title: Association of HLA-DQ gene with bowel transit, barrier function, and inflammation in irritable bowel syndrome with diarrhea.
abstract: Patients with irritable bowel syndrome (IBS) with diarrhea (IBS-D) carrying human leukocyte antigen (HLA)-DQ2/8 genotypes benefit from gluten withdrawal. Our objective was to compare gastrointestinal barrier function, mucosal inflammation, and transit in nonceliac IBS-D patients and assess association with HLA-DQ2/8 status. In 45 IBS-D patients who were naive to prior exclusion of dietary gluten, we measured small bowel (SB) and colonic mucosal permeability by cumulative urinary lactulose and mannitol excretion (0-2 h for SB and 8-24 h for colon), inflammation on duodenal and rectosigmoid mucosal biopsies (obtained in 28 of 45 patients), tight junction (TJ) protein mRNA and protein expression in SB and rectosigmoid mucosa, and gastrointestinal and colonic transit by validated scintigraphy. SB mucosal biopsies were stained with hematoxylin-eosin to assess villi and intraepithelial lymphocytes, and immunohistochemistry was used to assess CD3, CD8, tryptase, and zonula occludens 1 (ZO-1); colonic biopsy intraepithelial lymphocytes were quantitated. Associations of HLA-DQ were assessed using Wilcoxon's rank-sum test. Relative to healthy control data, we observed a significant increase in SB permeability (P < 0.001), a borderline increase in colonic permeability (P = 0.10), and a decrease in TJ mRNA expression in rectosigmoid mucosa in IBS-D. In HLA-DQ2/8-positive patients, ZO-1 protein expression in the rectosigmoid mucosa was reduced compared with that in HLA-DQ2/8-negative patients and colonic transit was slower than in HLA-DQ2/8-negative patients. No other associations with HLA genotype were identified. There is abnormal barrier function (increased SB permeability and reduced mRNA expression of TJ proteins) in IBS-D relative to health that may be, in part, related to immunogenotype, given reduced ZO-1 protein expression in rectosigmoid mucosa in HLA-DQ2/8-positive relative to HLA-DQ2/8-negative patients.
authors.affiliation: Clinical Enteric Neuroscience Translational and Epidemiological Research, College of Medicine, Mayo Clinic, Charlton 8-110, 200 First St. SW, Rochester, MN 55905, USA.
authors.forename: Maria I
authors.initials: MI
authors.lastname: Vazquez-Roque
authors.forename: Michael
authors.initials: M
authors.lastname: Camilleri
authors.forename: Thomas
authors.initials: T
authors.lastname: Smyrk
authors.forename: Joseph A
authors.initials: JA
authors.lastname: Murray
authors.forename: Jessica
authors.initials: J
authors.lastname: O'Neill
authors.forename: Paula
authors.initials: P
authors.lastname: Carlson
authors.forename: Jesse
authors.initials: J
authors.lastname: Lamsam
authors.forename: Deborah
authors.initials: D
authors.lastname: Eckert
authors.forename: Denise
authors.initials: D
authors.lastname: Janzow
authors.forename: Duane
authors.initials: D
authors.lastname: Burton
authors.forename: Michael
authors.initials: M
authors.lastname: Ryks
authors.forename: Deborah
authors.initials: D
authors.lastname: Rhoten
authors.forename: Alan R
authors.initials: AR
authors.lastname: Zinsmeister
mesh_terms: D003106:Colon / Q000000981:diagnostic imaging / Q000503:physiopathology; D003967:Diarrhea / Q000150:complications / Q000503:physiopathology*; D005260:Female; D005772:Gastrointestinal Transit / Q000276:immunology*; D005983:Glutens / Q000276:immunology; D006683:HLA-DQ Antigens / Q000235:genetics / Q000276:immunology*; D006801:Humans; D007413:Intestinal Mucosa / Q000503:physiopathology*; D007421:Intestine, Small / Q000503:physiopathology; D043183:Irritable Bowel Syndrome / Q000150:complications / Q000276:immunology* / Q000503:physiopathology*; D008297:Male; D010539:Permeability; D011446:Prospective Studies; D011877:Radionuclide Imaging; D019108:Tight Junctions / Q000378:metabolism
chemical_list: D006683:HLA-DQ Antigens; C053186:HLA-DQ2 antigen; C109756:HLA-DQ8 antigen; D005983:Glutens