A New Hypothesis for Clostridioides difficile Infection Vulnerability: Epithelial Damage and Inflammatory Repair May Prime the Host for Infection

Clostridioides difficile can persist within the colon across a spectrum ranging from colonization to severe infection (CDI). Although progression to CDI is strongly associated with antibiotic exposure and colonic inflammation, current models do not fully explain why hosts with similar risk factors can differ in their vulnerability to CDI. Here, it is hypothesized that epithelial damage, inflammation, and regeneration represent sequential stages in the development of CDI susceptibility. Specifically, epithelial damage associated with established CDI risk factors initiates inflammatory repair, generating regenerative epithelial states that are enriched for C. difficile toxin receptors and intracellular host targets while simultaneously creating a colonic environment favorable for pathogenesis. This hypothesis is supported by published evidence, secondary analyses of single-cell transcriptomic data from antibiotic-treated human colonoids, and extension of the model to additional bacterial and viral pathogens that target the inflamed colon. If validated experimentally, this framework may improve understanding of host susceptibility to CDI and provide a broader model for epithelial regeneration as a determinant of infection vulnerability within the inflamed colon.