Physiopathology of IBD. (a) The intestine is the largest mucosal surface exposed to the external environment. It constitutes an interface between the host and the luminal contents, which include nutrients and the highest count of resident microbes. Thus, the intestinal immune system meets more antigens than any other part of the body and it must discriminate between invasive organisms and harmless antigens, such as food, proteins, and commensal bacteria, to prevent infections or preserve the homeostasis. This intestinal homeostasis depends on the dynamic interaction between the microbiota, the intestinal epithelial cells, and the resident immune cells, which coordinate a response that keeps the balance between immunity and tolerance. (b) A breakdown of this balance triggers the chronic inflammatory process that characterizes inflammatory bowel disease. There are often several preexisting conditions that lead to the disease: first of all, a genetic susceptibility of the intestinal immune system to distinguish an environmental antigen presented within the gastrointestinal tract; secondly, the contact with the antigen; finally, usually due to an alteration of the permeability, the antigen is presented to the gastrointestinal mucosal immune system through its paracellular passage, which triggers the inflammatory cascade. During early inflammation, luminal antigens activate the different innate immune cells located in the intestine, including natural killer cells, mast cells, neutrophils, macrophages, and dendritic cells, and maintained inflammatory reaction promotes the activation of the adaptive immune response. Abnormally activated effector CD4+ T helper (Th) cells synthesize and release different inflammatory mediators that generate an amplified inflammation that originates from chronic tissue injury and epithelial damage.