The intestinal mucus creates a physical and chemical barrier that prevents direct contact between the luminal microbiota and the intestinal epithelium. Along the small intestine (SI), the mucus layer is relatively porous to different bacteria and thin. The colon (C) is equipped with a double mucus layer: the outer layer is relatively penetrable to bacteria; the inner layer is highly impenetrable to the microbiome (120–123). The intestinal epithelium comprises a single layer of heterogenous and highly specialized cell subtypes arising from common stem cell progenitors (Lgr5⁺ cells) at the bottom of the crypts. Intestinal epithelial cells (IECs) are tightly held together via strong cell adhesion proteins, forming a physical barrier that separates the contents of the intestinal lumen from the underlying lamina propria (124). Along with providing a physical barrier, cells within the intestinal epithelium produce and secrete molecules that help maintain intestinal homeostasis via a chemical barrier (124). Enterocytes (SI) and colonocytes (C) are the most abundant IECs. These cells recognize pathogen-associated molecular patterns via TLRs and NLRs (125–128). Enterocytes also express polymeric IgA receptors (pIgR) basolaterally, limiting intestinal permeability and susceptibility to intestinal inflammation and infections. Additional IEC types are goblet cells, which are responsible for the formation of the mucus layer through secretion of Muc2 mucin as well as other proteins; Paneth cells, which are found in the base of crypts within the SI that secrete antimicrobial peptides (AMP); tuft cells, which provide defense against helminth infections; and enteroendocrine cells, which secrete hormones. Intraepithelial lymphocytes (IELs) such as CD8⁺ T and γδ T cells are also found in the intestinal epithelium. Most immune cells are located in the lamina propria underneath the epithelial layer and in the gut-associated lymphoid tissues, which represent the key antigen sampling and adaptive immune inductive sites within the intestinal wall.