Host immunity and recurrent <i>Clostridioides difficile</i> infection: a comprehensive review

Clostridioides difficile is a leading cause of healthcare-associated gastrointestinal infection, with outcomes that range widely in severity. The pathogenesis of C. difficile is driven by virulence factors that induce colonic inflammation and epithelial damage. This illness is categorized as an urgent threat, and in recent years, its prevalence has increased, with recurrent episodes occurring in approximately 15–35% of cases. The life cycle of C. difficile infection (CDI) is multifactorial and strongly influenced by antibiotic exposure, host immune responses, the gut microbiota, and microbial metabolites. Disruption of intestinal homeostasis gradually alters the ecological niches of C. difficile and the immunological landscape of the disease. In addition to these risk factors, recurrent C. difficile infection (rCDI) can be exacerbated by certain ‘hypervirulent’ strains that are more difficult to eradicate. As in many infectious diseases, host immunological responses, particularly in rCDI, appear to play a crucial role in determining recovery versus recurrence. Recent strategies to address this problem include fecal microbiota transplantation (FMT) and novel therapeutic approaches such as polyclonal and monoclonal antibodies. Nevertheless, the immunological mechanisms underlying rCDI remain incompletely understood. A deeper insight into how the immune response develops and functions during rCDI may facilitate the identification of new therapeutic targets. In this review, we summarize current knowledge on C. difficile recurrence and highlight the host immune response in the context of rCDI.