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Am J Physiol Gastrointest Liver Physiol 297: G735-G750, 2009. First published August 6, 2009; doi:10.1152/ajpgi.90551.2008
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INFLAMMATION/IMMUNITY/MEDIATORS

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

V. S. Conlin,1,2,3 X. Wu,1,2 C. Nguyen,1,2 C. Dai,1,2 B. A. Vallance,1,2 A. M. J. Buchan,3 L. Boyer,1,2 and K. Jacobson1,2,3

1Child and Family Research Institute and 2Division of Gastroenterology, BC Children's Hospital, Vancouver; and 3Department of Cellular and Physiological Sciences, University of British Columbia, Vancouver, British Columbia, Canada

Submitted September 14, 2008 ; accepted in final form July 29, 2009

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.

tight junctions; Caco-2 cells; transepithelial resistance


Address for reprint requests and other correspondence: K. Jacobson, Division of Gastroenterology BC Children's Hospital, 4480 Oak St., Rm. K4-181, Vancouver, BC, Canada V6H 3V4 (e-mail: kjacobson{at}cw.bc.ca).






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