title: 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), which 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 and 14 GCD) were examined by H&E staining and semiquantitative 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.
authors.affiliation: Department of Pathology, The University of Chicago, Chicago, IL, USA.|Department of Pathology and Laboratory Medicine, Jackson Memorial Hospital, University of Miami, Miami, FL, USA.
authors.forename: Richard L
authors.initials: RL
authors.lastname: Wu
authors.affiliation: Division of Gastroenterology and Hepatology, Clinical Enteric Neuroscience Translational and Epidemiological Research, College of Medicine, Mayo Clinic, Rochester, MN, USA.
authors.forename: Maria I
authors.initials: MI
authors.lastname: Vazquez-Roque
authors.affiliation: Division of Gastroenterology and Hepatology, Clinical Enteric Neuroscience Translational and Epidemiological Research, College of Medicine, Mayo Clinic, Rochester, MN, USA.
authors.forename: Paula
authors.initials: P
authors.lastname: Carlson
authors.affiliation: Division of Gastroenterology and Hepatology, Clinical Enteric Neuroscience Translational and Epidemiological Research, College of Medicine, Mayo Clinic, Rochester, MN, USA.
authors.forename: Duane
authors.initials: D
authors.lastname: Burton
authors.affiliation: Division of Gastroenterology and Hepatology, Clinical Enteric Neuroscience Translational and Epidemiological Research, College of Medicine, Mayo Clinic, Rochester, MN, USA.
authors.forename: Madhusudan
authors.initials: M
authors.lastname: Grover
authors.affiliation: Division of Gastroenterology and Hepatology, Clinical Enteric Neuroscience Translational and Epidemiological Research, College of Medicine, Mayo Clinic, Rochester, MN, USA.
authors.forename: Michael
authors.initials: M
authors.lastname: Camilleri
authors.affiliation: Department of Pathology, The University of Chicago, Chicago, IL, USA.|Departments of Pathology and Medicine (GI), Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.
authors.forename: Jerrold R
authors.initials: JR
authors.lastname: Turner
mesh_terms: D000328:Adult; D062446:Claudin-2 / Q000378:metabolism; D057167:Claudins / Q000378:metabolism*; D003106:Colon / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D003967:Diarrhea / Q000209:etiology / Q000378:metabolism*; D055050:Diet, Gluten-Free; D005260:Female; D005983:Glutens / Q000008:administration & dosage / Q000009:adverse effects; D006801:Humans; D007150:Immunohistochemistry; D007413:Intestinal Mucosa / Q000378:metabolism; D007422:Intestines / Q000187:drug effects; D043183:Irritable Bowel Syndrome / Q000209:etiology / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D018994:Myosin Light Chains / Q000378:metabolism; D009219:Myosin-Light-Chain Kinase / Q000378:metabolism*; D010539:Permeability / Q000187:drug effects; D010766:Phosphorylation / Q000187:drug effects; D019108:Tight Junctions / Q000187:drug effects / Q000378:metabolism
chemical_list: D062446:Claudin-2; D057167:Claudins; D018994:Myosin Light Chains; C459596:claudin 15; D005983:Glutens; D009219:Myosin-Light-Chain Kinase; C502011:claudin 8