Interleukin-37 exacerbates experimental colitis in an intestinal microbiome-dependent fashion

Background: Inflammatory bowel disease (IBD) involves complicated crosstalk between host immunity and the gut microbiome, whereas the mechanics of how they govern intestinal inflammation remain poorly understood. In this study, we investigated the contribution of environmental factors to shaping gut microbiota composition in colitis mice that were transgenic for human IL-37, a natural anti-inflammatory cytokine possessing pathogenic and protective functions related to microbiota alterations. Methods: Mice transgenic expressing human IL-37 (IL-37tg) were housed under conventional and specific pathogen-free (SPF) conditions to develop a mouse model of dextran sulfate sodium (DSS)-induced colitis. 16S ribosomal RNA sequencing was used for analyzing fecal microbial communities. The efficacy of microbiota in the development of colitis in IL-37tg mice was investigated after antibiotic treatment and fecal microbiota transplantation (FMT). The mechanism by which IL-37 worsened colitis was studied by evaluating intestinal epithelial barrier function, immune cell infiltration, the expression of diverse cytokines and chemokines, as well as activated signaling pathways. Results: We found that IL-37 overexpression aggravated DSS-induced colitis in conventional mice but protected against colitis in SPF mice. These conflicting results from IL-37tg colitis mice are ascribed to a dysbiosis of the gut microbiota in which detrimental bacteria increased in IL-37tg conventional mice. We further identified that the outcome of IL-37-caused colon inflammation is strongly related to intestinal epithelial barrier impairment caused by pathogenic bacteria, neutrophils, and NK cells recruitment in colon lamina propria and mesenteric lymph node to enhance inflammatory responses in IL-37tg conventional mice. Conclusions: The immunoregulatory properties of IL-37 are detrimental in the face of dysbiosis of the intestinal microbiota, which contributes to exacerbated IBD occurrences that are uncontrollable by the immune system, suggesting that depleting gut pathogenic bacteria or maintaining intestinal microbial and immune homeostasis could be a promising therapeutic strategy for IBD.