"Br. J. Clin. Pharmacol."},{"issue":"9","key":"2026092210562241000_cit10","doi-asserted-by":"publisher","first-page":"2751","DOI":"10.3390\/ph3092751","article-title":"Clinical toxicities of histone deacetylase\ninhibitors","volume":"3","author":"Subramanian","year":"2010","journal-title":"Pharmaceuticals"},{"key":"2026092210562241000_cit11","doi-asserted-by":"publisher","first-page":"15mw9","DOI":"10.26434\/chemrxiv-2025-15mw9","article-title":"Profiling Biological\nEffects of Microbiome Metabolites via Machine Learning","author":"Chung","year":"2025","journal-title":"ChemRxiv"},{"key":"2026092210562241000_cit12","doi-asserted-by":"publisher","DOI":"10.15252\/embr.202255664","article-title":"Local and systemic\neffects of microbiome-derived\nmetabolites","volume":"23","author":"Spivak","year":"2022","journal-title":"EMBO Rep."},{"issue":"12","key":"2026092210562241000_cit13","doi-asserted-by":"publisher","first-page":"2940","DOI":"10.1016\/j.immuni.2025.11.006","article-title":"A host-centric view of the microbiota metabolome","volume":"58","author":"Yamada","year":"2025","journal-title":"Immunity"},{"key":"2026092210562241000_cit14","doi-asserted-by":"publisher","first-page":"638","DOI":"10.3389\/fgene.2019.00638","article-title":"Epigenetic regulation at the interplay\nbetween gut microbiota and\nhost metabolism","volume":"10","author":"Miro-Blanch","year":"2019","journal-title":"Front. 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Chem."},{"issue":"9","key":"2026092210562241000_cit18","doi-asserted-by":"publisher","first-page":"587","DOI":"10.1016\/j.jnutbio.2007.08.002","article-title":"Inhibition\nof histone-deacetylase activity by short-chain fatty acids and some\npolyphenol metabolites formed in the colon","volume":"19","author":"Waldecker","year":"2008","journal-title":"J. Nutr. Biochem."},{"issue":"10","key":"2026092210562241000_cit19","doi-asserted-by":"publisher","first-page":"858","DOI":"10.3390\/nu3100858","article-title":"Regulation\nof inflammation\nby short-chain fatty acids","volume":"3","author":"Vinolo","year":"2011","journal-title":"Nutrients"},{"key":"2026092210562241000_cit20","doi-asserted-by":"publisher","first-page":"1179237X17729900","DOI":"10.1177\/1179237x17729900","article-title":"Epigenetic\nregulation of gene expression induced by\nbutyrate in colorectal cancer: involvement of microRNA","volume":"9","author":"Bishop","year":"2017","journal-title":"Genet. Epigenet."},{"key":"2026092210562241000_cit21","doi-asserted-by":"publisher","first-page":"196","DOI":"10.1038\/s42255-024-01191-9","article-title":"Short-chain\nfatty\nacid metabolites propionate and butyrate are unique epigenetic regulatory\nelements linking diet, metabolism and gene expression","volume":"7","author":"Nshanian","year":"2025","journal-title":"Nat. Metab."},{"issue":"7827","key":"2026092210562241000_cit22","doi-asserted-by":"publisher","first-page":"108","DOI":"10.1038\/s41586-020-2604-2","article-title":"Microbiota-derived\nmetabolite promotes HDAC3 activity\nin the gut","volume":"586","author":"Wu","year":"2020","journal-title":"Nature"},{"key":"2026092210562241000_cit23","doi-asserted-by":"publisher","first-page":"895","DOI":"10.1038\/s41573-023-00774-7","article-title":"Artificial intelligence for natural\nproduct drug discovery","volume":"22","author":"Mullowney","year":"2023","journal-title":"Nat. Rev. Drug Discovery"},{"key":"2026092210562241000_cit24","unstructured":"National Center for Biotechnology Information.\n          .  PubChem Bioassay Record\nfor AID 2718, Fluorescence Cell-Free Homogeneous Primary HTS to Identify\nInhibitors of Histone Deacetylase 3. Source: Broad Institute 2025."},{"key":"2026092210562241000_cit25","doi-asserted-by":"publisher","first-page":"143","DOI":"10.1007\/978-3-030-14632-0_5","article-title":"Cheminformatic\nanalysis of natural product fragments","volume-title":"Progress\nin the Chemistry of Organic Natural Products","author":"Reker","year":"2019"},{"key":"2026092210562241000_cit26","doi-asserted-by":"publisher","first-page":"1072","DOI":"10.1038\/nchem.2095","article-title":"Revealing\nthe macromolecular targets of complex natural products","volume":"6","author":"Reker","year":"2014","journal-title":"Nat. Chem."},{"issue":"7","key":"2026092210562241000_cit27","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0271260","article-title":"An empirical evaluation\nof sampling methods for the\nclassification of imbalanced data","volume":"17","author":"Kim","year":"2022","journal-title":"PLoS One"},{"issue":"3","key":"2026092210562241000_cit28","doi-asserted-by":"publisher","first-page":"408","DOI":"10.1109\/TSMC.1972.4309137","article-title":"Asymptotic\nproperties of nearest neighbor rules using edited data","volume":"SMC-2","author":"Wilson","year":"1972","journal-title":"IEEE Trans. Syst. Man Cybern."},{"key":"2026092210562241000_cit29","doi-asserted-by":"publisher","first-page":"321","DOI":"10.1613\/jair.953","article-title":"SMOTE:\nSynthetic Minority Over-sampling Technique","volume":"16","author":"Chawla","year":"2002","journal-title":"J. Artif. Intell. 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Biotechnol."},{"issue":"1","key":"2026092210562241000_cit36","doi-asserted-by":"publisher","first-page":"1","DOI":"10.36876\/acst.1004","article-title":"Determination\nof HMF in some instant foods and its biodegradation by lactic acid\nbacteria in medium and food","volume":"1","author":"Alper Oral","year":"2015","journal-title":"Ann. Chromatogr.\nSep. Tech."},{"issue":"2","key":"2026092210562241000_cit37","doi-asserted-by":"publisher","first-page":"134","DOI":"10.1016\/j.resmic.2008.11.002","article-title":"Bacillus subtilis isolated from the human gastrointestinal tract","volume":"160","author":"Hong","year":"2009","journal-title":"Res. 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Biosci."},{"key":"2026092210562241000_cit40","doi-asserted-by":"publisher","first-page":"872988","DOI":"10.3389\/fphar.2022.872988","article-title":"Characteristics of serum\nmetabolites and gut microbiota in diabetic\nkidney disease","volume":"13","author":"Zhang","year":"2022","journal-title":"Front. Pharmacol."},{"issue":"10","key":"2026092210562241000_cit41","doi-asserted-by":"publisher","first-page":"103316","DOI":"10.1016\/j.drudis.2022.07.001","article-title":"The role of gut microbial \u03b2-glucuronidase\nin drug disposition\nand development","volume":"27","author":"Gao","year":"2022","journal-title":"Drug Discovery Today"},{"issue":"1","key":"2026092210562241000_cit42","doi-asserted-by":"publisher","first-page":"2236749","DOI":"10.1080\/19490976.2023.2236749","article-title":"Gut microbial \u03b2-glucuronidase:\nA vital regulator in female\nestrogen metabolism","volume":"15","author":"Hu","year":"2023","journal-title":"Gut Microbes"},{"issue":"7","key":"2026092210562241000_cit43","doi-asserted-by":"publisher","first-page":"1775","DOI":"10.3390\/cells10071775","article-title":"Butyrate and the\nintestinal epithelium: Modulation\nof proliferation and inflammation in homeostasis and disease","volume":"10","author":"Salvi","year":"2021","journal-title":"Cells"},{"issue":"7","key":"2026092210562241000_cit44","doi-asserted-by":"publisher","first-page":"2485S","DOI":"10.1093\/jn\/133.7.2485S","article-title":"Inhibition\nof histone deacetylase activity by butyrate","volume":"133","author":"Davie","year":"2003","journal-title":"J. Nutr."},{"key":"2026092210562241000_cit45","doi-asserted-by":"publisher","first-page":"6134","DOI":"10.1111\/febs.70289","article-title":"Butyrate suppresses mucosal inflammation in inflammatory\nbowel disease primarily through HDAC3 inhibition in monocytes and\nmacrophages","volume":"292","author":"Parada-Venegas","year":"2025","journal-title":"FEBS J."},{"issue":"2","key":"2026092210562241000_cit46","doi-asserted-by":"publisher","first-page":"432","DOI":"10.1016\/j.immuni.2018.12.018","article-title":"The short-chain fatty acid butyrate imprints an antimicrobial\nprogram in macrophages","volume":"50","author":"Schulthess","year":"2019","journal-title":"Immunity"},{"key":"2026092210562241000_cit47","doi-asserted-by":"publisher","first-page":"43","DOI":"10.1186\/s13321-021-00522-2","article-title":"GNINA 1.0: molecular\ndocking with deep learning","volume":"13","author":"McNutt","year":"2021","journal-title":"J. Cheminf."}],"container-title":["ACS Omega"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/pubs.acs.org\/doi\/pdf\/10.1021\/acsomega.5c12875","content-type":"application\/pdf","content-version":"vor","intended-application":"unspecified"},{"URL":"https:\/\/pubs.acs.org\/acsodf\/article-pdf\/11\/37\/54936\/68396710\/acsomega.5c12875.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/pubs.acs.org\/acsodf\/article-pdf\/11\/37\/54936\/68396710\/acsomega.5c12875.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,9,22]],"date-time":"2026-09-22T15:50:21Z","timestamp":1790092221000},"score":1,"resource":{"primary":{"URL":"https:\/\/pubs.acs.org\/acsodf\/article\/11\/37\/54936\/5421937\/Machine-Learning-Guided-Discovery-of-Microbiome"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,9,6]]},"references-count":47,"journal-issue":{"issue":"37","published-online":{"date-parts":[[2026,9,6]]},"published-print":{"date-parts":[[2026,9,22]]}},"URL":"https:\/\/doi.org\/10.1021\/acsomega.5c12875","relation":{},"ISSN":["2470-1343"],"issn-type":[{"value":"2470-1343","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,9,6]]}}}