Kurzfassung

The last decade has witnessed an explosion of research into the molecular networks ensuring maintenance of a mutualistic relationship between microbes and host cell systems such as epithelia and the immune system at mucosal surfaces. Failure of such homeostatic programs leads to susceptibility to intestinal infection or to chronic inflammation causing debilitating human diseases such as inflammatory bowel diseases (e.g., ulcerative colitis, Crohn’s disease) or inflammation-induced intestinal...The last decade has witnessed an explosion of research into the molecular networks ensuring maintenance of a mutualistic relationship between microbes and host cell systems such as epithelia and the immune system at mucosal surfaces. Failure of such homeostatic programs leads to susceptibility to intestinal infection or to chronic inflammation causing debilitating human diseases such as inflammatory bowel diseases (e.g., ulcerative colitis, Crohn’s disease) or inflammation-induced intestinal cancer. Much has been learned about how the microbiota contributes to intestinal homeostasis through the identification of host molecules sensing microbiota and even of specific microbiota controlling distinct aspects of immune cell function. In contrast to the role of the microbiota, the role of nutrients for development and function of the intestinal immune system has been a matter of speculation owing to the fact that molecular sensors of dietary molecules are widely unknown. Given the broad role of nutrients in metabolic diseases and the impact of intestinal cancer on human health, research into the question of how the power of nutrients can be harnessed for improving human health and for the prevention of disease is much warranted.
We have recently found that the aryl hydrocarbon receptor (AhR), a ligand-inducible transcription factor, is required for the development of innate immune system components (Kiss, Science 2011). The AhR serves as a sensor for dietary AhR ligands that are contained in high concentrations in vegetables of the Brassicaceae family (e.g., broccoli, brussel’s sprouts). Specifically, a subset of innate lymphocytes (ILC) referred to as lymphoid tissue inducer (LTi) cells or RORγt⁺ ILC that is involved in maintaining epithelial barrier function and resistance to intestinal infections, required diet-induced AhR signals for its maintenance and expansion. We found that AhR directly regulates expression of the receptor tyrosine kinase Kit which may be the key regulator for the maintenance of RORγt⁺ ILC. The data established the first molecular link between diets and the development of immune system components. Based on these preliminary data, we aim to systematically define the role of diet-induced changes for the function and differentiation of mucosa-associated innate lymphocytes and to uncover how innate lymphoctes regulate epithelial adaptation by controlling niche support for intestinal epithelial stem cells. We propose to address the following three specific aims: (1) to interrogate the role of RORγt⁺ ILC in controling the intestinal stem cell niche, (2) to test the role of diet-controled, tunable Kit signals for maintenance and function of RORγt⁺ ILC and (3) to probe the role of dietary phytochemicals for plasticity of transcriptional programs controling RORγt⁺ ILC effector fates. To achieve these goals we will combine mouse genetics, complex phenotyping, state-of-the-art multicolor fate labeling and pre-clinical disease models.
These aims will for the first time allow to test the role of nutrients in a defined molecular pathway for human health. They have the potential to unravel an entire regulatory niveau in mucosal biology and may reveal new potential therapeutic or prophylactic strategies for intestinal infections, inflammation and cancer.» weiterlesen» einklappen