NOD2 promotes protective responses and recovery from Candida tropicalis infection in dextran sodium sulfate (DSS) colitic mice

Although it is well established that the gut microbiome plays an important role in GI health and disease, recent studies also underscore the complexity and contribution of intestinal fungal communities by, for example, promoting dysbiosis in mouse models of colitis and Crohn’s disease patients, which both have higher levels of Candida tropicalis (Ct) vs controls. Also, proteins encoded by IBD susceptibility loci, such as pattern recognition receptors (PRRs), not only recognize bacterial products, but in the case of NOD2, also detects the fungal cell wall component, chitin. Yet, how PRRs regulate intestinal fungal immunity and how fungi impact colitis is poorly understood. Herein, we show that while Ct infection does not exacerbate colitis in WT controls, Nod2^−/− mice show a higher fungal burden and delayed recovery after DSS challenge, indicating NOD2’s protective role and ability to promote fungal clearance during experimental colitis. In the absence of NOD2, epithelial barrier function is compromised, with increased immune cell infiltration and muscle wall thickening. Nod2^−/− mice specifically infected with Ct, and not other commensal species, express reduced colonic IL-6 (promotes Th17 and ILC3s), as well as IL-22 and IL-17 (cytokines that maintain epithelial barrier integrity), and show a decreased frequency of MLN-derived IL-17⁺ ILC3s vs WT, suggesting that delay in fungal clearance and recovery from colitis in Nod2^−/− mice may be due to the inability to mount protective type 3 immune responses. Overall, these findings reveal that opportunistic fungal infections during colitis impede gut mucosal healing, and that NOD2 may not only impact the gut microbiome, but also the mycobiome, possibly through an IL-17-mediated mechanism.