Stress induces more serious barrier dysfunction in follicle-associated epithelium than villus epithelium involving mast cells and protease-activated receptor-2

Lei Zhang,Tao Bai,Wei Qian,Jun Song,Xiao-Hua Hou

doi:10.1038/s41598-017-05064-y

Lei Zhang, Tao Bai + Show 3 more

Open Access

https://doi.org/10.1038/s41598-017-05064-y

Copy DOI

Abstract

Psychological stress has been associated with intestinal epithelial hyperpermeability, the basic process in various functional and organic bowel diseases. In the present study, we aimed to clarify the differences and underlining mechanisms in stress-induced barrier disruption in functionally and structurally distinct epitheliums, including the villus epithelium (VE) and follicle-associated epithelium (FAE), a specialized epithelium overlaid the domes of Peyer’s lymphoid follicles. Employing an Ussing Chamber system, the epithelial permeability was assessed in rats following water avoidance stress (WAS) in vivo and in mucosa tissues exposed to corticotropin-releasing factor (CRF) ex vivo. Decreased transepithelial resistance (TER) and increased paracellular and transcellular macromolecular permeability in colon, ileal VE and FAE had been observed in WAS rats and in CRF-exposed mucosa. Especially, the barrier dysfunction was more serious in the FAE. Moreover, WAS upregulated the expression of mast cell tryptase and protease-activated receptor-2 (PAR2), which positively correlated with epithelial conductance. Mast cell stabilizer cromolyn sodium obviously alleviated the barrier disruption induced by WAS in vivo and CRF in vitro. Serine protease inhibitor aprotinin and FUT-175, and selective PAR2 antagonist ENMD-1068 effectively inhibited the CRF-induced FAE hyperpermeability. Altogether, it concluded that the FAE was more susceptible to stress, and the mast cells and PAR2 signaling played crucial roles in this process.

Highlights

The human intestinal epithelium makes up the largest barrier, with a surface area up to 400 m2, separating the body from the luminal environment, such as toxins and antigens from food and microbes[1, 2]
For the first time, we mapped the different susceptibility of functionally distinct epitheliums to stress-induced intestinal injury, which indicated that the follicle-associated epithelium (FAE) was more sensitive to stress-exposure
We demonstrated that inhibition of mast cells and blocking the protease/protease-activated receptor-2 (PAR2) signaling obviously improved the barrier dysfunction in FAE

Summary

Introduction

The human intestinal epithelium makes up the largest barrier, with a surface area up to 400 m2, separating the body from the luminal environment, such as toxins and antigens from food and microbes[1, 2]. Increased epithelial permeability may enhance the passage of antigens, facilitate the invasion of bacteria and lead to mucosal injury and inflammation. This process is the common pathophysiological basis of numerous organic and functional intestinal disorders such as inflammatory bowel disease and irritable bowel syndrome[3]. The precise mechanisms of stress-induced mast cell-mediated intestinal hyper-permeability remain poorly elucidated, in functionally and structurally distinct regions of the gastrointestinal tract. We aimed to assess the mechanisms and differences in stress-induced barrier dysfunction in structurally and functionally distinct epitheliums of the gut, including the colonic epithelium, ileal VE and FAE

Objectives

Methods

Results

Conclusion