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<p>Psychological stress causes gut microbial dysbiosis and cancer progression, yet how gut microbiota determines psychological stress-induced tumor development remains unclear. Here we showed that psychological stress promotes breast tumor growth and cancer stemness, an outcome that depends on gut microbiota in germ-free and antibiotic-treated mice. Metagenomic and metabolomic analyses revealed that psychological stress markedly alters the composition and abundance of gut microbiota, especially <i>Akkermansia muciniphila</i> (<i>A. muciniphila</i>), and decreases short-chain fatty acid butyrate. Supplement of active <i>A. muciniphila</i>, butyrate or a butyrate-producing high fiber diet dramatically reversed the oncogenic property and anxiety-like behavior of psychological stress in a murine spontaneous tumor model or an orthotopic tumor model. Mechanistically, RNA sequencing analysis screened out that butyrate decreases LRP5 expression to block the activation of Wnt/β-catenin signaling pathway, dampening breast cancer stemness. Moreover, butyrate as a HDAC inhibitor elevated histone H3K9 acetylation level to transcriptionally activate ZFP36, which further accelerates LRP5 mRNA decay by binding adenine uridine-rich (AU-rich) elements of LRP5 transcript. Clinically, fecal <i>A. muciniphila</i> and serum butyrate were inversely correlated with tumoral LRP5/β-catenin expression, poor prognosis and negative mood in breast cancer patients. Altogether, our findings uncover a microbiota-dependent mechanism of psychological stress-triggered cancer stemness, and provide both clinical biomarkers and potential therapeutic avenues for cancer patients undergoing psychological stress.</p>

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Gut dysbiosis conveys psychological stress to activate LRP5/β-catenin pathway promoting cancer stemness

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年3月5日

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  • Bai Cui,
  • Huandong Luo,
  • Bin He,
  • Xinyu Liu,
  • Dekang Lv,
  • Xiaoyu Zhang,
  • Keyu Su,
  • Sijia Zheng,
  • Jinxin Lu,
  • Cenxin Wang,
  • Yuqing Yang,
  • Zhuoran Zhao,
  • Xianxian Liu,
  • Xu Wang,
  • Yingrui Zhao,
  • Xiaoshan Nie,
  • Yuanyuan Jiang,
  • Ziyu Zhang,
  • Congcong Liu,
  • Xinyi Chen,
  • Anqi Cai,
  • Zhumeng Lv,
  • Zhihang Liu,
  • Fan An,
  • Yunkun Zhang,
  • Qiulong Yan,
  • Keith W. Kelley,
  • Guowang Xu,
  • Lingzhi Xu,
  • Quentin Liu,
  • Fei Peng

摘要

Psychological stress causes gut microbial dysbiosis and cancer progression, yet how gut microbiota determines psychological stress-induced tumor development remains unclear. Here we showed that psychological stress promotes breast tumor growth and cancer stemness, an outcome that depends on gut microbiota in germ-free and antibiotic-treated mice. Metagenomic and metabolomic analyses revealed that psychological stress markedly alters the composition and abundance of gut microbiota, especially Akkermansia muciniphila (A. muciniphila), and decreases short-chain fatty acid butyrate. Supplement of active A. muciniphila, butyrate or a butyrate-producing high fiber diet dramatically reversed the oncogenic property and anxiety-like behavior of psychological stress in a murine spontaneous tumor model or an orthotopic tumor model. Mechanistically, RNA sequencing analysis screened out that butyrate decreases LRP5 expression to block the activation of Wnt/β-catenin signaling pathway, dampening breast cancer stemness. Moreover, butyrate as a HDAC inhibitor elevated histone H3K9 acetylation level to transcriptionally activate ZFP36, which further accelerates LRP5 mRNA decay by binding adenine uridine-rich (AU-rich) elements of LRP5 transcript. Clinically, fecal A. muciniphila and serum butyrate were inversely correlated with tumoral LRP5/β-catenin expression, poor prognosis and negative mood in breast cancer patients. Altogether, our findings uncover a microbiota-dependent mechanism of psychological stress-triggered cancer stemness, and provide both clinical biomarkers and potential therapeutic avenues for cancer patients undergoing psychological stress.