As the leading cause of hospital-associated infections, Clostridioides difficile is a serious public health concern. The host immune response is a major determinant of disease outcome, and previous works have identified specific components of the immune response that protect against disease or drive pathology. Cytokines are central to the regulation of the immune system and have been targeted for therapies in autoimmunity and oncology. Interleukin (IL)-22 promotes epithelial regeneration in colitis models, and previous works have shown that IL-22 is protective against C. difficile infection by enhancing complement-mediated clearance of disseminating bacteria and promoting the growth of commensal bacteria that outcompete C. difficile for nutrients. Interferon lambda (IFN-l) plays an important role in regulating immune responses at barrier sites, and recent works have shown that it is also protective in colitis models by promoting intestinal stem cell proliferation and regulating the inflammatory response. In this dissertation, we investigated the potential for therapeutic benefit of IL-22 induction by toll-like receptor 7 (TLR7) stimulation and additionally explored the role for IFN-l signaling in the protection against C. difficile infection. We found that oral administration of the TLR7 agonist R848 mitigated disease following C. difficile infection by stimulating the production of IL-22 from innate lymphoid cells (ILCs). This led to increased proliferation of intestinal stem cells, reducing toxin-mediated intestinal damage and limiting the systemic dissemination of C. difficile toxin. We also identified a critical role for IFN-l signaling in regulating the immune response to C. difficile infection. Together, our results demonstrate the utility of targeting protective cytokines for immunomodulation to combat C. difficile infection.