Gluten-induced symptoms in diarrhea-predominant irritable bowel syndrome are associated with increased myosin light chain kinase activity and claudin-15 expression

Abstract

The mechanisms underlying diarrhea-predominant irritable bowel syndrome (IBS-D) are poorly understood, but increased intestinal permeability is thought to contribute to symptoms. A recent clinical trial of gluten-free diet (GFD) demonstrated symptomatic improvement, relative to gluten-containing diet (GCD), that was associated with reduced intestinal permeability in non-celiac disease IBS-D patients. The aim of this study was to characterize intestinal epithelial tight junction composition in IBS-D before and after dietary gluten challenge. Biopsies from 27 IBS-D patients (13 GFD; 14 GCD) were examined by H&E staining and semi-quantitative immunohistochemistry for phosphorylated myosin II regulatory light chain (MLC), MLC kinase, claudin-2, claudin-8, and claudin-15. Diet-induced changes were assessed and correlated with urinary mannitol excretion (after oral administration). In the small intestine, epithelial MLC phosphorylation was increased or decreased by GCD or GFD, respectively, and this correlated with increased intestinal permeability (P < 0.03). Colonocyte expression of the paracellular Na+ channel claudin-15 was also markedly augmented following GCD challenge (P < 0.05). Conversely, colonic claudin-2 expression correlated with reduced intestinal permeability (P < 0.03). Claudin-8 expression was not affected by dietary challenge. These data show that alterations in MLC phosphorylation and claudin-15 and claudin-2 expression are associated with gluten-induced symptomatology and intestinal permeability changes in IBS-D. The results provide new insight into IBS-D mechanisms and can explain permeability responses to gluten challenge in these patients.

Motility Disorders in Celiac Disease and Non-Celiac Gluten Sensitivity: The Impact of a Gluten-Free Diet

“…Experimental data showed that transgenic mice, sensitized by gluten, had an altered barrier function and enhanced muscle contractility [ 32 ]. Furthermore, gluten-induced symptoms in IBS-D patients were associated with increased myosin light chain kinase activity and claudin-15 expression, as described in a recent trial [ 33 ].…”

The Overlapping Area of Non-Celiac Gluten Sensitivity (NCGS) and Wheat-Sensitive Irritable Bowel Syndrome (IBS): An Update

“…Both enhanced intestinal permeability and increased smooth muscle contractility reverted to normal after gluten withdrawal [ 54 ]. A recent clinical trial in patients with IBS with predominant diarrhea (IBS-D) confirmed the close relationship between wheat-containing food and a subgroup of IBS cases [ 55 ]. Withdrawal of wheat led to a significant improvement of intestinal symptoms together with a reduced small intestinal permeability, whereas wheat-containing food challenge was followed by the recurrence of symptoms and altered barrier function.…”

The mucosal barrier at a glance

“…Although this discussion has focused on inflammatory bowel disease and graft-versus-host disease, which has been studied extensively, other examples of disease-associated gut barrier loss abound, including those that occur within the contexts of intestinal infection (Halliez et al, 2016;In et al, 2016;Zolotarevsky et al, 2002), irritable bowel syndrome (Bertiaux-Vandaële et al, 2011;Martínez et al, 2013;Wu et al, 2016), celiac disease (Schumann et al, 2012;Setty et al, 2015;Szakál et al, 2010) and environmental enteric dysfunction (Kelly et al, 2016;Vinetz et al, 2016;Yu et al, 2016). Although studied to a lesser extent, barrier defects also occur in pulmonary, renal and dermatologic diseases.…”