Gliadin-dependent neuromuscular and epithelial secretory responses in gluten-sensitive HLA-DQ8 transgenic mice

E. F. Verdu, X. Huang, J. Natividad, J. Lu, P. A. Blennerhassett, C. S. David, D. M. McKay, J. A. Murray

Research output: Contribution to journalArticle

99 Scopus citations

Abstract

Celiac disease is a gluten intolerance caused by a T-cell response against human leukocyte antigen (HLA)-DQ2 and DQ8-bound gluten peptides. Some subjects experience gastrointestinal symptoms in the absence of villous atrophy. Here we investigate the potential mechanisms of gut dysfunction in gluten-sensitive HLA-DQ8 transgenic mice. HLA-DQ8 mice were sensitized and gavaged with gliadin 3X/wk for 3 wk (G/G). Controls included 1) nonsensitized mice gavaged with rice (C); 2) gliadin-sensitized mice gavaged with rice (G/R); and 3) BSA-sensitized mice gavaged with BSA (BSA/BSA). CD3+ intraepithelial lymphocyte, macrophage, and FOX-P3-positive cell counts were determined. Acetylcholine release, small intestinal contractility, and epithelial ion transport were measured. Gut function was investigated after gluten withdrawal and in HLA-DQ6 mice. Intestinal atrophy was not observed in G/G mice. Recruitment of intraepithelial lymphocyte, macrophages, and FOX-P3+ cells were observed in G/G, but not in C, G/R, or BSA/BSA mice. This was paralleled by increased acetylcholine release from the myenteric plexus, muscle hypercontractility, and increased active ion transport in G/G mice. Changes in muscle contractility normalized in DQ8 mice after a gluten withdrawal. HLA-DQ6 controls did not exhibit the abnormalities in gut function observed in DQ8 mice. Gluten sensitivity in HLA-DQ8 mice induces immune activation in the absence of intestinal atrophy. This is associated with cholinergic dysfunction and a prosecretory state that may lead to altered water movements and dysmotility. The results provide a mechanism by which gluten could induce gut dysfunction in patients with a genetic predisposition but without fully evolved celiac disease.

Original languageEnglish (US)
Pages (from-to)G217-G225
JournalAmerican Journal of Physiology - Gastrointestinal and Liver Physiology
Volume294
Issue number1
DOIs
StatePublished - Dec 1 2007

Keywords

  • Food sensitivity
  • Intestinal ion transport
  • Muscle contractility

ASJC Scopus subject areas

  • Physiology
  • Hepatology
  • Gastroenterology
  • Physiology (medical)

Fingerprint Dive into the research topics of 'Gliadin-dependent neuromuscular and epithelial secretory responses in gluten-sensitive HLA-DQ8 transgenic mice'. Together they form a unique fingerprint.

  • Cite this