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
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. Epithelial barrier function requires a contiguous layer of cells as well as the junctions that seal the paracellular space between epithelial cells. Compromised intestinal barrier function has been associated with a number of disease states, both intestinal and systemic. Unfortunately, most current clinical data are correlative, making it difficult to separate cause from effect in interpreting the importance of barrier loss. Some data from experimental animal models suggest that compromised epithelial integrity might have a pathogenic role in specific gastrointestinal diseases, but no FDA-approved agents that target the epithelial barrier are presently available. To develop such therapies, a deeper understanding of both disease pathogenesis and mechanisms of barrier regulation must be reached. Here, we review and discuss mechanisms of intestinal barrier loss and the role of intestinal epithelial barrier function in pathogenesis of both intestinal and systemic diseases. We conclude with a discussion of potential strategies to restore the epithelial barrier.
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The authors acknowledge NIH grants F30DK103511 (M.A.O.), T32HD007009 (M.A.O.), R01DK61931 (J.R.T.) and R01DK68271 (J.R.T.).
The authors declare no competing financial interests.
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Odenwald, M., Turner, J. The intestinal epithelial barrier: a therapeutic target?. Nat Rev Gastroenterol Hepatol 14, 9–21 (2017). https://doi.org/10.1038/nrgastro.2016.169
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