{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,3]],"date-time":"2026-06-03T11:28:58Z","timestamp":1780486138144,"version":"3.54.1"},"reference-count":48,"publisher":"Oxford University Press (OUP)","issue":"1","license":[{"start":{"date-parts":[[2025,8,13]],"date-time":"2025-08-13T00:00:00Z","timestamp":1755043200000},"content-version":"vor","delay-in-days":224,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"State Key Laboratory on Technologies for Chinese Medicine Pharmaceutical Process Control and Intelligent Manufacture","award":["NZYSKL240205"],"award-info":[{"award-number":["NZYSKL240205"]}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82304807"],"award-info":[{"award-number":["82304807"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004608","name":"Natural Science Foundation of Jiangsu Province","doi-asserted-by":"publisher","award":["BK20220299"],"award-info":[{"award-number":["BK20220299"]}],"id":[{"id":"10.13039\/501100004608","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Kunshan Key Research and Development Plan","award":["KS2203"],"award-info":[{"award-number":["KS2203"]}]},{"name":"Primary Research and Development Plan of Jiangsu Province, China","award":["BK20241912"],"award-info":[{"award-number":["BK20241912"]}]},{"name":"Primary Research and Development Plan of Jiangsu Province, China","award":["BE2019721"],"award-info":[{"award-number":["BE2019721"]}]},{"name":"Scientific Research Project of Jiangsu Health Commission","award":["M2024064"],"award-info":[{"award-number":["M2024064"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2025,1,2]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>Microbiota-associated factors are increasingly recognized as significant contributors to the progression of ulcerative colitis, and microbial modulation has emerged as an effective therapy for this condition. The herbal compound silibinin has demonstrated properties that modulate gut microbiota. Herein, we investigated the response of gut microbiota to silibinin in ameliorating colitis, using a mouse model of colitis coupled with antibiotic exposure. Results indicated that antibiotic pretreatment negated the benefits of silibinin in mice with colitis. Furthermore, fecal microbiota transplantation involving silibinin-modulated gut microbiota further substantiated the gut microbiota-dependent effects of silibinin. Within the metabolic profiles of silibinin-regulated microbiota, we identified that Alistipes-associated (R)-2,3-dihydroxy-isovalerate exhibited the most pronounced anti-inflammatory effects in vitro and demonstrated protective effects against colitis. Moreover, (R)-2,3-dihydroxy-isovalerate reinstated the protective effects of silibinin in mice with colitis under antibiotic exposure. These effects were primarily mediated via the targeting of the colonic GABA transporter 3 (GAT-3) by (R)-2,3-dihydroxy-isovalerate. We further revealed that the retinoic acid receptor \u03b2 and the retinoid-related orphan nuclear receptor \u03b3t may mediate the impact of silibinin-derived microbiota and (R)-2,3-dihydroxy-isovalerate on colitis. Additionally, the knockdown of colonic GAT-3 diminished the impact of silibinin on the GAT-3\/retinoic acid receptor \u03b2\/retinoid-related orphan nuclear receptor \u03b3t axis and colitis. Our findings highlight that (R)-2,3-dihydroxy-isovalerate, enriched from microbiota derived from silibinin, can target the GAT-3\/retinoic acid receptor \u03b2\/retinoid-related orphan nuclear receptor \u03b3t axis, which is essential for anti-colitis properties of silibinin-regulated microbiota.<\/jats:p>","DOI":"10.1093\/ismejo\/wraf175","type":"journal-article","created":{"date-parts":[[2025,8,13]],"date-time":"2025-08-13T11:12:14Z","timestamp":1755083534000},"source":"Crossref","is-referenced-by-count":6,"title":["Silibinin-derived microbiota enrich (R)-2,3-dihydroxy-isovalerate and ameliorate colitis via the GAT-3\/RAR\u03b2\/ROR\u03b3t axis"],"prefix":"10.1093","volume":"19","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-6754-7655","authenticated-orcid":false,"given":"Baofei","family":"Yan","sequence":"first","affiliation":[{"name":"State Key Laboratory on Technologies for Chinese Medicine Pharmaceutical Process Control and Intelligent Manufacture, Nanjing University of Chinese Medicine , Nanjing 210023 ,","place":["P. R. China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xian","family":"Zheng","sequence":"additional","affiliation":[{"name":"Department of Pharmacy, Affiliated Kunshan Hospital of Jiangsu University , Kunshan 215399 ,","place":["P. R. China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Danya","family":"Lu","sequence":"additional","affiliation":[{"name":"State Key Laboratory on Technologies for Chinese Medicine Pharmaceutical Process Control and Intelligent Manufacture, Nanjing University of Chinese Medicine , Nanjing 210023 ,","place":["P. R. China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ting","family":"Li","sequence":"additional","affiliation":[{"name":"State Key Laboratory on Technologies for Chinese Medicine Pharmaceutical Process Control and Intelligent Manufacture, Nanjing University of Chinese Medicine , Nanjing 210023 ,","place":["P. R. China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xi","family":"Chen","sequence":"additional","affiliation":[{"name":"Jiangsu Engineering Research Center for Precision Prevention and Treatment of Digestive and Reproductive System Tumors , Huaian 223003 ,","place":["P. R. China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhitao","family":"Shao","sequence":"additional","affiliation":[{"name":"State Key Laboratory on Technologies for Chinese Medicine Pharmaceutical Process Control and Intelligent Manufacture, Nanjing University of Chinese Medicine , Nanjing 210023 ,","place":["P. R. China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tingming","family":"Fu","sequence":"additional","affiliation":[{"name":"State Key Laboratory on Technologies for Chinese Medicine Pharmaceutical Process Control and Intelligent Manufacture, Nanjing University of Chinese Medicine , Nanjing 210023 ,","place":["P. R. 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