Association of HLA-DQ gene with bowel transit, barrier function, and inflammation in irritable bowel syndrome with diarrhea

Maria I Vazquez Roque, Michael Camilleri, Thomas Christopher Smyrk, Joseph A Murray, Jessica O'Neill, Paula Carlson, Jesse Lamsam, Deborah Eckert, Denise Janzow, Duane Burton, Michael Ryks, Deborah Rhoten, Alan R. Zinsmeister

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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 HLADQ2/ 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.

Original languageEnglish (US)
JournalAmerican Journal of Physiology - Gastrointestinal and Liver Physiology
Volume303
Issue number11
DOIs
StatePublished - Dec 1 2012

Fingerprint

Irritable Bowel Syndrome
HLA Antigens
Diarrhea
Inflammation
Genes
Permeability
Mucous Membrane
Zonula Occludens-1 Protein
Tight Junction Proteins
Glutens
Tight Junctions
Nonparametric Statistics
Biopsy
Messenger RNA
Genotype
Lymphocytes
Gastrointestinal Transit
Lactulose
Tryptases
Mannitol

Keywords

  • Celiac
  • Gluten
  • Immunogenotype
  • Lactulose
  • Mannitol

ASJC Scopus subject areas

  • Gastroenterology
  • Physiology (medical)
  • Physiology
  • Hepatology

Cite this

Association of HLA-DQ gene with bowel transit, barrier function, and inflammation in irritable bowel syndrome with diarrhea. / Vazquez Roque, Maria I; Camilleri, Michael; Smyrk, Thomas Christopher; Murray, Joseph A; O'Neill, Jessica; Carlson, Paula; Lamsam, Jesse; Eckert, Deborah; Janzow, Denise; Burton, Duane; Ryks, Michael; Rhoten, Deborah; Zinsmeister, Alan R.

In: American Journal of Physiology - Gastrointestinal and Liver Physiology, Vol. 303, No. 11, 01.12.2012.

Research output: Contribution to journalArticle

Vazquez Roque, Maria I ; Camilleri, Michael ; Smyrk, Thomas Christopher ; Murray, Joseph A ; O'Neill, Jessica ; Carlson, Paula ; Lamsam, Jesse ; Eckert, Deborah ; Janzow, Denise ; Burton, Duane ; Ryks, Michael ; Rhoten, Deborah ; Zinsmeister, Alan R. / Association of HLA-DQ gene with bowel transit, barrier function, and inflammation in irritable bowel syndrome with diarrhea. In: American Journal of Physiology - Gastrointestinal and Liver Physiology. 2012 ; Vol. 303, No. 11.
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AU - O'Neill, Jessica

AU - Carlson, Paula

AU - Lamsam, Jesse

AU - Eckert, Deborah

AU - Janzow, Denise

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