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<p>Obesity is a major risk factor for colorectal cancer (CRC), yet the mechanisms linking obesity-associated gut dysbiosis to tumor progression remain unclear. Here, we show that a high-fat diet and fecal microbiota from patients with obesity-associated CRC deplete the GABA-producing commensal <i>Bacteroides ovatus</i>, resulting in reduced luminal GABA and accelerated tumorigenesis. Microbial GABA activates epithelial GABAB receptor signaling and induces TPI1 through the PI3K–HIF1α pathway. Increased TPI1-derived glyceraldehyde-3-phosphate inhibits PPP1CA, maintains YAP phosphorylation, restricts nuclear YAP activity, and suppresses pentose phosphate pathway flux, thereby limiting tumor growth. Consistently, obesity-associated CRC exhibits reduced fecal GABA, decreased TPI1 expression, and metabolic rewiring. A GABA-deficient <i>B. ovatus</i> mutant fails to restore GABA or suppress tumors despite normal colonization, whereas oral GABA supplementation or recolonization with wild-type <i>B. ovatus</i> markedly reduces tumor burden. These findings identify a microbiota–neurotransmitter–metabolism axis linking obesity to CRC and suggest microbiota-based GABA restoration as a potential preventive strategy.</p>

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Obesity-driven microbial GABA depletion promotes metabolic rewiring and colorectal cancer progression

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年7月27日

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  • Wei Guo,
  • Kaiyue Sun,
  • Xia Wang,
  • Mengmeng Li,
  • Zheng Li,
  • Xizan Yue,
  • Yi Yin,
  • Tengfei Ma,
  • Yikun Li,
  • Xiaoning Xu,
  • Jianbo Liu,
  • Jiahao Zhang,
  • Cuiyu Zhang,
  • Panpan Feng,
  • Ruijie Ma,
  • Jiayi Ren,
  • Jie Liu,
  • Changan Liu,
  • Xiang Gao,
  • Dawei Chen,
  • Jingxin Li

摘要

Obesity is a major risk factor for colorectal cancer (CRC), yet the mechanisms linking obesity-associated gut dysbiosis to tumor progression remain unclear. Here, we show that a high-fat diet and fecal microbiota from patients with obesity-associated CRC deplete the GABA-producing commensal Bacteroides ovatus, resulting in reduced luminal GABA and accelerated tumorigenesis. Microbial GABA activates epithelial GABAB receptor signaling and induces TPI1 through the PI3K–HIF1α pathway. Increased TPI1-derived glyceraldehyde-3-phosphate inhibits PPP1CA, maintains YAP phosphorylation, restricts nuclear YAP activity, and suppresses pentose phosphate pathway flux, thereby limiting tumor growth. Consistently, obesity-associated CRC exhibits reduced fecal GABA, decreased TPI1 expression, and metabolic rewiring. A GABA-deficient B. ovatus mutant fails to restore GABA or suppress tumors despite normal colonization, whereas oral GABA supplementation or recolonization with wild-type B. ovatus markedly reduces tumor burden. These findings identify a microbiota–neurotransmitter–metabolism axis linking obesity to CRC and suggest microbiota-based GABA restoration as a potential preventive strategy.