2. Academic Validation
  3. Ketogenic diet inhibits glioma progression by promoting gut microbiota-derived butyrate production

Ketogenic diet inhibits glioma progression by promoting gut microbiota-derived butyrate production

  • Cancer Cell. 2025 Sep 25:S1535-6108(25)00394-0. doi: 10.1016/j.ccell.2025.09.002.
Ming-Liang Chen 1,  Ying He 2,  Xun-Hu Dong 3,  Hao-Fei Liu 4,  Ze-Xuan Yan 5,  Xiao-Lu Lu 5,  Qing-Qing Miao 5,  Qing-Ning Zhao 5,  Hang Zhang 6,  Li Luo 6,  Shuai Wang 5,  Jing-Yuan Li 5,  Dong-Fang Xiang 5,  Yong Lin 5,  Tian-Ran Li 5,  Xin-Yue Zhou 7,  Yang-Yang Zhou 5,  Min Mao 5,  Xia Zhang 5,  Hong Wei 7,  Yu Shi 6,  Xin-Dong Liu 6,  Yi-Fang Ping 6,  Xiu-Wu Bian 8
Affiliations

Affiliations

  • 1 Institute of Pathology, Medical Research Center for Glioma, Southwest Cancer Center, the First Affiliated Hospital (Southwest Hospital) and School of Basic Medical Sciences, Army Medical University (Third Military Medical University), and the Key Laboratory of Tumor Immunopathology, the Ministry of Education (Third Military Medical University), Chongqing 400038, China; Institute of Toxicology, School of Military Preventive Medicine, Army Medical University (Third Military Medical University), Chongqing 400038, China. Electronic address: chenml@tmmu.edu.cn.
  • 2 Institute of Pathology, Medical Research Center for Glioma, Southwest Cancer Center, the First Affiliated Hospital (Southwest Hospital) and School of Basic Medical Sciences, Army Medical University (Third Military Medical University), and the Key Laboratory of Tumor Immunopathology, the Ministry of Education (Third Military Medical University), Chongqing 400038, China; Department of Ultrasound, Xinqiao Hospital, Army Medical University (Third Military Medical University), Chongqing 400037, China.
  • 3 Institute of Toxicology, School of Military Preventive Medicine, Army Medical University (Third Military Medical University), Chongqing 400038, China.
  • 4 Organoid Innovation Center, CAS Key Laboratory of Nano-Bio Interface, Division of Nanobiomedicine, Suzhou Institute of Nano-Tech and Nano-Bionics, Chinese Academy of Sciences, Suzhou 215123, China.
  • 5 Institute of Pathology, Medical Research Center for Glioma, Southwest Cancer Center, the First Affiliated Hospital (Southwest Hospital) and School of Basic Medical Sciences, Army Medical University (Third Military Medical University), and the Key Laboratory of Tumor Immunopathology, the Ministry of Education (Third Military Medical University), Chongqing 400038, China.
  • 6 Institute of Pathology, Medical Research Center for Glioma, Southwest Cancer Center, the First Affiliated Hospital (Southwest Hospital) and School of Basic Medical Sciences, Army Medical University (Third Military Medical University), and the Key Laboratory of Tumor Immunopathology, the Ministry of Education (Third Military Medical University), Chongqing 400038, China; Chongqing Institute of Advanced Pathology and Yu-Yue Scientific Research Center for Pathology, Jinfeng Laboratory, Chongqing 401329, China.
  • 7 Chongqing Institute of Advanced Pathology and Yu-Yue Scientific Research Center for Pathology, Jinfeng Laboratory, Chongqing 401329, China.
  • 8 Institute of Pathology, Medical Research Center for Glioma, Southwest Cancer Center, the First Affiliated Hospital (Southwest Hospital) and School of Basic Medical Sciences, Army Medical University (Third Military Medical University), and the Key Laboratory of Tumor Immunopathology, the Ministry of Education (Third Military Medical University), Chongqing 400038, China; Chongqing Institute of Advanced Pathology and Yu-Yue Scientific Research Center for Pathology, Jinfeng Laboratory, Chongqing 401329, China. Electronic address: bianxiuwu@263.net.
PMID: 41005305 DOI: 10.1016/j.ccell.2025.09.002
Abstract

The ketogenic diet (KD) is a potential therapeutic strategy for glioma; however, the underlying mechanisms remain unclear. Herein, we first identify that glioma patients exhibit a distinct gut microbial profile characterized by reduced butyrate-producing bacteria abundance, particularly R. faecis, along with decreased butyrate levels. Notably, KD reshapes the gut microbiota especially enriching A. muciniphila in a mucin-2-dependent manner, elevates butyrate production, and activates Caspase-3 in microglia. These changes promote an anti-tumor microglial phenotype, ultimately suppressing glioma progression in mice. Crucially, KD's anti-glioma effect is notably abolished by Antibiotics treatment; germ-free condition; or specific depletion of mucin-2, microglia, or microglial Caspase-3. Furthermore, butyrate, A. muciniphila, R. faecis, or A. muciniphila plus R. faecis restores KD-induced microglial Caspase-3 activation and the anti-tumor phenotype of microglia in antibiotics-treated or germ-free mice. These findings highlight that targeting the gut microbiota by KD or supplementing with butyrate could be an effective strategy for glioma therapy.

Keywords

butyrate; caspase-3; glioma; gut microbiota; ketogenic diet; microglia.

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