Therapeutic options to modulate barrier defects in inflammatory bowel disease.

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 apoptosis 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-alpha and interferon-gamma are important for CD, while Th2 responses are dominated by interleukin (IL)-13 and TNF-alpha 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-alpha 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-beta 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.