Deficiency of IL-22-binding protein enhances the ability of the gut microbiota to protect against enteric pathogens

Interleukin 22 (IL - 22) promotes intestinal barrier integrity, stimulating epithelial cells to enact defense mechanisms against enteric infections, including the production of antimicrobial peptides. IL - 22 binding protein (IL - 22BP) is a soluble decoy encoded by the Il22ra2 gene that decreases IL - 22 bioavailability, attenuating IL - 22 signaling. The impact of IL - 22BP on gut microbiota composition and functioning is poorly understood. We found that Il22ra2 -/- mice are better protected against Clostridioides difficile and Citrobacter rodentium infections. This protection relied on IL - 22 - induced antimicrobial mechanisms before the infection occurred, rather than during the infection itself. Indeed, the gut microbiota of Il22ra2 -/- mice mitigated infection of wild - type (WT) mice when transferred via cohousing or by cecal microbiota transplantation. Indicator species analysis of WT and Il22ra2 -/- mice with and without cohousing disclosed that IL22BP deficiency yields a gut bacterial composition distinct from that of WT mice. Manipulation of dietary fiber content, measurements of intestinal short - chain fatty acids and oral treatment with acetate disclosed that resistance to C. difficile infection is related to increased production of acetate by Il22ra2 -/- - associated microbiota. Together, these findings suggest that IL - 22BP represents a potential therapeutic target for those at risk for or with already manifest infection with this and perhaps other enteropathogens.