Rehydration rescues Il22-/- mice from lethal Citrobacter rodentium infection

Interleukin-22 (IL-22) is considered indispensable for host defence against Citrobacter rodentium (CR), with 100% mortality of Il22 ^−/− mice post infection. While IL-22 promotes epithelial barrier integrity and antimicrobial peptide production, the precise mechanism underlying Il22 ^−/− lethality remains unclear. Here, we show that Il22 ^−/− mice succumb to CR infection due to dehydration rather than uncontrolled bacterial burden or inability to regenerate intestinal epithelium. Proteomic analysis at 9 days post infection (dpi) revealed significant downregulation of ion transporters (Slc26a3, Aqp8, Ca2, Ca4, Slc5a8, Slc15a1) in Il22 ^−/− colonic epithelial cells, suggesting an association between IL-22 deficiency and impaired fluid-electrolyte balance. Fluid therapy (FT), initiated at 5 dpi and lasted for 2 weeks, fully rescued Il22 ^−/− mice, restoring survival without affecting bacterial burden, immune responses, or epithelial integrity. Recovered Il22 ^−/− mice exhibited epithelial regeneration and protection against reinfection, demonstrating that IL-22-independent pathways support long-term mucosal recovery. These findings overturn the long-standing paradigm that IL-22 is indispensable for host survival from CR infection, revealing that dehydration is the primary cause of mortality. Importantly, this study underscores the necessity of incorporating supportive therapies into preclinical infection models to better reflect physiological conditions and enhance translational relevance.