Vasoactive intestinal polypeptide promotes intestinal barrier homeostasis and protection against colitis in mice.

Xiujuan Wu,Allison M J Buchan,Yasmin Nasser,Chris C M Waterhouse,Natasha R Ryz,Vijay Morampudi,William T Gibson,Bruce A Vallance,Kevan Jacobson,Kirk S Bergstrom,Oana E Popescu,Ganive Bhinder,Victoria S Conlin,Hong B Yu,James A Waschek,Simon Patrick Hogan

doi:10.1371/journal.pone.0125225

Abstract

Inflammatory bowel disease is a chronic gastrointestinal inflammatory disorder associated with changes in neuropeptide expression and function, including vasoactive intestinal peptide (VIP). VIP regulates intestinal vasomotor and secretomotor function and motility; however, VIP’s role in development and maintenance of colonic epithelial barrier homeostasis is unclear. Using VIP deficient (VIPKO) mice, we investigated VIP’s role in epithelial barrier homeostasis, and susceptibility to colitis. Colonic crypt morphology and epithelial barrier homeostasis were assessed in wildtype (WT) and VIPKO mice, at baseline. Colitic responses were evaluated following dinitrobenzene sulfonic acid (DNBS) or dextran-sodium sulfate (DSS) exposure. Mice were also treated with exogenous VIP. At baseline, VIPKO mice exhibited distorted colonic crypts, defects in epithelial cell proliferation and migration, increased apoptosis, and altered permeability. VIPKO mice also displayed reduced goblet cell numbers, and reduced expression of secreted goblet cell factors mucin 2 and trefoil factor 3. These changes were associated with reduced expression of caudal type homeobox 2 (Cdx2), a master regulator of intestinal function and homeostasis. DNBS and DSS-induced colitis were more severe in VIPKO than WT mice. VIP treatment rescued the phenotype, protecting VIPKO mice against DSS colitis, with results comparable to WT mice. In conclusion, VIP plays a crucial role in the development and maintenance of colonic epithelial barrier integrity under physiological conditions and promotes epithelial repair and homeostasis during colitis.

Highlights

The intestinal epithelium and overlying secreted mucus layer are all that separates the host from its intestinal luminal environment
As previous studies have shown a link between vasoactive intestinal peptide (VIP) and goblet cell production of mucin 2 (Muc2) and the trefoil proteins [25, 26], we focused on colonic goblet cell distribution, maturation, and secretory capacity in naïve WT, VIPKO and VIP treated VIPKO mice
The present study explores the role of the enteric neuroendocrine system and VIP in the regulation of intestinal barrier defenses

Summary

Introduction

The intestinal epithelium and overlying secreted mucus layer are all that separates the host from its intestinal luminal environment. The ENS regulates gastrointestinal (GI) physiology and function, in part through secretion of neuropeptides, including VIP [2]. In IBD, intestinal inflammation can disrupt ENS structure and function, causing patients to experience abdominal pain, urgency and diarrhea, even during quiescent disease [2]. It was recently shown that VIP and its receptor VPAC1 could not be detected in tissues from IBD patients suffering severe mucosal damage [5]. These findings suggest dysregulated VIP responses may contribute to IBD pathogenesis, but at present, the role of VIP in maintaining intestinal health is largely unexplored

Methods

Results

Conclusion