Credit: NPG

Pathobionts such as Clostridium difficile can cause severe disease when intestinal homeostasis is disrupted; however, the immune response to pathobionts is poorly defined. Reporting in Immunity, Inohara and colleagues show that interleukin-22 (IL-22) regulates the complement system to eliminate pathobionts that enter the systemic circulation.

C. difficile commonly overgrows in the intestine of patients who have received broad-spectrum antibiotics and this dysbiosis can lead to colitis. The authors investigated whether IL-22 — which controls the microbiota by enhancing the expression of antimicrobial peptides and by regulating the repair of damaged intestinal epithelium — has a role in C. difficile-induced colitis. Indeed, C. difficile infection of antibiotic-treated mice led to increased levels of IL-22 in the intestine, lungs and liver, and Il22−/− mice showed higher mortality rates than wild-type mice. Of note, Il22−/− and wild-type mice showed similar numbers of intestinal neutrophils and macrophages, and a comparable degree of intestinal damage after C. difficile infection. Thus, IL-22 contributes to protection against C. difficile through mechanisms that are independent of the recruitment of inflammatory cells.

Given that the composition of the faecal microbiota and the numbers of C. difficile were similar in wild-type and Il22−/− mice after infection, the authors tested whether IL-22 could have a role in the systemic clearance of commensal bacteria that translocate to extraintestinal organs after C. difficile infection. Indeed, Il22−/− mice showed increased numbers of commensal bacteria in the liver, spleen, kidneys and lungs compared with wild-type mice, but similar numbers of bacteria were found in faecal samples. Notably, treatment with ciprofloxacin — which kills many commensals but not C. difficile — reduced the number of translocated bacteria and thereby protected the Il22−/− mice from lethality induced by C. difficile infection. Hence, IL-22 is important for the clearance of bacteria that translocate to extraintestinal sites after C. difficile infection.

As intestinal pathobionts and nonpathobionts showed similar induction of cytotoxicity and cytokine induction in host tissue cells in vitro, the authors hypothesized that pathobiont strains evade host immune responses. In fact, pathobionts isolated from C. difficile-infected Il22−/− mice were more resistant to neutrophil killing and phagocytosis by macrophages than commensal strains. Phagocytosis was dependent on complement factor C3, and C3 deposition on C. difficile was lower than on commensal strains although pathobionts and nonpathobionts elicited similar levels of complement activation. These results indicate that pathobionts have increased resistance to complement-mediated phagocytosis.

injection of recombinant IL-22 induced C3 expression

Finally, the authors investigated whether IL-22 regulates the complement system. In accordance with IL-22-induced gene expression profiles, the authors found that the expression of C3 was increased in the liver and intestine after C. difficile infection but the induction of C3 was substantially lower in Il22−/− mice than in controls. Furthermore, injection of recombinant IL-22 induced C3 expression in wild-type mice and increased the expression of C3 in the liver of Il22−/− mice after C. difficile infection.

This study indicates that by regulating the expression of C3, IL-22 has a protective role in host defence against pathobionts that translocate systemically after C. difficile infection.