2. Academic Validation
  3. High fructose consumption aggravates inflammation by promoting effector T cell generation via inducing metabolic reprogramming

High fructose consumption aggravates inflammation by promoting effector T cell generation via inducing metabolic reprogramming

  • Signal Transduct Target Ther. 2025 Aug 26;10(1):271. doi: 10.1038/s41392-025-02359-9.
Xiao Ma # 1 2,  Jiao Chen # 3,  Fang Wang # 4,  Xinzou Fan 1,  Zhenhong Li 1,  Hantian Liang 1,  Hao Cheng 1,  Fang Nan 1,  Yubin Lin 1,  Xiaoshuang Song 1,  Jianan Zhang 1,  Fan Gao 1,  Wei Zhang 1 2,  Wenwen Jin 5,  Huiyuan Zhang 2,  Jiyu Tong 6,  Hong Jiang 7,  Xikun Zhou 1,  Qiang Zou 8,  Hongbo Hu 2,  Aiping Tong 9,  WanJun Chen 10,  Dunfang Zhang 11 12
Affiliations

Affiliations

  • 1 Department of Biotherapy, State Key Laboratory of Biotherapy and Cancer Center, Collaborative Innovation Center of Biotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan, China.
  • 2 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.
  • 3 State Key Laboratory of Oral Diseases and National Center for Stomatology and National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, Sichuan, China.
  • 4 Innovation Center of Nursing Research, Nursing Key Laboratory of Sichuan Province, West China Hospital, Sichuan University, Chengdu, Sichuan, China.
  • 5 Mucosal Immunology Section, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, MD, USA.
  • 6 Department of Immunology, West China School of Basic Medical Sciences and Forensic Medicine, Key Laboratory of Birth Defects and Related Diseases of Women and Children, West China Second University Hospital, Sichuan University, Chengdu, Sichuan, China.
  • 7 Department of Pancreatic Surgery, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu, Sichuan, China.
  • 8 Shanghai Chest Hospital & Shanghai Institute of Immunology, State Key Laboratory of Systems Medicine for Cancer, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
  • 9 Department of Biotherapy, State Key Laboratory of Biotherapy and Cancer Center, Collaborative Innovation Center of Biotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan, China. aipingtong@scu.edu.cn.
  • 10 Mucosal Immunology Section, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, MD, USA. wchen@nih.gov.
  • 11 Department of Biotherapy, State Key Laboratory of Biotherapy and Cancer Center, Collaborative Innovation Center of Biotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan, China. izdf@163.com.
  • 12 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. izdf@163.com.
  • # Contributed equally.
PMID: 40854873 DOI: 10.1038/s41392-025-02359-9
Abstract

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.

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