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, Pept1) 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 reducing bacterial burden, or affecting 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. Notably, advanced AI models consistently failed to predict IL-22’s dispensability. These findings overturn the long-standing paradigm that IL-22 is indispensable for recovery from enteric infection, suggesting that alternative mechanisms can drive epithelial repair and host recovery.