The intestinal epithelial barrier: a therapeutic target?

Abstract

A fundamental function of the intestinal epithelium is to act as a barrier that regulates interactions between the 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 significance of barrier loss. Some data from experimental animal models suggest that compromised epithelial integrity may play a pathogenic role in specific gastrointestinal diseases, but no FDA-approved therapies for targeting the epithelial barrier are presently available. In order for this goal to be achieved, a deeper understanding of both disease pathogenesis and mechanisms of barrier regulation must be reached.

Helminths and intestinal barrier function

“…16 The paracellular space is in fact a continuity between the gut lumen and the mucosa and is often considered in terms of a pore pathway, a high capacity, size-and charge-selective route, and a lower capacity leak pathway that allows entry of larger molecules (e.g., 4 kDa dextrans). 17 Research over the last 25-years has defined the molecular composition of the TJ, its' dynamic nature, the mechanisms that regulate its' opening and the impact of microbial pathogens (including protozoans) on enteric epithelial paracellular permeability. 18 Briefly, the TJ is composed of many transmembrane proteins: TJ-associated MARVEL (MAL and related proteins for vesicle trafficking and membrane) proteins (TAMPs) include occludin, tricellulin (restricted to tri-cellular junctions) and MarvelD3; claudins, a 27-member family, are single-spanning transmembrane proteins that interact homotypically with the extracellular domain of claudins on neighboring cells; and, single transmembrane immunoglobulin-like junction adhesion molecules (JAMs).…”

“…18 Briefly, the TJ is composed of many transmembrane proteins: TJ-associated MARVEL (MAL and related proteins for vesicle trafficking and membrane) proteins (TAMPs) include occludin, tricellulin (restricted to tri-cellular junctions) and MarvelD3; claudins, a 27-member family, are single-spanning transmembrane proteins that interact homotypically with the extracellular domain of claudins on neighboring cells; and, single transmembrane immunoglobulin-like junction adhesion molecules (JAMs). 17 These proteins reside in cholesterol-rich, detergent-insoluble lipid domains of the plasmalemma and are connected to a peri-junctional ring of actin and myosin via the scaffolding proteins zona occludens (ZO)-1, -2 and -3. The function of TJ and ZO proteins is phosphorylation dependent.…”

ER-stress mobilization of death-associated protein kinase-1–dependent xenophagy counteracts mitochondria stress–induced epithelial barrier dysfunction

“…A defect in epithelial barrier function is implied in this hypothesis. With the exceptions of uptake by microfold (M) cells or dendritic cell pseudopodia, material in the gut lumen enters the submucosa via the epithelial tight junctions (paracellular) or by crossing the enterocyte (transcellular) (12): regulation of both pathways is energy dependent. With that, it can be proposed that perturbed epithelial mitochondria function would increase gut permeability to initiate disease or precipitate relapses in IBD.…”

MicroRNA-122a Regulates Zonulin by Targeting EGFR in Intestinal Epithelial Dysfunction

“…Intestinal barrier mainly consists of complete intestinal epithelial cells [23], with tight junction between the adjacent cells [24,25]. Human intestine faces with the highest bacterial load, approximately more than 500 different types of microorganisms [26].…”