Upfront fecal microbiota transplantation for the management of immune checkpoint inhibitor mediated diarrhea and colitis

Upfront fecal microbiota transplantation for the management of immune checkpoint inhibitor mediated diarrhea and colitis | 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 Upfront fecal microbiota transplantation for the management of immune checkpoint inhibitor mediated diarrhea and colitis Yinghong Wang, Christopher Fan, Krishnavathana Varatharajalu, and 29 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-5455153/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 Introduction : Immune checkpoint inhibitors have revolutionized cancer therapy; however, adverse events from an unchecked immune system such as immune checkpoint inhibitor mediated diarrhea and colitis (IMDC) can develop. Fecal microbiota transplantation (FMT) remains an option for patients with refractory colitis, but has not been tested in an upfront setting. Methods : From an open-label, phase I/II clinical trial (NCT0403861) starting June 2021, we report an analysis of adult patients with IMDC treated with upfront FMT. We performed fecal shotgun metagenomic sequencing, metabolomic, transcriptomic and immunofluorescence profiling pre-FMT and post-FMT and and plasma biomarkers of inflamamtion and immune response pre-FMT to predict response. Results : 13 patients were treated with FMT, of which 11 (84.6%) achieved clinical response with a median time to clinical improvement of 1(1-5) days. Among responders sequenced with baseline and follow-up (n = 8), 6 patients (75%) had an increase in alpha diversity post-FMT. Notably, in responders Lacrimispora amygdalina and Alistipes shahii increased independently at both 2 and 4 weeks post FMT. Interestingly, aspartic and propionic acid decreased post-FMT (p < 0.05). Using multiplex immunohistochemical immunofluorescence staining of samples obtained at presentation, we determined that total CK+ and CK+Ki67+ cell populations were reduced in non-responder patients. Additionally, there was a trend toward lower pre- and post-FMT CD20+, CD20+Ki67+, CD4+FOXP3+, and CD8+FOXP3+ cell populations in non-responder patients. Immune cell-type abundance scores showed increased plasma cells, neutrophils, (M1 and M2) macrophages, memory activated and resting memory CD4+ T cells , CD8+ T cells,T follicular helper (Tfh) cells, regulatory T cells (Treg), in pre-FMT samples which all decreased dramatically in post-FMT samples, likely related to response to FMT. Non-responders had lower baseline plasma GDF2, TLR3, CCL22, and FGF21 and higher baseline plasma CXCL14, OSM, IL-1β and IFNG. Conclusion : FMT is a promising front-line therapeutic option for patients who develop IMDC with high efficacy and favorable safety profile. Additional microbiome, blood and tissue analysis provides insights in future directions of potential mechanisms and targets for development of novel therapeutic intervention. Biological sciences/Microbiology/Microbial communities/Microbiome Biological sciences/Immunology/Mucosal immunology Fecal microbiota transplantation (FMT) immune checkpoint inhibitor mediated diarrhea and colitis (IMDC) checkpoint inhibitor toxicity Full Text Additional Declarations There is NO Competing Interest. Supplementary Files 663SupplementarytablenoMRNWithDonorsNewversion.docx SupplementaryTable1 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. 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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-5455153","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Biological Sciences - Article","associatedPublications":[],"authors":[{"id":380477747,"identity":"0655f62f-d6b6-4f2f-ad94-131e50028073","order_by":0,"name":"Yinghong 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colitis","fulltext":[],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":false,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":true,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":true,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":true,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"nature-portfolio","isNatureJournal":true,"hasQc":false,"allowDirectSubmit":false,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"","title":"Nature Portfolio","twitterHandle":"","acdcEnabled":false,"dfaEnabled":false,"editorialSystem":"ejp","reportingPortfolio":"","inReviewEnabled":true,"inReviewRevisionsEnabled":false},"keywords":"Fecal microbiota transplantation (FMT), immune checkpoint inhibitor mediated diarrhea and colitis (IMDC), checkpoint inhibitor toxicity","lastPublishedDoi":"10.21203/rs.3.rs-5455153/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-5455153/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eIntroduction\u003c/strong\u003e: Immune checkpoint inhibitors have revolutionized cancer therapy; however, adverse events from an unchecked immune system such as immune checkpoint inhibitor mediated diarrhea and colitis (IMDC) can develop. Fecal microbiota transplantation (FMT) remains an option for patients with refractory colitis, but has not been tested in an upfront setting.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMethods\u003c/strong\u003e: From an open-label, phase I/II clinical trial (NCT0403861) starting June 2021, we report an analysis of adult patients with IMDC treated with upfront FMT. We performed fecal shotgun metagenomic sequencing, metabolomic, transcriptomic and immunofluorescence profiling pre-FMT and post-FMT and and plasma biomarkers of inflamamtion and immune response pre-FMT to predict response.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eResults\u003c/strong\u003e: 13 patients were treated with FMT, of which 11 (84.6%) achieved clinical response with a median time to clinical improvement of 1(1-5) days. Among responders sequenced with baseline and follow-up (n = 8), 6 patients (75%) had an increase in alpha diversity post-FMT. Notably, in responders Lacrimispora amygdalina and Alistipes shahii increased independently at both 2 and 4 weeks post FMT. Interestingly, aspartic and propionic acid decreased post-FMT (p \u0026lt; 0.05). Using multiplex immunohistochemical immunofluorescence staining of samples obtained at presentation, we determined that total CK+ and CK+Ki67+ cell populations were reduced in non-responder patients. Additionally, there was a trend toward lower pre- and post-FMT CD20+, CD20+Ki67+, CD4+FOXP3+, and CD8+FOXP3+ cell populations in non-responder patients. Immune cell-type abundance scores showed increased plasma cells, neutrophils, (M1 and M2) macrophages, memory activated and resting memory CD4+ T cells , CD8+ T cells,T follicular helper (Tfh) cells, regulatory T cells (Treg), in pre-FMT samples which all decreased dramatically in post-FMT samples, likely related to response to FMT. Non-responders had lower baseline plasma GDF2, TLR3, CCL22, and FGF21 and higher baseline plasma CXCL14, OSM, IL-1β and IFNG.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConclusion\u003c/strong\u003e: FMT is a promising front-line therapeutic option for patients who develop IMDC with high efficacy and favorable safety profile. Additional microbiome, blood and tissue analysis provides insights in future directions of potential mechanisms and targets for development of novel therapeutic intervention.\u003c/p\u003e","manuscriptTitle":"Upfront fecal microbiota transplantation for the management of immune checkpoint inhibitor mediated diarrhea and colitis","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-01-13 02:08:36","doi":"10.21203/rs.3.rs-5455153/v1","editorialEvents":[],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"nature-communications","isNatureJournal":true,"hasQc":false,"allowDirectSubmit":false,"externalIdentity":"NCOMMS","sideBox":"Learn more about [Nature Communications](http://www.nature.com/ncomms/)","snPcode":"","submissionUrl":"https://mts-ncomms.nature.com/","title":"Nature Communications","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"ejp","reportingPortfolio":"Nature Communications","inReviewEnabled":true,"inReviewRevisionsEnabled":false}}],"origin":"","ownerIdentity":"4cdfa5d4-411b-4a2a-b10a-6f73be0a8ba5","owner":[],"postedDate":"January 13th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"under-review","subjectAreas":[{"id":40520378,"name":"Biological sciences/Microbiology/Microbial communities/Microbiome"},{"id":40520379,"name":"Biological sciences/Immunology/Mucosal immunology"}],"tags":[],"updatedAt":"2025-08-22T13:05:50+00:00","versionOfRecord":[],"versionCreatedAt":"2025-01-13 02:08:36","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-5455153","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-5455153","identity":"rs-5455153","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}