Phenotypic changes in colonocytes following acute stress or activation of mast cells in mice: implications for delayed epithelial barrier dysfunction

Abstract

Background and aim: Stressful life events are known to modulate the development or relapse of disease in both inflammatory bowel disease and irritable bowel disease patients but underlying mechanisms remain unclear. Stress is known to effect mast cells, interferon c (IFN-c), and myosin light chain phosphorylation to trigger colonic epithelial barrier dysfunction. The aim of this study was to investigate whether acute stress induced or chemical mast cell activation impaired expression and function of epithelial tight junctions, and altered colonocyte differentiation in mice. Methods: Colonic paracellular permeability was assessed as the in vivo lumen to blood ratio of 51 Cr-EDTA in different groups of mice (controls, stressed, mast cell degranulator BrX-537A treated), pretreated or not with the mast cell stabiliser doxantrazole. Involvement of mast cells and IFN-c was evaluated in wild-type and IFN-c deficient mice. Tight junction alteration was assessed by histology, transmission electron microscopy, and real time reverse transcription-polymerase chain reaction. Colonocyte differentiation was determined by protein kinase C f (PKCf) immunofluorescence and western blotting, and alkaline phosphatase activity assay. Results: Acute stress induced a three day delayed increase in colonic paracellular permeability which involved mast cell degranulation and overproduction of IFN-c. The colonic epithelial barrier was morphologically altered and expression of mRNA encoding tight junction proteins ZO-2 and occludin was decreased. Moreover, three days after acute stress, colonocyte differentiation was reduced, as shown by decreased expression of both PKCf isotype and alkaline phosphatase. Conclusion: These data highlight new mechanisms whereby an acute stress acts on the gastrointestinal tract by inducing alterations in colonocyte differentiation and decreased expression of mRNA encoding tight junction proteins. Thus phenotypic changes in colonocytes could pave the way for stress related intestinal disorders.

Role of Corticotropin-releasing Factor in Gastrointestinal Permeability

“…In rodents, acute or subchronic stressors, including restraint stress, cold restraint stress, WAS, mild noise stress, and mixed restraint and acoustic stress, increased tissue conductance, and the fluxes of 3 H mannitol, 51 Cr-labeled EDTA, horseradish peroxidase, in the jejunum, ileum, and colon. 32,50,54,[69][70][71][72] These results indicate the ability of stress to modulate paracellular and transcellular transport of ions, and small and large macromolecules. Multiple mechanisms have been invocated to explain stress-mediated transport abnormalities.…”

Stress signaling pathways activated by weaning mediate intestinal dysfunction in the pig

“…Breaches in intestinal barrier function have been shown to be a pathophysiological event in several postweaning swine enteric diseases such as Escherichia coli edema disease, Clostridium difficile infections, and transmissible gastroenteritis (10,29,44). It is also becoming increasingly recognized that stress-induced breakdown of the intestinal barrier is central to several important stress-associated gastrointestinal disorders in humans, including inflammatory bowel diseases and irritable bowel syndrome (2,9,38).…”

Hodgkin's lymphoma and late onset egg allergy: is there a causal relationship?

“…Some studies in mice models proved that physical and psychological stress can induce intestinal sensitisation to luminal antigens and oral tolerance disruption by inducing alterations in colonocyte differentiation and decreased expression of RNAm encoding tight junction proteins, with a consequent increase in paracellular permeability and excessive uptake of luminal material. 8,9 Stress is also associated to gut flora changes, with the possible consequences already discussed above.…”