Ma Xiao, Chen Jiao, Wang Fang, Fan Xinzou, Li Zhenhong, Liang Hantian, Cheng Hao, Nan Fang, Lin Yubin, Song Xiaoshuang, Zhang Jianan, Gao Fan, Zhang Wei, Jin Wenwen, Zhang Huiyuan, Tong Jiyu, Jiang Hong, Zhou Xikun, Zou Qiang, Hu Hongbo, Tong Aiping, Chen WanJun, Zhang Dunfang
Department of Biotherapy, State Key Laboratory of Biotherapy and Cancer Center, Collaborative Innovation Center of Biotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan, China.
Center for Immunology and Hematology, Department of Biotherapy and Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan, China.
Signal Transduct Target Ther. 2025 Aug 26;10(1):271. doi: 10.1038/s41392-025-02359-9.
The intake of sugars, especially glucose and fructose, has significantly increased with the change of lifestyle. Excessive intake of sugar has been proven to be associated with tumors and inflammatory diseases. Fructose directly mediates innate immune responses; however, whether it can directly regulate T-cell immunity remains unknown. We show that high fructose consumption accelerates the development of inflammatory bowel disease (IBD) by promoting the generation of T helper 1 (Th1) and T helper 17 (Th17) cells. It was demonstrated that fructose promotes the differentiation of Th1 and Th17 cells directly by enhancing mechanistic target of rapamycin complex 1 (mTORC1) activation through the glutamine metabolism-dependent pathway. Reactive oxygen species (ROS)-induced activation of transforming growth factor-β (TGF-β) is also involved in fructose-induced Th17 cell generation. Moreover, metformin can reverse Th1 and Th17 cell generation induced by fructose by suppressing mTORC1 activation and reducing ROS-mediated TGF-β activation. Finally, we identified metformin as an in vivo therapeutic drug for relieving high fructose consumption-induced T-cell inflammation and colitis aggravation. Our study revealed a previously unknown adverse effect of high fructose consumption in disrupting immune homeostasis and exacerbating IBD by directly promoting T-cell immunity, and showed metformin is a potential therapeutic for reversing the T cell immune imbalance caused by long-term high fructose consumption.
随着生活方式的改变，糖的摄入量显著增加，尤其是葡萄糖和果糖。过量摄入糖已被证明与肿瘤和炎症性疾病有关。果糖直接介导先天免疫反应；然而，它是否能直接调节T细胞免疫仍不清楚。我们发现，高糖饮食通过促进辅助性T细胞1（Th1）和辅助性T细胞17（Th17）的产生，加速炎症性肠病（IBD）的发展。研究表明，果糖通过谷氨酰胺代谢依赖性途径增强雷帕霉素复合物1（mTORC1）的活性，直接促进Th1和Th17细胞的分化。活性氧（ROS）诱导的转化生长因子-β（TGF-β）激活也参与了果糖诱导的Th17细胞生成。此外，二甲双胍可以通过抑制mTORC1的激活和减少ROS介导的TGF-β激活，逆转果糖诱导的Th1和Th17细胞生成。最后，我们确定二甲双胍是一种体内治疗药物，可以缓解高糖饮食诱导的T细胞炎症和结肠炎加重。我们的研究揭示了高糖饮食在破坏免疫稳态和通过直接促进T细胞免疫加重IBD方面以前未知的不良影响，并表明二甲双胍是一种潜在的治疗方法，可以逆转长期高糖饮食引起的T细胞免疫失衡。
