The intestinal epithelial barrier: a therapeutic target?

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. 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.

Figure 1. The apical junctional complex is necessary for epithelial barrier formation

A) Intestinal epithelia consist of a single layer of epithelial cells separating the luminal contents (apical) from the underlying lamina propria (basal). This section of human jejunal epithelium stained with hematoxylin and eosin demonstrates that a series of individual cells form a community apical border which comprises the luminal surface. Bar = 10 μm. B) Transmission electron microscopy (TEM) of small intestinal epithelium demonstrates intercellular junctions and a dense microvillus brush border. Note the exclusion of membranous organelles from the dense band of cortical actin just beneath the brush border. Bar = 1 μm. Inset: Apical junctional complex, composed of the tight junction (TJ), adherens junction (AJ) and desmosome (D). Bar = 200 nm. C) Scanning electron microscopy (SEM) of small intestinal epithelium demonstrates the continuous brush border surface of the small intestine. Bar = 4 μm. Inset: Dense, tightly-packed microvillus array. Bar = 500 nm. D) Individual epithelial cells are held together and communicate with one another through a series of junctions within the apical junctional complex. The apical junctional complex is positioned near the apical surface along the lateral membrane and is comprised of the tight junction, adherens junction, and desmosomes. A simplified cartoon of the apical junctional complex is shown on the right.

Figure 2. Three distinct paracellular epithelial permeability pathways are disrupted during disease pathogenesis

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.