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

Interleukin-22 (IL-22) is considered indispensable for host defence against Citrobacter rodentium, with 100% mortality of Il22^-/- mice. While IL-22 promotes epithelial barrier integrity and production of antimicrobial peptides, the precise mechanism underlying lethality remains unclear. Here, we show that following C. rodentium infection Il22^-/- mice succumb due to dehydration, rather than failure to control bacterial burden or regenerate damaged intestinal epithelium. Proteomic and gene expression analysis reveal greater enterocyte depletion in C. rodentium-infected Il22^-/- mice, resulting in significant reductions in ion transporter abundances. We show that while not reducing bacterial load, improving the gut barrier integrity, or affecting immune responses, fluid therapy (FT) fully rescues Il22^-/- mice by correcting systemic dehydration. Survival is associated with locally increased Reg3b, IL-17F and IL-10 levels, suggesting activation of compensatory pathways that potentially support recovery in the absence of IL-22. Recovered Il22^-/- mice exhibit epithelial cell regeneration and tissue physiology similarly to C. rodentium-infected Il22^+/+ mice. These findings suggest that dehydration is the primary cause of mortality in Il22^-/- mice and reveal that IL-22 prevent this outcome by preserving epithelial integrity and fluid-ion absorption. Importantly, this study underscores the necessity of incorporating supportive therapies into preclinical infection models to better reflect physiological settings and improve their relevance in modelling human disease.