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Open Access Highly Accessed Research article

Increased intestinal permeability and tight junction disruption by altered expression and localization of occludin in a murine graft versus host disease model

Rainer Noth1, Julia Lange-Grumfeld1, Eckhard Stüber1, Marie-Luise Kruse1, Mark Ellrichmann1, Robert Häsler2, Jochen Hampe1, Burkhard Bewig1, Philip Rosenstiel2, Stefan Schreiber12 and Alexander Arlt1*

Author Affiliations

1 Department of Internal Medicine, University Hospital Schleswig-Holstein, Campus Kiel, 24105 Kiel, Germany

2 Institute of Clinical Molecular Biology, University Hospital Schleswig-Holstein, Campus Kiel, 24105 Kiel, Germany

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BMC Gastroenterology 2011, 11:109  doi:10.1186/1471-230X-11-109

Published: 6 October 2011

Abstract

Background

Hematopoietic stem cell transplantation is increasingly performed for hematologic diseases. As a major side effect, acute graft versus host disease (GvHD) with serious gastrointestinal symptoms including diarrhea, gastrointestinal bleeding and high mortality can be observed. Because surveillance and biopsies of human gastrointestinal GvHD are difficult to perform, rare information of the alterations of the gastrointestinal barrier exists resulting in a need for systematic animal models.

Methods

To investigate the effects of GvHD on the intestinal barrier of the small intestine we utilized an established acute semi allogenic GvHD in C57BL/6 and B6D2F1 mice.

Results

By assessing the differential uptake of lactulose and mannitol in the jejunum, we observed an increased paracellular permeability as a likely mechanism for disturbed intestinal barrier function. Electron microscopy, immunohistochemistry and PCR analysis indicated profound changes of the tight-junction complex, characterized by downregulation of the tight junction protein occludin without any changes in ZO-1. Furthermore TNF-α expression was significantly upregulated.

Conclusions

This analysis in a murine model of GvHD of the small intestine demonstrates serious impairment of intestinal barrier function in the jejunum, with an increased permeability and morphological changes through downregulation and localization shift of the tight junction protein occludin.