Clostridioides difficile is an intestinal bacterial pathogen that can cause diarrhea, pseudomembranous colitis, and sepsis in populations that exhibit gut dysbiosis, or a disruption of the indigenous gut microbiome. The hallmark of C. difficile infection (CDI) is a robust host inflammatory response characterized by tissue damage to the intestinal epithelium. Simultaneously, host inflammatory processes are required for defense against CDI and can predict clinical disease severity. Additionally, the extent to which CDI impacts epithelial functions has not been explored in detail and may provide possible therapeutic functions through harnessing regenerative functions. The first part of this thesis explores this immunological conundrum in acute CDI, and the latter explores effects of CDI on intestinal epithelial cells, specifically, intestinal stem cells and related regenerative functions. In Chapter 2, we found that host-derived microbiota-dependent inflammation, as in loss of IL-10 signaling, can mediate host defenses against CDI via IL-22 signaling in a mouse model of infection. Immunological tuning may thus serve as a possible prophylactic strategy in populations susceptible to CDI. In Chapter 3, we found that the intestinal stem cell population is reduced in vivo and their regenerative functions, as measured by organoid formation, are dramatically impaired during CDI. Thus, restoring intestinal stem cell functions, for example via IL-22 modulating treatments, is a possible therapeutic approach to prevent damage to or fortify the intestinal epithelial barrier. Collectively, these data support more precise investigation into immunoregulatory and proinflammatory circuits that could attenuate clinical CDI and the critical role of intestinal epithelial cell types, especially intestinal stem cells, in C. difficile pathogenesis.