During homeostasis (left) there is little underlying mucosal immune activity, and the tight junction-regulated “leak” and “pore” pathways define intestinal permeability. In the presence of an intact epithelium, the tight junction-independent “unrestricted” pathway is sealed. During disease pathogenesis (right), increased mucosal immune activation leads to TNF and IL-13 production, which can lead to increased permeability across the leak and pore pathways, respectively. As disease progresses further, epithelial apoptosis occurs and permeability across the unrestricted pathway dominates. Multiple therapeutic approaches have been proposed to both inhibit disease progression or to restore epithelial barriers after disease onset.