The mucus layer, sitting atop the intestinal epithelium, is a key component of the mucosal barrier and also is both a source of nutrients and a microhabitat for bacterial members of the microbiota. The epithelial crypt-villus axis differs between the small and large intestine. The populating enterocyte populations vary as well. M cells and Paneth cells are restricted to the small intestine. Intestinal immune cells that mediate tolerance-inducing responses and participate in host defense, localize to inductive sites. These sites include Peyers patches (small intestine), lymphoid follicles, and colonic patches (large intestine) and effector sites such as the epithelium and underlying lamina propria.

The commensal microbiota, intestinal epithelial cells, and intestinal immune cells engage in a complex crosstalk. Epithelial cells, M cells, and dendritic cells (DCs) can directly sense and sample the intestinal contents and communicate information about the microbiota to other subsets of immune cells. The Toll-like receptors are one class of microbe-sensing molecules expressed by epithelial cells, M cells and DCs. Cytokines, chemokines, and host and microbial metabolites are key molecular mediators of intestinal homeostasis that influence responses of both host and microbe.