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Pathogenesis of IBD
Dig Dis 2009;27:450–454 DOI: 10.1159/000233283

Therapeutic Options to Modulate Barrier Defects in Inflammatory Bowel Disease
Nina A. Hering Jörg-Dieter Schulzke
Department of General Medicine, Charité Center 10, Campus Benjamin Franklin, Berlin, Germany

Key Words Apoptosis Barrier function Crohn’s disease Flavonoids Glutamine Inflammatory bowel disease ProbioticsTight junction Ulcerative colitis Zinc

Abstract In inflammatory bowel disease (IBD), epithelial barrier function is impaired contributing to diarrhea by a leak flux mechanism and perpetuating inflammation by an increased luminal antigen uptake. This barrier of the intestinal epithelium is composed of the apical enterocyte membrane and the epithelial tight junction (TJ) and can be affected by TJalterations, induction of epithelial apoptoses and appearance of gross lesions like erosions or ulcers as well as by accelerated transcytotic antigen uptake. TJ strands are reduced in Crohn’s disease (CD) and strand breaks appear. Several of the 24 claudins are concerned in CD as e.g. claudin-2, -5 and -8. The epithelial apoptotic rate has also been shown to be elevated causing focal lesions. As faras regulation is concerned, Th1 cytokines like TNF- and interferon- are important for CD, while Th2 responses are dominated by interleukin (IL)-13 and TNF- in ulcerative colitis (UC). IL-13 does stimulate epithelial apoptosis as well as upregulates claudin-2 in UC. Together with an IL-13-dependent restitution arrest, this may explain why ulcer lesions are seen already early in UC but only inadvanced stages of CD. Luminal antigen uptake occurs via TJ discontinuities, epithelial gross lesions and endocytotically. Therapeutically, anti-inflammatory remedies as e.g.

TNF- antibodies are most effective in improving active IBD and in parallel repairing barrier function. Again, this is assumed to be due to reduced cytokine release in active IBD, as a result of immune cell apoptosis. However,other agents can also directly affect barrier function. Glutamine is discussed as a candidate for barrier therapy but has never been shown to have a direct barrier influence in CD, although it is an important metabolic fuel for enterocytes and has been shown to preserve barrier functions in laboratory models. Also, probiotics and TGF- and have beneficial effects in models, but no data exist onbarrier repair in IBD. In contrast, zinc has been shown to improve barrier function in CD, although the inherent mechanisms are unknown. Finally, food components can strengthen the epithelial barrier as for example the flavonoid quercetin which has been shown to upregulate claudin-4 within the epithelial TJ.
Copyright © 2009 S. Karger AG, Basel

Introduction

Intestinal inflammation isaccompanied by altered epithelial barrier function in small and large intestine. This has two main consequences. First, ions and water can passively diffuse from the circulation to the intestinal lumen and cause leak flux diarrhea. The second consequence regards antigens and macromolecules, which under normal conditions cross the epithelial barrier only in very limited amounts. However, if the barrierfunction is
Prof. Dr. Jörg-Dieter Schulzke Department of General Medicine, Charité – Campus Benjamin Franklin DE–12200 Berlin (Germany) Tel. +49 30 8445 2666, Fax +49 30 8445 4493 E-Mail joerg.schulzke@charite.de

© 2009 S. Karger AG, Basel 0257–2753/09/0274–0450$26.00/0 Fax +41 61 306 12 34 E-Mail karger@karger.ch www.karger.com Accessible online at: www.karger.com/ddi

Table 1. Barrierfunction, TJs and apoptosis in CD

Epithelial resistance Control CD 3984 2383 cm2 (10) • cm2 (10)**


TJ strand count 7.280.2 (6) 4.780.2 (6)***

Strand discontinuities 0.280.1 (6) 2.980.6 (6)***

Apoptotic rate 1.080.1% (10) 2.880.3% (8)***

In sigmoid colon of controls and patients with CD, epithelial resistance was measured by impedance spectroscopy. Epithelial TJs were characterized by...
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