Wnt2b Deficiency Causes Abnormal Intestinal Epithelial Development in Humans and Diminished Lgr5+ Stem Cells and Proliferation and in Humans and Mice

Background and aims: Wnt2b is an intestinal canonical Wnt which was previously thought to be fully redundant with other intestinal Wnts. Humans with Wnt2b deficiency have severe phenotypes, however, highlighting the critical importance of Wnt2b. We sought to understand why Wnt2b is critical for intestinal health. Methods: We investigated the intestinal health Wnt2b knock out (KO) mice at baseline. We also assessed the impacts of inflammatory challenge to the small intestine with anti-CD3e antibody and to the colon with dextran sodium sulfate (DSS) administration. In addition, we generated human intestinal organoids (HIOs) and enteroids from Wnt2b deficient patients for transcriptional and histologic analyses. Results: Wnt2b-/- mice were healthy and had normal small intestinal and colonic histology at baseline but decreased intestinal stem cells. Small intestinal response to anti-CD3e was similar to controls. The colons of Wnt2b KO mice were severely affected by DSS compared to controls, and this was due to impaired proliferative responses of stem cells during the early stages of injury. In contrast, HIOs generated from Wnt2b-deficient patients showed a developmental phenotype with abnormal epithelial organization and enriched mesenchymal signature and enteroids showed restricted growth. Conclusion: Wnt2b deficiency in mice more severely impacts the colon than the small intestine and is linked to impaired proliferative capacity. In human Wnt2b deficiency the epithelium is severely disorganized from the early stages of intestinal lineage specification in addition to having diminished intestinal stem cells and proliferation.