Section A Project A02

Inflammation-induced intestinal epithelial regulated necrosis as a novel modulator of bone resorption

Thanks to complementary expertises, project A02 will focus on inflammation-driven bacterial dysbiosis in the gut and how associated alterations in the metabolome affect joint and bone homeostasis. The project is built on the strong expertise of both PIs on mucosal and osteo-immunology and will delineate the impact of microbe-epithelial communication in the gut on the gut-bone axis. Preliminary data implicate that microbiota-dependent and -independent mechanisms driven by caspase-8 deficiency in the intestinal epithelium influence serotonin production in the gut, associated with a pathophysiological bone loss triggered by an alteration in osteoblast/osteoclast homeostasis. The key hypothesis of the project is that regulated necrosis of intestinal epithelial cells and associated alterations in intestinal metabolites (host and microbiota) promote inflammatory bone loss by altering tryptophan metabolism. They will follow their previous and preliminary data and mechanistically analyze how these novel players affect bone homeostasis and osteogenesis by taking advantage of a well-established mouse model for IBD (Casp8^ΔIEC mice) (Günther, et al., 2015; Günther, et al., 2011) as well as human biosamples and ex vivo organ cultures.