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This study reveals that intestinal kynurenine (Kyn) is persistently elevated after radiation and correlates with fibrosis severity in both murine models and human rectal cancer samples. Exogenous Kyn exacerbated RIF, whereas inhibition of indoleamine 2,3\u2010dioxygenase 1 (IDO1) attenuated fibrotic progression. Mechanistically, Kyn activates the aryl hydrocarbon receptor (AHR) to promote fibroblast activation and fibrosis. Antibiotic depletion of gut microbiota abrogates radiation\u2010induced IDO1\u2010Kyn upregulation and protects against RIF. Conversely, fecal microbiota transplantation from irradiated mice recapitulates the elevated IDO1\u2010Kyn phenotype. Metagenomic analysis identify radiation\u2010induced depletion of\n                    <jats:italic>Phocaeicola coprophilus<\/jats:italic>\n                    (\n                    <jats:italic>P. coprophilus<\/jats:italic>\n                    ), whose abundance inversely correlates with Kyn levels. Supplementation with live\n                    <jats:italic>P. coprophilus<\/jats:italic>\n                    suppresses IDO1\u2010Kyn signaling and ameliorates RIF. Untargeted metabolomics further show that radiation reduces 6\u2010methyluracil, a metabolite derived from\n                    <jats:italic>P. coprophilus<\/jats:italic>\n                    . Exogenous 6\u2010methyluracil replenishment inhibits repression of the IDO1\u2010Kyn axis and mitigates fibrosis. Together, these findings define a microbiota\u2013metabolite\u2013host pathway in which radiation depletes\n                    <jats:italic>P. coprophilus<\/jats:italic>\n                    , leading to loss of 6\u2010methyluracil and derepression of the IDO1\u2010Kyn\u2010AHR axis, thereby driving fibrogenesis. Restoration of either\n                    <jats:italic>P. coprophilus<\/jats:italic>\n                    or its metabolite 6\u2010methyluracil represents a promising therapeutic strategy against RIF.\n                  <\/jats:p>","DOI":"10.1002\/advs.202518502","type":"journal-article","created":{"date-parts":[[2026,1,21]],"date-time":"2026-01-21T06:35:29Z","timestamp":1768977329000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["<i>Phocaeicola coprophilus<\/i>\n                    \u2010Derived 6\u2010Methyluracil Attenuates Radiation\u2010Induced Intestinal Fibrosis by Suppressing the IDO1\u2010Kynurenine\u2010AHR Axis"],"prefix":"10.1002","volume":"13","author":[{"given":"Jiaxin","family":"Zhang","sequence":"first","affiliation":[{"name":"Department of Gastrocolorectal Surgery General Surgery Center The First Hospital of Jilin University  Changchun China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhen","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Gastrocolorectal Surgery General Surgery Center The First Hospital of Jilin University  Changchun China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shuang","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Gastrocolorectal Surgery General Surgery Center The First Hospital of Jilin University  Changchun China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chao","family":"Luo","sequence":"additional","affiliation":[{"name":"Department of Physiology and Pathophysiology School of Basic Medical Sciences and State Key Laboratory of Vascular Homeostasis and Remodeling Peking University  Beijing P. 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