Myeloid vitamin D receptor regulates Paneth cells and microbial homeostasis

Cross talk between immune cells and the intestinal crypt is critical in maintaining intestinal homeostasis. Recent studies highlight the direct impact of vitamin D receptor (VDR) signaling on intestinal and microbial homeostasis. However, the tissue-specific role of immune VDR signaling is not fully understood. Here, we generated a myeloid-specific VDR knockout (VDR^ΔLyz ) mouse model and used a macrophage/enteroids coculture system to examine tissue-specific VDR signaling in intestinal homeostasis. VDR^ΔLyz mice exhibited small intestine elongation and impaired Paneth cell in maturation and localization. Coculture of enteroids with VDR^-/- macrophages increased the delocalization of Paneth cells. VDR^ΔLyz mice exhibited significant changes in the microbiota taxonomic and functional files, and susceptibility to Salmonella infection. Interestingly, loss of myeloid VDR impaired Wnt secretion in macrophages, thus inhibiting crypt β-catenin signaling and disrupting Paneth cell differentiation in the epithelium. Taken together, our data have demonstrated that myeloid cells regulate crypt differentiation and the microbiota in a VDR-dependent mechanism. Dysregulation of myeloid VDR led to high risks of colitis-associated diseases. Our study provided insight into the mechanism of immune/Paneth cell cross talk in regulating intestinal homeostasis.