Mechanisms of epithelial barrier dysfunction in gastrointestinal infectious diseases

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Septic disease is the third common cause of death in Germany. Very often, the pathogens originate from the intestine. Main aim of this project is to define bacterial pathomechanisms and epithelial disturbances, which cause diarrhea and malabsorption as well as antigen uptake and bacterial translocation. This will improve our knowledge about the pathogenesis of intestinal infections and the resulting inflammatory processes in the intestine.Using electrophysiological, morphological and molecular techniques, we measure with miniaturized Ussing systems on human biopsies. In parallel, we search in epithelial and animal models for underlying pathomechanisms and signal transduction processes. In the present project, barrier function will be studied in patients with Clostridium difficile-induced colitis after antibiotic treatment. Toxins TcdA and TcdB as well as the binary toxin (CDT) will be investigated in 2d-organoid model of human colon in coculture with M1-macrophages in respect to changes in epithelial tight junctions and appearance of epithelial apoptoses and focal leaks in the intestinal epithelium. This follows the hypothesis that the binary toxin CDT binds to the epithelial tight junction protein LSR (angulin-1) and facilitates the epithelial uptake of TcdA and TcdB, as a result of which TcdA and TcdB translocate and initiate a cytokine response in the mucosal immune system. The barrier defect induced in this manner acts as permissive factor in pseudomembranous colitis. Based on this, protective influences of zinc, quercetin, vitamin D and others will be screened for therapeutic effects.In conclusion, this DFG grant application aims at the definition of relevant pathomechanisms and wants to improve our understanding of the regulation of intestinal epithelial transport and barrier function in the context of gastrointestinal diseases, which is the basis for preventive strategies.