Vasoactive intestinal polypeptide regulates barrier function via mast cells in human intestinal follicle‐associated epithelium and during stress in rats

Background Vasoactive intestinal polypeptide (VIP) has been implicated as a regulator of intestinal barrier function and inflammation. Our aim was to elucidate the role of VIP in follicle‐associated epithelium (FAE) and villus epithelium (VE) permeability following stress in rats and on human intestinal barrier function. Methods Rats were injected intraperitoneally (i.p.) with VIP receptor‐antagonists (anti‐VPACs), a mast cell stabilizer, doxantrazole (DOX), or NaCl, and submitted to acute water avoidance stress. Ileal segments were mounted in Ussing chambers to assess 51chromium‐edta (51Cr‐edta) and Escherichia (E.) coli (strain K‐12) permeability. Rat ileal and human ileal and colonic segments were exposed to VIP ± anti‐VPACs or DOX. An in vitro co‐culture model of human FAE was used to study epithelial‐VIP effects. VIP/VPACs distribution was assessed by microscopy. Key Results Stress increased 51Cr‐edta and E. coli permeability in VE and FAE. The increases were abolished by i.p. injection of DOX or anti‐VPACs. Ileal VIP‐exposure ex vivo increased bacterial passage and this was reduced by DOX. In human FAE ex vivo, VIP treatment doubled bacterial uptake, which was normalized by DOX or anti‐VPACs. No barrier effects were observed in human colonic tissue. VPACs were found in rat and human ileal follicles, with partial mast cell co‐localization. The co‐culture model confirmed VIP–mast cell–epithelial interactions in the regulation of barrier function. Conclusions & Inferences Stress affects the FAE barrier by mechanisms involving VIP and VPACs on mucosal mast cells. We suggest a regulatory role for VIP in the control of ileal permeability that may be relevant to bacterial–epithelial interactions in stress‐related intestinal disorders.