Interleukin-22 Regulates the Complement System to Promote Resistance against Pathobionts after Pathogen-Induced Intestinal Damage

•An enteropathogen induces translocation of pathobionts to extraintestinal organs•IL-22 is critical for systemic elimination of translocated pathobionts•Complement-resistant enterobacterial pathobionts induce host complication•IL-22 augments expression and binding of C3 to enterobacterial pathobionts

SummaryPathobionts play a critical role in disease development, but the immune mechanisms against pathobionts remain poorly understood. Here, we report a critical role for interleukin-22 (IL-22) in systemic protection against bacterial pathobionts that translocate into the circulation after infection with the pathogen Clostridium difficile. Infection with C. difficile induced IL-22, and infected Il22−/− mice harbored high numbers of pathobionts in extraintestinal organs despite comparable pathogen load and intestinal damage in mutant and wild-type mice. Pathobionts exhibited increased resistant against complement-mediated phagocytosis, and their intravenous administration resulted in high animal mortality. Selective removal of translocated commensals rescued Il22−/− mice, and IL-22 administration enhanced the elimination of pathobionts. Mechanistically, IL-22 augmented bacterial phagocytosis by increasing the expression and bacterial binding of complement C3. Our study demonstrates an unexpected role for IL-22 in controlling the elimination of pathobionts that enter the systemic circulation through the regulation of the complement system.