IL-22 and complement mediate systemic elimination of pathobionts

▸ Hasegawa M, Yada S, Liu, MZ, et al. Interleukin-22 regulates the complement system to promote resistance against pathobionts after pathogen-induced intestinal damage. Immunity 2014;41:620–32.

While the intestinal microbiota provides many benefits to the host, it also contains potentially dangerous species called pathobionts that play a critical role in disease development, particularly in immunocompromised hosts. When the healthy microbiota is disrupted, an accumulation of pathobionts and disease may result. Clostridium difficile, a Gram-positive anaerobic bacterium, overgrows in patients receiving broad-spectrum antibiotics and causes diarrhoea and life-threatening pseudomembranous colitis. Overgrowth of this bacteria is normally prevented by commensals when the immune system is intact. Recent studies indicate that pathobionts that have breached the compromised epithelial barrier during C. difficile infection and accumulate in extraintestinal organs and tissues contribute to disease pathogenesis and mortality. In this study, the authors investigate the immune mechanisms that protect the host against pathobionts. Using a well-established infection model and interleukin (IL)-22-deficient mice, the authors identified a protective role for IL-22 against C. difficile infection. The authors orally infected IL-22-deficient mice with C. difficile and observed increased translocation of enterobacterial pathobionts to extraintestinal organs, associated with increased mortality. These pathobionts were highly pathogenic when present in the blood, which was associated with their resistance to complement-mediated phagocytosis and killing by phagocytes. The mice were rescued by selective antibiotic treatment that removed commensal bacteria, but not C. difficile. The intestinal burden of C. difficile and the degree of intestinal damage were not altered in infected IL-22-deficient mice. Rather, IL-22 increased the expression of complement C3, which contributed to the clearance of certain pathobionts from peripheral organs. Altogether, this study highlights an important role for IL-22 in limiting pathobiont-induced systemic disease and identifies a mechanism by which pathobionts can escape host immunity. From a clinical standpoint, …