Intestinal epithelial cell death as modulator of intestinal dysbiosis, systemic autoimmunity and the onset of Arthritis

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Intestinal inflammation and dysbiosis have been linked to autoimmune diseases such as rheumatoid arthritis (RA), however, the underlying mechanisms remain incompletely understood. During the first funding period, we have shown that dysregulated intestinal epithelial cell death by altered CASP8 or HIF2α protein function affects the gut microbiota and subsequently immune cell functions locally in the gut and in the periphery. On a functional level, we could further uncover that HIF proteins influence tight junction biology and epithelial cell death upstream of caspase-8 with opposing functions in experimental arthritis. Interestingly, we further identified that epithelial necroptosis influences tryptophan metabolism and that supplementation of SCFAs ameliorates intestinal inflammation in CASP8 deficient mice. These data indicate that targeting intestinal epithelial cell death might represent a novel promising therapeutic option particularly during the early phase of arthritis. During the second funding period, we therefore propose to better delineate the link between epithelial hypoxia induced necroptosis, SCFAs and arthritis