The intestine is a unique organ which is continuously exposed to various antigens such as food-derived antigens, as well as both commensal and pathogenic bacteria, under physiological conditions. Intestinal epithelial cells constitute both a physical and an immunological barrier system against this vast array of antigens. The α1,2-fucose-conjugated carbohydrate chains expressed on intestinal epithelial cells are physiologically and immunologically important and are regulated by type III innate lymphoid cells (ILC3). IL-22-producing ILC3 induce anti-microbial molecules such as RegIIIγ, contributing to the formation of a safeguard system for homeostasis of commensal flora in the intestinal lumen, containment of Alcaligenes in Peyer's patches, and establishment of a defensive platform against infection by pathogenic bacteria. The other intestinal innate immune cell type, the mast cell, is also a critical player. Mast cells are activated by ATP produced in host cells and commensal flora, predisposing to the development of inflammatory bowel diseases. Furthermore, mucosal mast cells regulate the differentiation of follicular helper T cells through ATP signals and contribute to subsequent IgA affinity maturation and regulating the homeostasis of commensal microflora.