Immunotherapy restores therapeutic efficacy of fecal microbiome transplants to treat Clostridioides difficile.

Microbiome-based therapeutics to treat enteric bacterial infections requires stable engraftment of transplanted beneficial bacteria that target and eliminate the pathogen. 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 Clostridioides difficile infection in mice. In the absence of IL-10-mediated immunoregulation provided by Foxp3 + T reg cells, increased IFN-γ 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 C. difficile. FMT treatment success can be restored by antibody-mediated blockade of IFN-γ signaling, neutrophil depletion or inhibition of ROS/RNS production. Lastly, we developed an Il10 -mRNA-LNP immunotherapy to boost IL-10 signaling in FMT Non-Responsive mice and demonstrate that Il10 -mRNA-LNP administration is sufficient to restore FMT engraftment and subsequent resolution of C. difficile . Combined, these data support a mechanism by which IL-10 released by T reg cells limits IFN-γ mediated intestinal inflammation thereby promoting an intestinal microenvironment receptive to FMT engraftment and resolution of C. difficile . These data demonstrate that the host's immune status can be therapeutically modulated to improve microbiome-based approaches to treat infection.