Clostridioides difficile infection (CDI) is a leading cause of hospital acquired infection, resulting from microbiome disruption and associated with high rates of recurrence and mortality. Our lab has shown the importance of IL-33 in acute infection; antibiotic-mediated reduction in IL-33 drives disease susceptibility, while recombinant IL-33 confers protection. Further, while epithelial barrier damage in the colon is a hallmark of CDI, IL-33 is protective of tissue damage. Administration of IL-33 results in increased expression of amphiregulin (AREG), a ligand for the epidermal growth factor receptor (EGFR), in the mouse colon. EGFR family signaling is canonically important for tissue repair and associated with type 2 immune responses, which are protective during CDI. Consistent with this, we have shown that administration of AREG is protective during acute CDI, while the inhibition of AREG promotes disease severity. Further, we have shown that ILC2s, a cell population well established as crucial in clearing C. difficile, are a major source of AREG in the mouse gut during CDI.
Beyond acute infection, we hypothesize that AREG/EGFR signaling mediates healing following fecal microbiota transplant (FMT) by promoting regeneration of the colonic epithelium. Our lab has shown by RNA sequencing that FMT restores IL-33 signaling, EGFR ligands including AREG, and EGFR associated tissue repair processes, mediated in part by Myc and mTORC1, in the colonic epithelium of human patients.
Our data suggest that FMT induced AREG signaling promotes a proliferative signature in intestinal epithelial cells, resulting in barrier restoration crucial to clearing CDI. We are using a mouse model of tamoxifen-inducible, tissue specific knockout of EGFR in intestinal epithelial cells – EGFRflox/flox-villin-creER2 – to investigate whether EGFR signaling in intestinal epithelial cells is required for healing following FMT.