Vasoactive intestinal peptide ameliorates intestinal barrier disruption associated with Citrobacter rodentium -induced colitis

Aug 8, 2009American journal of physiology. Gastrointestinal and liver physiology

Vasoactive intestinal peptide reduces gut lining damage caused by Citrobacter rodentium infection

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Abstract

VIP treatment prevented the infection-induced increase in mannitol flux, a measure of paracellular permeability, achieving levels similar to control mice.

Bacterial pathogens disrupt epithelial barrier function, increasing permeability and allowing access to underlying tissues.
VIP administration did not affect bacterial attachment but reduced colitis-induced epithelial damage compared to controls.
VIP treatment preserved tight junction proteins, preventing their translocation during infection.
Infection with Enteropathogenic Escherichia coli (EPEC) in Caco-2 monolayers demonstrated VIP's protective effect on epithelial barrier function.
MLCK expression and myosin light chain phosphorylation were increased by EPEC infection, but VIP treatment mitigated this response.

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Attaching and effacing bacterial pathogens attach to the apical surface of epithelial cells and disrupt epithelial barrier function, increasing permeability and allowing luminal contents access to the underlying milieu. Previous in vitro studies demonstrated that the neuropeptide vasoactive intestinal peptide (VIP) regulates epithelial paracellular permeability, and the high concentrations and close proximity of VIP-containing nerve fibers to intestinal epithelial cells would support such a function in vivo. The aim of this study was to examine whether VIP treatment modulated Citrobacter rodentium-induced disruption of intestinal barrier integrity and to identify potential mechanisms of action. Administration of VIP had no effect on bacterial attachment although histopathological scoring demonstrated a VIP-induced amelioration of colitis-induced epithelial damage compared with controls. VIP treatment prevented the infection-induced increase in mannitol flux a measure of paracellular permeability, resulting in levels similar to control mice, and immunohistochemical studies demonstrated that VIP prevented the translocation of tight junction proteins: zonula occludens-1, occludin, and claudin-3. Enteropathogenic Escherichia coli (EPEC) infection of Caco-2 monolayers confirmed a protective role for VIP on epithelial barrier function. VIP prevented EPEC-induced increase in long myosin light chain kinase (MLCK) expression and myosin light chain phosphorylation (p-MLC). Furthermore, MLCK inhibition significantly attenuated bacterial-induced epithelial damage both in vivo and in vitro. In conclusion, our results indicate that VIP protects the colonic epithelial barrier by minimizing bacterial-induced redistribution of tight junction proteins in part through actions on MLCK and MLC phosphorylation.

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Vasoactive intestinal peptide ameliorates intestinal barrier disruption associated with Citrobacter rodentium -induced colitis

Abstract

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