Recent studies have highlighted the importance of cross-talk between our immune systems and our gut microbiota, the complex community of over 100 trillion commensal microorganisms (bacteria, archaea, fungi, and protozoans) that resides in the human gastrointestinal tract and which numbers about 10 times the total cells in the human body (1). The gut microbiota contribute profoundly to the function and structure of the gastrointestinal mucosa, establishing a robust network that provides us with increased digestive capacity for essential nutrients and non-nutrient factors, such as vitamins. It also protects us from infection by pathogenic microbes (2). Dysbiosis, or unbalanced shifts in the composition of the microbiota, may contribute to inflammatory bowel disease and necrotizing enterocolitis in premature infants, and are also increasingly linked to rheumatoid arthritis, multiple sclerosis, diabetes, and asthma, as well as obesity (2). The gastrointestinal tract, which is the largest mucosal surface in the body (with a surface area of about 300 m3 in adults), is lined by a single layer of polarized columnar epithelial cells firmly bound to one another by tight junctions and covered by a stratified mucus layer, that together provide a barrier containing the microbiota within the lumen. Cross-talk between the microbiota and immune cells of the mucosa [dendritic cells (DCs) and macrophages], communicated through this barrier, has regulated the evolution and development of our immune systems (3–6) and differentiated our ability to recognize and distinguish between beneficial and pathogenic microbes. Microbe recognition is achieved through epithelial cell and immune cell expression of germline-encoded pattern recognition receptors (PRRs) that bind discrete microbe-associated molecular patterns (MAMPS) expressed by both commensal and pathogenic microbes (7–9). PRR expression is tightly regulated on the apical and basolateral surfaces of the epithelial cells, such that binding of PRRs can activate a series of host defense reactions, including the directed release of soluble mediators, depending upon the nature of the antigen and the polarized epithelial surface communicating with the bacteria. Intestinal DCs orchestrate and direct mucosal adaptive immune responses, balancing immune tolerance to harmless antigens and effector responses against enteric pathogens (10). To facilitate these functions, populations of intestinal macrophages, and DCs, strategically located in the sub-epithelial lamina propria (11), sample luminal antigens provided by specialized epithelial cells (goblet cells) (12) or by inserting dendrites between epithelial cells into the lumen (13–15), and phagocytose pathogenic microbes that encroach into the mucosa (11). DCs expressing the mucosal marker CD103, migrate to the MLNs, where they present acquired mucosal antigenic molecules to responsive naive T cells (16, 17), inducing the expansion of tolerogenic or effector memory T cell populations expressing the gut homing markers α4β7 and CCR9 (18, 19), that support the T cell recruitment to the lamina propria.