A02: Yabal

Intestinal dysfunction and tissue damage associated with inflammatory bowel disease (IBD) is associated with increased cell death. IBD is also associated with changes in the commensal microbiota and increased levels of the cytokine TNF. We propose that the microbiota plays a role in regulating cell death decisions via the metabolites they produce in the gut. In this project, we therefore focus on elucidating the mechanisms underlying the regulation of cell death by microbiota-derived metabolites on intestinal epithelial cells. Based on strong preliminary data we first look specifically at the short-chain fatty acid (SCFA) butyrate and its impact on TNF-mediated cell death induction in primary epithelial cells. We will examine how butyrate impacts apoptotic, necroptotic and pyroptotic death programs at the transcriptional and post-translational level. We aim to determine whether specific epithelial cell types are more susceptible to undergoing different cell death programs than others. Together, the data generated by this study will elucidate how cell death decisions are modulated by the microbiota. Understanding this relationship will have implications for understanding how TNFR1 signaling can be modulated by agents other than the TNF-blockers now routinely used in clinics for IBD patients.