Publication Detail

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Gliadin, zonulin and gut permeability: Effects on celiac and non-celiac intestinal mucosa and intestinal cell lines.

Sandro Drago; Ramzi El Asmar; Mariarosaria Di Pierro; Maria Grazia Clemente; Amit Tripathi; Anna Sapone; Manjusha Thakar; Giuseppe Iacono; Antonio Carroccio; Cinzia D'Agate; et al. (Profiled Author: Alessio Fasano)

Mucosal Biology Research Center, Center for Celiac Research and Division of Pediatric Gastroenterology and Nutrition, University of Maryland, School of Medicine, Baltimore, MD 21201, USA.
Scandinavian journal of gastroenterology 2006;41(4):408-19.

OBJECTIVE: Little is known about the interaction of gliadin with intestinal epithelial cells and the mechanism(s) through which gliadin crosses the intestinal epithelial barrier. We investigated whether gliadin has any immediate effect on zonulin release and signaling. MATERIAL AND METHODS: Both ex vivo human small intestines and intestinal cell monolayers were exposed to gliadin, and zonulin release and changes in paracellular permeability were monitored in the presence and absence of zonulin antagonism. Zonulin binding, cytoskeletal rearrangement, and zonula occludens-1 (ZO-1) redistribution were evaluated by immunofluorescence microscopy. Tight junction occludin and ZO-1 gene expression was evaluated by real-time polymerase chain reaction (PCR). RESULTS: When exposed to gliadin, zonulin receptor-positive IEC6 and Caco2 cells released zonulin in the cell medium with subsequent zonulin binding to the cell surface, rearrangement of the cell cytoskeleton, loss of occludin-ZO1 protein-protein interaction, and increased monolayer permeability. Pretreatment with the zonulin antagonist FZI/0 blocked these changes without affecting zonulin release. When exposed to luminal gliadin, intestinal biopsies from celiac patients in remission expressed a sustained luminal zonulin release and increase in intestinal permeability that was blocked by FZI/0 pretreatment. Conversely, biopsies from non-celiac patients demonstrated a limited, transient zonulin release which was paralleled by an increase in intestinal permeability that never reached the level of permeability seen in celiac disease (CD) tissues. Chronic gliadin exposure caused down-regulation of both ZO-1 and occludin gene expression. CONCLUSIONS: Based on our results, we concluded that gliadin activates zonulin signaling irrespective of the genetic expression of autoimmunity, leading to increased intestinal permeability to macromolecules.

2 Originating Grant

• 1.

  Fasano, Alessio

  Gut permeability in the pathogenesis of Type 1 diabetes

  30 September 2003 - 31 August 2005

  NATIONAL INSTITUTE OF DIABETES AND DIGESTIVE AND KIDNEY DISEASES

• 2.

  FASANO, ALESSIO

  Zot, Zonulin, and Pathophysiology of Intestinal Tight Junctions

  1 May 1996 - 31 July 2016

  NATIONAL INSTITUTE OF DIABETES AND DIGESTIVE AND KIDNEY DISEASES

Scientific Context

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