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GRK 1482 Jahrbuch 2011-2014

Abstract Nutritional factors emerge to play a key role in the pathogenesis of chronic inflammatory diseases. Iron depletion was shown to prevent experimental ileitis in TNF∆ARE/WT mice and oral iron replacement the- rapy is often poorly tolerated by IBD patients. We hypothesize that luminal iron may directly affect the epithelium cell layer and/or may influence gut health via changes in the bacterial milieu. The focus of this project is on a better understanding of iron-influenced inflamm- atory processes in experimental settings. Introduction The gastrointestinal tract acts as an important bar- rier between the host and the luminal environment of the gut including nutritional as well as bacteri- al factors. In inflammatory bowel diseases (IBD), represented by the two major form Crohn‘s disease (CD) and ulcerative colitis (UC), the barrier between the lumen and the host is disrupted. Despite a long history of research the etiology of IBD is not yet fully understood. Beside other life style factors nutri- tional components emerged to be one of the most prominent environmental triggers for the develop- ment of chronic intestinal inflammation. Luminal iron was identified to be able to influence inflammatory processes in the gut in TNF∆ARE/WT mice [1]. TNF∆ARE/WT mice carry a genetic modi- fication in the untranslated region of an AU-rich element (ARE) in the TNF gene leading to an im- paired regulation of the TNF expression. They are used as a model for Crohn’s disease and develop a severe intestinal inflammation in their distal ileum accompanied by villous atrophy, crypt hyperplasia and leukocyte infiltration when kept on a conventi- onal diet. We observed that TNF∆ARE/WT mice were almost completely protected from the intestinal inflammation when the mice were fed an iron sul- fate-depleted diet. Corresponding to these findings about one third of the patients with IBD suffer from iron deficiency anemia due to an inappropriate nu- tritional iron intake and/or due to a loss of iron as a result of inflammatory processes in their gut but an oral iron replacement therapy (normally ferrous sulfate) is often poorly tolerated [3]. Furthermore, we showed that the depletion of lu- minal iron induced a compositional alteration of the gut microbiota with iron-dependent changes in bacteria belonging to the geni Bifidobacterium, Turicibacter, Succinivibrio and Desulfovibrio [1, see fig. 1]. Besides, we found that a gluten-fortified diet forti- fied the inflammation in TNF∆ARE/WT mice. Gluten- derived peptides failed to induce a CD4+ T-cell ac- tivation while reduced occludin expression levels suggest a negative role of gluten on the intestinal barrier integrity [2]. PhD FELLOWS Page 44 | GRK Progress Report 2011-2014 Annemarie Schmidt (M.Sc.) Nutrition and Immunology PhD 7/2 Impact of dietary iron in the regulation of chronic intestinal inflammations