Vasoactive intestinal peptide ameliorates intestinal barrier disruption associated withCitrobacter rodentium-induced colitis

Abstract

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.

Enteric Glia Cells Attenuate Cytomix-Induced Intestinal Epithelial Barrier Breakdown

“…While the focus in our lab has remained on the ability of VNS to signal to EGCs, several studies have shown that enteric neurons may also be involved in maintaining intestinal epithelial barrier integrity. Studies by both Conlin, et al and Neunlist, et al have revealed the importance of the enteric neuron-secreted mediator, vasoactive intestinal peptide (VIP), which reduces intestinal barrier permeability and improves tight junction protein expression [26,27]. Given this data and the well-established connections between the Vagus nerve and the ENS, it is conceivable that VNS may also be directly innervating enteric neurons to secrete barrier-inducing mediators such as VIP.…”

Enteric glia protect against Shigella flexneri invasion in intestinal epithelial cells: a role for S-nitrosoglutathione

“…Indeed, in a recent study, pharmacological reduction of intestinal permeability by blockage of tight junctions has been shown to attenuate intestinal inflammation in IL10−/− mice 3. Similarly, enhancement of IEB tight junction expression and resistance with vasoactive intestinal peptide4 reduced IEB lesions induced by pathogens such as Citrobacter rodentium 5…”

Vasoactive intestinal peptide loss leads to impaired CNS parenchymal T-cell infiltration and resistance to experimental autoimmune encephalomyelitis

“…The fact that VIP inhibits the release of proinflammatory mediators by activated macrophages, promotes Th2 versus Th1 responses, and induces the generation of regulatory T cells (Tregs), suggested that its receptors may be targets for anti-inflammatory drugs. Accordingly, subsequent studies showed that VIP treatment inhibits ongoing inflammatory responses in murine models of septic shock, Crohn's disease, and rheumatoid arthritis (8)(9)(10)(11). However, the role of the endogenous peptide in maintaining the balance between potentially harmful and beneficial actions of the immune system remains to be elucidated.…”