{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,12]],"date-time":"2026-10-12T20:24:10Z","timestamp":1791836650055,"version":"4.3.4"},"reference-count":31,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2025,5,20]],"date-time":"2025-05-20T00:00:00Z","timestamp":1747699200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:sec><jats:title>Purpose<\/jats:title><jats:p>Programmed death ligand 1 (PD-L1) is a potential target for autoimmune disease therapies. The gut microbiota plays a critical role in autoimmunity, and may influence therapeutic outcomes of immune therapies in cancer. However, the relationship between PD-L1 and gut microbiota in autoimmune conditions remains unclear. This study aims to investigate the effect of PD-L1 knockout on gut microbiota in an experimental autoimmune uveitis (EAU) model.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>EAU was induced via immunization with interphotoreceptor retinoid-binding protein peptide 651-670 (IRBP651-670) in either wild type (WT) or PD-L1 knockout (KO) C57BL\/6J female mice. Sham adjuvant was administered to WT or PD-L1 KO mice as healthy controls. The severity of EAU was evaluated through clinical evaluation and histopathological gradings. The characteristics of gut microbiota was analyzed using metagenomic sequencing.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Each group consisted of three biological replicates. The clinical and histopathological scores of EAU were significantly higher in KO_EAU mice than in WT_EAU mice. WT_EAU mice exhibited lower microbial richness than their healthy controls (WT mice), while PD-L1 KO in EAU mice (KO_EAU group) led to increased richness when compared to wild type EAU mice (WT_EAU group). EAU induced a reduction in the abundance of <jats:italic>Akkermansia muciniphila A<\/jats:italic> and an increased in <jats:italic>CAG-485<\/jats:italic> sp<jats:italic>002362485<\/jats:italic>. PD-L1 knockout in EAU led to an increased abundance of families Bacteroidaceae, Lachnospiraceae and Ruminococcaceae. EAU was associated with declining microbial tryptophan metabolism and up-regulated functions related to lipid and carbohydrate metabolism; PD-L1 knockout in EAU further increased the metabolism of glycan and biosynthesis of 3-deoxy-\u03b1-D-manno-2-octulosonate (Kdo), a key component of bacterial lipopolysaccharide (LPS).<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>Both EAU and PD-L1 knockout modulate gut microbiota, affecting microbial composition - particularly <jats:italic>Akkermansia<\/jats:italic>, <jats:italic>CAG-485<\/jats:italic>, Bacteroidaceae, Lachnospiraceae and Ruminococcaceae - and microbial functions such as lipid, carbohydrate and glycan metabolism.<\/jats:p><\/jats:sec>","DOI":"10.3389\/fimmu.2025.1600673","type":"journal-article","created":{"date-parts":[[2025,5,20]],"date-time":"2025-05-20T10:06:13Z","timestamp":1747735573000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":5,"title":["Influence of programmed death ligand 1 (PD-L1) knockout on gut microbiota in experimental autoimmune uveitis"],"prefix":"10.3389","volume":"16","author":[{"given":"Junxiang","family":"Gu","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yixian","family":"Ma","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qing","family":"Chang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ling","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2025,5,20]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1007\/s10238-015-0345-6","article-title":"Autoimmune uveitis: clinical, pathogenetic, and therapeutic features","volume":"16","author":"Prete","year":"2016","journal-title":"Clin Exp Med"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.1007\/s00281-019-00758-z","article-title":"Resolution of uveitis","volume":"41","author":"Wildner","year":"2019","journal-title":"Semin Immunopathol"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.1016\/j.cca.2010.04.017","article-title":"Uveitis: Mechanisms and recent advances in therapy","volume":"411","author":"Srivastava","year":"2010","journal-title":"Clin Chim Acta"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.1172\/JCI42440","article-title":"A look at autoimmunity and inflammation in the eye","volume":"120","author":"Caspi","year":"2010","journal-title":"J Clin Investigation"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.1016\/j.jaci.2011.07.008","article-title":"Regulation of TH17 and regulatory T cells in patients with Beh\u00e7et disease","volume":"128","author":"Direskeneli","year":"2011","journal-title":"J Allergy Clin Immunol"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.1016\/s1568-9972(03)00011-9","article-title":"An HLA-peptide mimics organ-specific antigen in autoimmune uveitis: its role in pathogenesis and therapeutic induction of oral tolerance","volume":"2","author":"Thurau","year":"2003","journal-title":"Autoimmun Rev"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.1016\/j.autrev.2016.09.001","article-title":"Dry eye disease and uveitis: A closer look at immune mechanisms in animal models of two ocular autoimmune diseases","volume":"15","author":"Bose","year":"2016","journal-title":"Autoimmun Rev"},{"key":"B8","doi-asserted-by":"publisher","DOI":"10.1007\/s10238-023-01028-x","article-title":"Autoimmune diseases and gut microbiota: a bibliometric and visual analysis from 2004 to 2022","volume":"23","author":"Zhang","year":"2023","journal-title":"Clin Exp Med"},{"key":"B9","doi-asserted-by":"publisher","DOI":"10.1016\/j.febslet.2014.03.019","article-title":"Relationship between gut microbiota and development of T cell associated disease","volume":"588","author":"Kosiewicz","year":"2014","journal-title":"FEBS Lett"},{"key":"B10","doi-asserted-by":"publisher","DOI":"10.3389\/fmicb.2022.902106","article-title":"The gut microbiota: master of puppets connecting the epidemiology of infectious, autoimmune, and metabolic disease","volume":"13","author":"Larsen","year":"2022","journal-title":"Front Microbiol"},{"key":"B11","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1000082107","article-title":"Proinflammatory T-cell responses to gut microbiota promote experimental autoimmune encephalomyelitis","author":"Lee","year":"2011","journal-title":"P Natl Acad Sci USA"},{"key":"B12","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0173032","article-title":"The dual role of short fatty acid chains in the pathogenesis of autoimmune disease models","volume":"12","author":"Mizuno","year":"2017","journal-title":"PloS One"},{"key":"B13","doi-asserted-by":"publisher","first-page":"551","DOI":"10.1126\/scitranslmed.aax2220","article-title":"Gut microbiota dysbiosis and altered tryptophan catabolism contribute to autoimmunity in lupus-susceptible mice","volume":"12","author":"Choi","year":"2020","journal-title":"Sci Transl Med"},{"key":"B14","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMra1514296","article-title":"Molecular and biochemical aspects of the PD-1 checkpoint pathway","volume":"375","author":"Boussiotis","year":"2016","journal-title":"New Engl J Med"},{"key":"B15","doi-asserted-by":"publisher","DOI":"10.1016\/j.jaut.2021.102702","article-title":"Cellular and molecular regulation of the programmed death-1\/programmed death ligand system and its role in multiple sclerosis and other autoimmune diseases","volume":"123","author":"Iba\u00f1ez-Vega","year":"2021","journal-title":"J Autoimmun"},{"key":"B16","doi-asserted-by":"publisher","DOI":"10.1084\/jem.20022119","article-title":"Critical role of the programmed death-1 (PD-1) pathway in regulation of experimental autoimmune encephalomyelitis","volume":"198","author":"Salama","year":"2003","journal-title":"J Exp Med"},{"key":"B17","doi-asserted-by":"publisher","DOI":"10.1210\/jc.2009-1404","article-title":"Programmed death ligand 1 (PD-L1) gene variants contribute to autoimmune Addison\u2019s disease and Graves\u2019 disease susceptibility","volume":"94","author":"Mitchell","year":"2009","journal-title":"J Clin Endocrinol Metab"},{"key":"B18","doi-asserted-by":"publisher","DOI":"10.1189\/jlb.3A1014-466RR","article-title":"Recovery from experimental autoimmune uveitis promotes induction of antiuveitic inducible Tregs","volume":"97","author":"Lee","year":"2015","journal-title":"J Leukoc Biol"},{"key":"B19","doi-asserted-by":"publisher","first-page":"56","DOI":"10.1186\/s40364-024-00607-8","article-title":"Gut microbiota and metabolites signatures of clinical response in anti-PD-1\/PD-L1 based immunotherapy of biliary tract cancer","volume":"12","author":"Zhu","year":"2024","journal-title":"Biomark Res"},{"key":"B20","doi-asserted-by":"publisher","DOI":"10.1158\/2326-6066.CIR-19-1014","article-title":"The gut microbiome is associated with clinical response to anti-PD-1\/PD-L1 immunotherapy in gastrointestinal cancer","volume":"8","author":"Peng","year":"2020","journal-title":"Cancer Immunol Res"},{"key":"B21","doi-asserted-by":"publisher","DOI":"10.1007\/978-1-60761-720-4_22","article-title":"Rodent models of experimental autoimmune uveitis","volume":"900","author":"Agarwal","year":"2012","journal-title":"Methods Mol Biol (Clifton N.J.)"},{"key":"B22","doi-asserted-by":"publisher","DOI":"10.1136\/gutjnl-2018-317836","article-title":"Alterations of gut microbiome in autoimmune hepatitis","volume":"69","author":"Wei","year":"2020","journal-title":"Gut"},{"key":"B23","doi-asserted-by":"publisher","DOI":"10.1128\/mBio.01548-14","article-title":"Intestinal dysbiosis associated with systemic lupus erythematosus","volume":"5","author":"Hevia","year":"2014","journal-title":"MBio"},{"key":"B24","doi-asserted-by":"publisher","DOI":"10.1111\/ijcp.14038","article-title":"Study of gut microbiome in Egyptian patients with autoimmune thyroid diseases","volume":"75","author":"El-Zawawy","year":"2021","journal-title":"Int J Clin Pract"},{"key":"B25","doi-asserted-by":"publisher","DOI":"10.1080\/19490976.2019.1700754","article-title":"Altered gut microbiome composition in patients with Vogt-Koyanagi-Harada disease","volume":"11","author":"Ye","year":"2020","journal-title":"Gut Microbes"},{"key":"B26","doi-asserted-by":"publisher","DOI":"10.1136\/annrheumdis-2019-215743","article-title":"Metagenome-wide association study of gut microbiome revealed novel aetiology of rheumatoid arthritis in the Japanese population","volume":"79","author":"Kishikawa","year":"2020","journal-title":"Ann Rheum Dis"},{"key":"B27","doi-asserted-by":"publisher","first-page":"9","DOI":"10.3390\/microorganisms10091820","article-title":"Bacterial compositional shifts of gut microbiomes in patients with rheumatoid arthritis in association with disease activity","volume":"10","author":"El","year":"2022","journal-title":"Microorganisms"},{"key":"B28","doi-asserted-by":"publisher","first-page":"135","DOI":"10.1186\/s40168-018-0520-6","article-title":"A metagenomic study of the gut microbiome in Behcet\u2019s disease","volume":"6","author":"Ye","year":"2018","journal-title":"Microbiome"},{"key":"B29","doi-asserted-by":"publisher","DOI":"10.1016\/j.jaut.2023.103055","article-title":"Gut microbial signatures and their functions in Behcet\u2019s uveitis and Vogt-Koyanagi-Harada disease","volume":"137","author":"Wang","year":"2023","journal-title":"J Autoimmun"},{"key":"B30","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.1001628","article-title":"IDO upregulates regulatory T cells via tryptophan catabolite and suppresses encephalitogenic T cell responses in experimental autoimmune encephalomyelitis","volume":"185","author":"Yan","year":"2010","journal-title":"J Immunol (Baltimore Md: 1950)"},{"key":"B31","doi-asserted-by":"publisher","DOI":"10.1111\/brv.12114","article-title":"Kdo2 -lipid A: structural diversity and impact on immunopharmacology","volume":"90","author":"Wang","year":"2015","journal-title":"Biol Rev Cambridge Philos Society"}],"container-title":["Frontiers in Immunology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2025.1600673\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,5,20]],"date-time":"2025-05-20T10:06:14Z","timestamp":1747735574000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2025.1600673\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,5,20]]},"references-count":31,"alternative-id":["10.3389\/fimmu.2025.1600673"],"URL":"https:\/\/doi.org\/10.3389\/fimmu.2025.1600673","relation":{},"ISSN":["1664-3224"],"issn-type":[{"value":"1664-3224","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,5,20]]},"article-number":"1600673"}}