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The host factors that determine whether a microbiome transplant engrafts remain largely unresolved. Here we demonstrate that Interleukin-10 (IL-10) signaling deficiency leads to impaired fecal microbiota transplantation (FMT) engraftment and failure to resolve\n                  <jats:italic>Clostridioides difficile<\/jats:italic>\n                  infection in mice. In the absence of IL-10-mediated immunoregulation provided by Foxp3\n                  <jats:sup>+<\/jats:sup>\n                  T\n                  <jats:sub>reg<\/jats:sub>\n                  cells, increased IFN-\u03b3 signaling in the intestine leads to elevated production of reactive oxygen\/nitrogen species (ROS\/RNS) by neutrophils and epithelial cells that supports the growth of inflammation-tolerant microbes, inhibits FMT engraftment, and impairs resolution of\n                  <jats:italic>C. difficile.<\/jats:italic>\n                  FMT treatment success can be restored by antibody-mediated blockade of IFN-\u03b3 signaling, neutrophil depletion or inhibition of ROS\/RNS production. Lastly, we developed an\n                  <jats:italic>Il10<\/jats:italic>\n                  -mRNA-LNP immunotherapy to boost IL-10 signaling in FMT Non-Responsive mice and demonstrate that\n                  <jats:italic>Il10<\/jats:italic>\n                  -mRNA-LNP administration is sufficient to restore FMT engraftment and subsequent resolution of\n                  <jats:italic>C. difficile<\/jats:italic>\n                  . Combined, these data support a mechanism by which IL-10 released by T\n                  <jats:sub>reg<\/jats:sub>\n                  cells limits IFN-\u03b3 mediated intestinal inflammation thereby promoting an intestinal microenvironment receptive to FMT engraftment and resolution of\n                  <jats:italic>C. difficile<\/jats:italic>\n                  . These data demonstrate that the host\u2019s immune status can be therapeutically modulated to improve microbiome-based approaches to treat infection.\n                <\/jats:p>","DOI":"10.64898\/2026.09.17.752434","type":"posted-content","created":{"date-parts":[[2026,9,23]],"date-time":"2026-09-23T22:35:18Z","timestamp":1790202918000},"source":"Crossref","is-referenced-by-count":0,"title":["Immunotherapy restores therapeutic efficacy of fecal microbiome transplants to treat\n                  <i>Clostridioides difficile<\/i>"],"prefix":"10.64898","author":[{"given":"Subham","family":"Mridha","sequence":"first","affiliation":[{"name":"Department of Microbiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Md Zahidul","family":"Alam","sequence":"additional","affiliation":[{"name":"Department of Microbiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA"},{"name":"Department of Pathology and Laboratory Medicine, Brody School of Medicine, East Carolina University, Greenville NC, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joshua E.","family":"Denny","sequence":"additional","affiliation":[{"name":"Department of Microbiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ellie N.","family":"Hulit","sequence":"additional","affiliation":[{"name":"Department of Microbiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jeffrey R.","family":"Maslanka","sequence":"additional","affiliation":[{"name":"Department of Microbiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA"},{"name":"Immunology Graduate Group, University of Pennsylvania, Philadelphia, Pennsylvania, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nontokozo V.","family":"Mdluli","sequence":"additional","affiliation":[{"name":"Department of Microbiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Minh","family":"Tran-Ha","sequence":"additional","affiliation":[{"name":"Department of Microbiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kevin S","family":"Mears","sequence":"additional","affiliation":[{"name":"Department of Microbiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daivon D.","family":"Brown","sequence":"additional","affiliation":[{"name":"Department of Microbiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mohamad-Gabriel","family":"Alameh","sequence":"additional","affiliation":[{"name":"Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA"},{"name":"Penn Institute for RNA Innovation, Perelman School of Medicine; 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