WNT2B Deficiency Causes Enhanced Susceptibility to Colitis Due to Increased Inflammatory Cytokine Production

Background and aims Humans with WNT2B deficiency have severe intestinal disease, including significant inflammatory injury, highlighting a critical role for WNT2B. We sought to understand how WNT2B contributes to intestinal homeostasis. Methods We investigated the intestinal health of Wnt2b knock out (KO) mice. We assessed the baseline histology and health of the small intestine and colon, as well as the impact of inflammatory challenge using dextran sodium sulfate (DSS). We also evaluated human intestinal tissue. Results Mice with WNT2B deficiency had normal baseline histology but enhanced susceptibility to DSS colitis due to an increased early injury response. While ISC markers were decreased, epithelial proliferation was similar to controls. Wnt2b KO mice showed an enhanced inflammatory signature after DSS treatment. Wnt2b KO colon and human WNT2B-deficient organoids both had increased levels of CXCR4 and IL6, and biopsy tissue from humans showed increased neutrophils. Conclusion WNT2B is important for regulation of inflammation in the intestine. Absence of WNT2B leads to increased expression of inflammatory cytokines and increased susceptibility to gastrointestinal inflammation, particularly in the colon.