Epithelial TSC1-mTOR controls RIPK3-dependent necroptosis and susceptibility to IBD by sensing dietary and microbial metabolites

Abstract

Abstract Intestinal epithelial cells (IECs) are responsible for the sensing and uptake of dietary and microbial metabolites, yet how dietary and microbial components exert on intestinal homeostasis and Inflammatory Bowel Diseases (IBDs) has yet to be better understood. Here we firstly identified epithelial necroptosis as a key process influenced by nutrients protein and fatty acid, as feeding high-protein or high-fat diet to mice led to mTOR activation and aberrant necrosis in IECs. Notably, genetic ablation of TSC1 in the IECs mimicked the effect of high-protein/fat feeding, resulting in mTOR dysregulation, epithelial necrosis and hyper-susceptibility to colitis. Mechanistically, our data demonstrated that aberrant activation of mTOR could result in the overexpression of RIPK3 in enterocytes, whereby rendering epithelial necrosis and ensuing colitis, a process could be reversed by microbiota-depletion or rapamycin treatment. Remarkably, this mTOR-RIP3-necrosis axis seemed to underlie the pathogenesis of human IBDs as well. Furthermore, we found that mTOR-regulated selective autophagy might have contributed to the degradation of RIPK3 in IECs, revealing an intricate association between autophagy and necroptosis. Together, our data unravel an unsuspected link between metabolism and necroptosis, and highlight a crucial role for TSC1-mTOR in the maintenance of intestinal homeostasis and prevention of colonic inflammation through coordinating epithelial metabolism, autophagy and necroptosis.