Gut microbial interaction networks control autoimmunity to neuroretina

Gut microbial interaction networks control autoimmunity to neuroretina | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Biological Sciences - Article Gut microbial interaction networks control autoimmunity to neuroretina Amy Zhang*, Reiko Horai*, Yingyos Jittayasothorn, Jonathan H. Badger, and 20 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-9528424/v1 This work is licensed under a CC BY 4.0 License Status: Under Review Version 1 posted You are reading this latest preprint version Abstract The gut microbiome influences the development of immune-mediated inflammatory diseases, including autoimmune uveitis, a sight-threatening ocular inflammation driven by retina-specific T cells1. Using a model of spontaneous autoimmune uveitis (sEAU) we showed that gut commensals provide immune stimuli that trigger disease2. Here we report that uveitis-promoting microbes are present in human gut flora and that colonization of germ-free (GF) mice with commensals from healthy human donors was sufficient to provoke disease. Severity of sEAU correlated with expansion of Akkermansia and contraction of short-chain fatty acid (SCFA)–producing Firmicutes, followed by decreased SCFA levels and a dominant gut Th1 effector response. Mechanistic gain-of-function experiments, enriching GF sEAU mice with Akkermansia, reproduced these microbiome, metabolite and immune phenotype shifts, and exacerbated disease, suggesting that Akkermansia promotes autoimmunity by outcompeting SCFA-producers and enhancing Th1-type responses. An inverse correlation between Akkermansia (Verrucomicrobia) and Firmicutes was also present in patients with uveitis, multiple sclerosis and Crohn’s disease. These findings reveal a stereotypic gut microbial interaction network that regulates systemic immune balance, and may represent an ecologically conserved mechanism through which the gut microbiome modulates autoimmune and inflammatory diseases. *Amy Zhang & Reiko Horai share equal contribution. Biological sciences/Immunology/Autoimmunity Biological sciences/Microbiology/Microbial communities/Microbiome Gut microbiome Autoimmune uveitis Akkermansia Short-chain fatty acids Th1 effector response human flora Full Text Additional Declarations There is NO Competing Interest. Supplementary Files nrreportingsummary20251234696A.pdf Reporting Summary Cite Share Download PDF Status: Under Review Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-9528424","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Biological Sciences - Article","associatedPublications":[],"authors":[{"id":631715467,"identity":"c1262a48-31fd-45df-b5a5-4f6c51680913","order_by":0,"name":"Amy Zhang*","email":"","orcid":"","institution":"Laboratory of Immunology, National Eye Institute, National Institutes of Health, Bethesda, MD, USA","correspondingAuthor":false,"prefix":"","firstName":"Amy","middleName":"","lastName":"Zhang*","suffix":""},{"id":631715468,"identity":"5ce8fe84-7065-4276-8c57-f87e5bc1c9a8","order_by":1,"name":"Reiko Horai*","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAArElEQVRIiWNgGAWjYBACAyA+2MBgkzh/RgJpWtIK2yRI0cLYwHC4kngt5tKHDx6cUXEepIX5xcc2IrRY9qUlHNxw5nZum/wDNsuZxGgxOMNjcPBhG1CLRAKbMc8ZorTwfwBqOZdOihYehoMb2w4kg/zymKeCKC1sBgdnnEkGaklsY5xBnBbmxx97KuyAUZl8+MMHAyK0IAHGNgnSNAAB8weStYyCUTAKRsGIAAA2Vj/smjnQMwAAAABJRU5ErkJggg==","orcid":"","institution":"Laboratory of Immunology, National Eye Institute, National Institutes of Health, Bethesda, MD, USA","correspondingAuthor":true,"prefix":"","firstName":"Reiko","middleName":"","lastName":"Horai*","suffix":""},{"id":631715469,"identity":"69b4e760-215d-452b-a12c-fb730945701b","order_by":2,"name":"Yingyos Jittayasothorn","email":"","orcid":"","institution":"Laboratory of Immunology, National Eye Institute, National Institutes of Health, Bethesda, MD, USA","correspondingAuthor":false,"prefix":"","firstName":"Yingyos","middleName":"","lastName":"Jittayasothorn","suffix":""},{"id":631715470,"identity":"adb41ea1-5add-432f-9a26-574a8603e0f4","order_by":3,"name":"Jonathan H. 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Using a model of spontaneous autoimmune uveitis (sEAU) we showed that gut commensals provide immune stimuli that trigger disease2. Here we report that uveitis-promoting microbes are present in human gut flora and that colonization of germ-free (GF) mice with commensals from healthy human donors was sufficient to provoke disease. Severity of sEAU correlated with expansion of Akkermansia and contraction of short-chain fatty acid (SCFA)–producing Firmicutes, followed by decreased SCFA levels and a dominant gut Th1 effector response. Mechanistic gain-of-function experiments, enriching GF sEAU mice with Akkermansia, reproduced these microbiome, metabolite and immune phenotype shifts, and exacerbated disease, suggesting that Akkermansia promotes autoimmunity by outcompeting SCFA-producers and enhancing Th1-type responses. An inverse correlation between Akkermansia (Verrucomicrobia) and Firmicutes was also present in patients with uveitis, multiple sclerosis and Crohn’s disease. These findings reveal a stereotypic gut microbial interaction network that regulates systemic immune balance, and may represent an ecologically conserved mechanism through which the gut microbiome modulates autoimmune and inflammatory diseases.\u003c/p\u003e\n\u003cp\u003e\u003cbr\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e*Amy Zhang \u0026amp; Reiko Horai share equal contribution.\u003c/strong\u003e\u003c/p\u003e","manuscriptTitle":"Gut microbial interaction networks control autoimmunity to neuroretina","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2026-05-04 12:06:44","doi":"10.21203/rs.3.rs-9528424/v1","editorialEvents":[],"status":"published","journal":{"display":false,"email":"[email protected]","identity":"nature","isNatureJournal":true,"hasQc":false,"allowDirectSubmit":false,"externalIdentity":"nature","sideBox":"Learn more about [Nature](http://www.nature.com/nature/)","snPcode":"","submissionUrl":"","title":"Nature","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"ejp","reportingPortfolio":"Nature","inReviewEnabled":true,"inReviewRevisionsEnabled":false}}],"origin":"","ownerIdentity":"7ffe6d53-ed3e-403a-8e9a-91b88cff6fa0","owner":[],"postedDate":"May 4th, 2026","published":true,"recentEditorialEvents":[{"type":"editorInvitedReview","content":"This content is not available.","date":"2026-05-11T11:25:07+00:00","index":3,"fulltext":"This content is not available."},{"type":"reviewerAgreed","content":"This content is not available.","date":"2026-05-06T08:58:39+00:00","index":3,"fulltext":"This content is not available."},{"type":"reviewerAgreed","content":"This content is not available.","date":"2026-05-05T09:11:40+00:00","index":2,"fulltext":"This content is not available."},{"type":"reviewerAgreed","content":"This content is not available.","date":"2026-05-04T12:51:23+00:00","index":1,"fulltext":"This content is not available."},{"type":"reviewersInvited","content":"4","date":"2026-04-29T11:17:55+00:00","index":"","fulltext":""}],"rejectedJournal":[],"revision":"","amendment":"","status":"under-review","subjectAreas":[{"id":67240116,"name":"Biological sciences/Immunology/Autoimmunity"},{"id":67240117,"name":"Biological sciences/Microbiology/Microbial communities/Microbiome"}],"tags":[],"updatedAt":"2026-05-04T12:06:44+00:00","versionOfRecord":[],"versionCreatedAt":"2026-05-04 12:06:44","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-9528424","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-9528424","identity":"rs-9528424","version":["v1"]},"buildId":"XKTyCvWXoU3ODBz1xrDgd","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}