Therapeutic Options to Modulate Barrier Defects in Inflammatory Bowel DiseaseHering N.A. · Schulzke J.-D.
Department of General Medicine, Charité Center 10, Campus Benjamin Franklin, Berlin, Germany
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 TJ alterations, 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 far as regulation is concerned, Th1 cytokines like TNF-α and interferon-γ are important for CD, while Th2 responses are dominated by interleukin (IL)-13 and TNF-α 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 in advanced stages of CD. Luminal antigen uptake occurs via TJ discontinuities, epithelial gross lesions and endocytotically. Therapeutically, anti-inflammatory remedies as e.g. TNF-α 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-β and have beneficial effects in models, but no data exist on barrier 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.
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
Published online: November 04, 2009
Number of Print Pages : 5
Number of Figures : 0, Number of Tables : 2, Number of References : 21
Digestive Diseases (Clinical Reviews)
Vol. 27, No. 4, Year 2009 (Cover Date: November 2009)
Journal Editor: Malfertheiner P. (Magdeburg)
ISSN: 0257-2753 (Print), eISSN: 1421-9875 (Online)
For additional information: http://www.karger.com/DDI