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

肠道炎症和生物失调与类风湿性关节炎(RA)等自身免疫性疾病有关，然而，其潜在的机制仍不完全清楚。在第一个资助期，我们已经表明，CASP8或HIF2α蛋白功能改变导致的肠道上皮细胞死亡失调会影响肠道微生物区系，随后影响肠道局部和外周的免疫细胞功能。在功能水平上，我们可以进一步发现，在实验性关节炎中，HIF蛋白影响紧密连接生物学和caspase-8上游的上皮细胞死亡，但功能相反。有趣的是，我们进一步确认上皮性坏死下垂影响色氨酸代谢，补充SCFAs可改善CASP8缺陷小鼠的肠道炎症。这些数据表明，以肠上皮细胞死亡为靶点可能是一种新的有前途的治疗选择，特别是在关节炎的早期阶段。因此，在第二个资助期内，我们建议更好地界定上皮性缺氧所致的坏死性下垂、短链脂肪酸和关节炎之间的联系。

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