Context-dependent epithelial and immune programs shape intestinal resilience or vulnerability following prior colitis

BACKGROUND & AIMS: Prior intestinal inflammation can leave durable immune and epithelial alterations, yet how these changes influence responses to subsequent injury remains unclear. Infectious and sterile colitis share core features, including barrier disruption and cytokine secretion. We therefore investigated whether the nature of the initial inflammatory event shapes protection or susceptibility during later intestinal insult. METHODS: We used reciprocal mouse models of Citrobacter rodentium (CR) infection and dextran sodium sulphate (DSS)-induced colitis to define how prior infectious versus sterile colitis shapes secondary disease. Barrier integrity, immune cell populations, cytokine production, and susceptibility to wild-type and CR mutants that cause limited epithelial barrier disruption were assessed. RESULTS: Mice recovered from CR infection were protected against DSS-induced colitis, displaying reduced weight loss, preserved epithelial architecture, and lower inflammatory pathology. This protection required type III secretion system effector-mediated epithelial injury during primary infection and was associated with sustained IL-17A signalling, which contributed to the protective phenotype. In contrast, mice recovered from DSS colitis exhibited persistent epithelial barrier defects, chronic colonic neutrophilia, and heightened susceptibility to CR infection despite elevated IL-17A. Infection with CR mutants that cause minimal epithelial damage still resulted in severe disease in DSS-experienced mice, indicating that unresolved epithelial barrier dysfunction is a major contributor to vulnerability. CONCLUSIONS: The nature of the primary colitis is associated with distinct epithelial and immune programs that persist beyond resolution of inflammation. Infectious colitis is associated with a protective mucosal state where IL-17A is a key contributor in a broader protective response, whereas sterile colitis is associated with persistent epithelial barrier dysfunction that is associated with increased susceptibility to subsequent infection. These findings highlight how inflammatory history influences long-term intestinal resilience or vulnerability.