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Abstract
Loss of integrity of the epithelial/mucosal barrier in the small intestine has been associated with different pathologies that originate and/or develop in the gastrointestinal tract. We showed recently that mucin, the main protein in the mucus layer, is disrupted during early periods of intestinal ischemia. This event is accompanied by entry of pancreatic digestive enzymes into the intestinal wall. We hypothesize that the mucin-containing mucus layer is the main barrier preventing digestive enzymes from contacting the epithelium. Mucin breakdown may render the epithelium accessible to pancreatic enzymes, causing its disruption and increased permeability. The objective of this study was to investigate the role of mucin as a protection for epithelial integrity and function. A rat model of 30 min splanchnic arterial occlusion (SAO) was used to study the degradation of two mucin isoforms (mucin 2 and 13) and two epithelial membrane proteins (E-cadherin and toll-like receptor 4, TLR4). In addition, the role of digestive enzymes in mucin breakdown was assessed in this model by luminal inhibition with acarbose, tranexamic acid, or nafamostat mesilate. Furthermore, the protective effect of the mucin layer against trypsin-mediated disruption of the intestinal epithelium was studied in vitro. Rats after SAO showed degradation of mucin 2 and fragmentation of mucin 13, which was not prevented by protease inhibition. Mucin breakdown was accompanied by increased intestinal permeability to FITC-dextran as well as degradation of E-cadherin and TLR4. Addition of mucin to intestinal epithelial cells in vitro protected against trypsin-mediated degradation of E-cadherin and TLR4 and reduced permeability of FITC-dextran across the monolayer. These results indicate that mucin plays an important role in the preservation of the mucosal barrier and that ischemia but not digestive enzymes disturbs mucin integrity, while digestive enzymes actively mediate epithelial cell disruption.
Highlights
The intestinal epithelium covering the gastrointestinal tract consists of a monolayer of enterocytes covered by a mucus gel layer
In order to determine if trypsin disrupts the epithelial cells in a like manner to that observed in vivo in the rat model of intestinal ischemia and whether addition of a mucin layer prevents this, we studied an in vitro model using a monolayer of rat intestinal epithelial cells
In a recent study we showed that 30 minutes of intestinal ischemia results in mucin disruption and transport of digestive enzymes from the lumen of the intestine into the intestinal wall and subsequently the systemic circulation [22]
Summary
The intestinal epithelium covering the gastrointestinal tract consists of a monolayer of enterocytes covered by a mucus gel layer. Together these two layers provide a dynamic and regulated barrier allowing selective passage of luminal contents into the intestinal wall. The major protein component of the mucus layer is mucin, which consists of several isoforms, both secreted and membrane associated. Mucin is believed to protect the epithelial surface of the small intestine from luminal digestive enzymes, abrasion by food particles, and pathogens by forming a barrier between the lumen and the intestinal epithelium [8,9,10,11]. The epithelial cells form a selective barrier to molecules found in the lumen; this barrier depends on the integrity of intercellular junctions and the extracellular plasma membrane proteins. Changes in the environment of epithelial cells make these molecules targets for proteolytic attack [12], cause disruption of cell structure components influencing intracellular signaling [13,14,15], and impair epithelial barrier function [16]
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