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Here we identify the microbiota-derived octadecanoid-hydroxy-fatty-acid metabolite 10-hydroxystearic acid (10-HSA), produced by\n                    <jats:italic>Lactiplantibacillus plantarum<\/jats:italic>\n                    , as a key mediator of gut epithelial barrier repair in human intestinal epithelial cells in vitro, ex vivo and in the non-human primate model of HIV\/AIDS. X-ray crystallography and transcriptomics combined with functional analyses revealed that 10-HSA directly binds PPAR\u03b1, inducing lipid metabolism, mitochondrial regeneration and subsequent epigenetic histone crotonylation, thereby promoting gut epithelial renewal. Co-administration of 10-HSA with anti-retroviral therapy in SIV-infected macaques accelerated viral suppression, resolved systemic inflammation, repaired gut epithelial integrity and recovered the gut microbiota. These findings identify a microbiota-derived lipid metabolite\u2013PPAR\u03b1\u2013histone crotonylation axis that activates gut epithelial regeneration. This study defines a host\u2013microbiome metabolic pathway that restores epithelial\u2013immune homeostasis and enhances the efficacy of anti-retroviral therapy.\n                  <\/jats:p>","DOI":"10.1038\/s41564-026-02433-0","type":"journal-article","created":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T09:08:36Z","timestamp":1785402516000},"page":"2365-2383","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Microbiota-derived 10-hydroxystearic acid activates PPAR\u03b1 to restore gut epithelial barrier integrity and enhance anti-retroviral therapy"],"prefix":"10.1038","volume":"11","author":[{"given":"Dylan","family":"Kramer","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Clarissa","family":"Santos Rocha","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christopher A.","family":"Gaulke","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marie","family":"Nearing","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sumathi","family":"Sankaran-Walters","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0008-3354-190X","authenticated-orcid":false,"given":"Ikaika","family":"Loque","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anugraha","family":"Kidigannappa","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0005-9320-3601","authenticated-orcid":false,"given":"Eric","family":"Pham","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shuang","family":"Hu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0005-4757-0566","authenticated-orcid":false,"given":"Patrawin","family":"Wanakumjorn","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ramona","family":"Abbattista","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7925-4086","authenticated-orcid":false,"given":"Abhaya","family":"Dandekar","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9946-3846","authenticated-orcid":false,"given":"Roland","family":"Faller","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6346-8028","authenticated-orcid":false,"given":"Satya","family":"Dandekar","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,7,30]]},"reference":[{"key":"2433_CR1","doi-asserted-by":"publisher","first-page":"31","DOI":"10.1097\/QCO.0000000000000341","volume":"30","author":"DB Gootenberg","year":"2017","unstructured":"Gootenberg, D. 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