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Key Points The intestinal epithelium is a dynamic cellular layer that serves as a barrier between luminal contents and the underlying immune system while simultaneously supporting water, nutrient and ion transport Tight junctions are the primary determinants of barrier function in intact epithelia and are composed of a complex network of transmembrane and cytosolic proteins accompanied by cytoskeletal and regulatory proteins Two distinct pathways — termed pore and leak — regulate paracellular flux in intact epithelia whereas the unrestricted flux pathway is the dominant route across ulcerated or denuded epithelia Reduced intestinal epithelial barrier function is associated with a variety of gastrointestinal and systemic diseases, including IBD and graft versus host disease, respectively, but is insufficient to cause disease in the absence of other insults Experimental evidence suggests that barrier defects contribute to IBD, as mouse models demonstrate that increased paracellular permeability accelerates experimental colitis and that preservation of tight junction barrier function delays disease progression Although no currently available therapeutics specifically modulate epithelial barrier function, promising approaches to target the pore, leak, and unrestricted pathways are being investigated Abstract A fundamental function of the intestinal epithelium is to act as a barrier that limits interactions between luminal contents such as the intestinal microbiota, the underlying immune system and the remainder of the body, while supporting vectorial transport of nutrients, water and waste products