Impact of the intestinal microbiota and microbiota mediated immuneresponses on the host cell death machinery in the intestinalepithelium

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Previous studies identified a caspase-independent mode of programmed cell death, denoted necroptosis, which is mediated by the ripoptosome protein complex. In a very recent study we could demonstrate a critical role for caspase-8 in regulating necroptosis of intestinal epithelial cells and intestinal immune homeostasis. Mice with a conditional deletion of caspase-8 in the intestinal epithelium (Casp8ΔIEC) spontaneously develop inflammatory lesions in the terminal ileum and are highly susceptible to experimentally induced colitis. Casp8ΔIEC mice lack Paneth cells due to necroptosis and demonstrate decreased expression of antimicrobial peptides, suggesting dysregulated anti-microbial immune response of the intestinal epithelium. How necroptosis of Paneth cells is triggered, whether Paneth cell necroptosis induces barrier dysfunction and is causative of inflammation remains an open question and is the subject of the current proposal.As preliminary data for this proposal, we demonstrate alterations in the composition and distribution of the microbial flora. Moreover we found a direct attachment of microbes to intestinal epithelial cells in Casp8ΔIEC mice and a profound systemic spread of bacteria upon challenge of these mice with DSS. Thus, our data so far implicate a critical role of caspase-8 and Paneth cell necroptosis in regulating intestinal immune homeostasis and antimicrobial defence.The overall goal of the project is to investigate the relationship between Paneth cell necroptosis, the microbial flora of the gut and intestinal inflammation. Accordingly, we will determine the role of the intestinal microbiota on necroptosis, ripoptosome complex formation and necroptosis-induced intestinal inflammation in different in vitro and in vivo systems. Our analyses will include conventional and gnotobiotic mouse strains that will be left untreated or will be treated in experimental disease models, including models of intestinal infection and inflammation. Moreover, we will study how Paneth cell necroptosis affects the composition of the microbial flora and barrier function in the gut.The project described in this proposal will provide novel insights into the regulation of necroptosis in the intestinal epithelium and its consequences for intestinal immune homeostasis. A better understanding of these pathways might uncover new therapeutic options for the treatment of intestinal infection and inflammation.