The Center for Microbes, Development and Health, Chinese Academy of Sciences (CAS) Key Laboratory of Molecular Virology and Immunology, Institut Pasteur of Shanghai; CAS Center for Excellence in Molecular Cell Science; University of Chinese Academy of Sciences, CAS, Shanghai, China.
Center for Allergic and Inflammatory Diseases & Department of Otolaryngology, Head and Neck Surgery, Affiliated Eye, Ear, Nose and Throat Hospital, Fudan University, Shanghai, China.
J Clin Invest. 2020 Apr 1;130(4):2111-2128. doi: 10.1172/JCI133264.
Although Western diet and dysbiosis are the most prominent environmental factors associated with inflammatory bowel diseases (IBDs), the corresponding host factors and cellular mechanisms remain poorly defined. Here we report that the TSC1/mTOR pathway in the gut epithelium represents a metabolic and innate immune checkpoint for intestinal dysfunction and inflammation. mTOR hyperactivation triggered by Western diet or Tsc1 ablation led to epithelium necroptosis, barrier disruption, and predisposition to dextran sulfate sodium-induced colitis and inflammation-associated colon cancer. Mechanistically, our results uncovered a critical role for TSC1/mTOR in restraining the expression and activation of RIPK3 in the gut epithelium through TRIM11-mediated ubiquitination and autophagy-dependent degradation. Notably, microbiota depletion by antibiotics or gnotobiotics attenuated RIPK3 expression and activation, thereby alleviating epithelial necroptosis and colitis driven by mTOR hyperactivation. mTOR primarily impinged on RIPK3 to potentiate necroptosis induced by TNF and by microbial pathogen-associated molecular patterns (PAMPs), and hyperactive mTOR and aberrant necroptosis were intertwined in human IBDs. Together, our data reveal a previously unsuspected link between the Western diet, microbiota, and necroptosis and identify the mTOR/RIPK3/necroptosis axis as a driving force for intestinal inflammation and cancer.
虽然西方饮食和菌群失调是与炎症性肠病（IBD）最相关的突出环境因素，但相应的宿主因素和细胞机制仍未得到明确界定。在这里，我们报告称，肠道上皮细胞中的 TSC1/mTOR 途径代表了肠道功能障碍和炎症的代谢和先天免疫检查点。西方饮食或 Tsc1 缺失引起的 mTOR 过度激活导致上皮细胞坏死、屏障破坏，并易患葡聚糖硫酸钠诱导的结肠炎和炎症相关结肠癌。从机制上讲，我们的研究结果揭示了 TSC1/mTOR 在通过 TRIM11 介导的泛素化和自噬依赖性降解来抑制肠道上皮细胞中 RIPK3 的表达和激活方面的关键作用。值得注意的是，抗生素或无菌动物对微生物群的耗竭减弱了 RIPK3 的表达和激活，从而减轻了由 mTOR 过度激活引起的上皮坏死和结肠炎。mTOR 主要通过 TNF 和微生物病原体相关分子模式（PAMPs）来影响 RIPK3 以增强坏死，而过度活跃的 mTOR 和异常的坏死在人类 IBD 中相互交织。总之，我们的数据揭示了西方饮食、微生物群和坏死之间以前未被怀疑的联系，并确定了 mTOR/RIPK3/坏死途径是肠道炎症和癌症的驱动力。
