The intestinal epithelium forms a barrier between the gut lumen and the body. The barrier is potentially challenged by the high turnover of epithelial cells being shed. Our laboratories have shown that the epithelium is punctuated by discontinuities called "gaps" that have the diameter of an epithelial cell and are devoid of cellular contents. At least a proportion of gaps are formed by the shedding of epithelial cells. These gaps are filled with an unknown substance that maintains local barrier function. Gaps have been identified in the mouse by in vivo confocal microscopy and in humans by confocal endomicroscopy. They can be distinguished from goblet cells by the absence of a nucleus and are found in Math1-/- mice where goblet cells are absent. Cell shedding and gap formation is increased by TNF-alpha. Barrier function is lost after TNF-alpha in approximately 20% of shedding events. These observations suggest that loss of barrier function at sites of cell shedding may be important in intestinal diseases where an increase in epithelial permeability plays a role in pathogenesis.