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

  • Signal Transduct Target Ther. 2025 Mar 5;10(1):79. doi: 10.1038/s41392-025-02159-1.
Bai Cui  #  1 ,  Huandong Luo  #  1  2 ,  Bin He  #  1 ,  Xinyu Liu  #  3 ,  Dekang Lv  #  1 ,  Xiaoyu Zhang  1 ,  Keyu Su  1 ,  Sijia Zheng  3 ,  Jinxin Lu  1 ,  Cenxin Wang  1 ,  Yuqing Yang  1 ,  Zhuoran Zhao  1 ,  Xianxian Liu  1 ,  Xu Wang  1 ,  Yingrui Zhao  1 ,  Xiaoshan Nie  1 ,  Yuanyuan Jiang  1 ,  Ziyu Zhang  1 ,  Congcong Liu  1 ,  Xinyi Chen  1 ,  Anqi Cai  1 ,  Zhumeng Lv  1 ,  Zhihang Liu  1 ,  Fan An  1 ,  Yunkun Zhang  4 ,  Qiulong Yan  5 ,  Keith W Kelley  6 ,  Guowang Xu  3 ,  Lingzhi Xu  7 ,  Quentin Liu  8  9 ,  Fei Peng  10
Affiliations
  • 1. Institute of Cancer Stem Cell, Dalian Medical University, Dalian, China.
  • 2. State Key Laboratory of Oncology in South China, Cancer Center, Sun Yat-sen University, Guangzhou, China.
  • 3. Key Laboratory of Separation Sciences for Analytical Chemistry, National Chromatographic R&A Center, Dalian Institute of Chemical Physics, Chinese Academy of Sciences (CAS), Dalian, China.
  • 4. Department of Pathology, The Second Hospital of Dalian Medical University, Dalian, China.
  • 5. Department of Microbiology, College of Basic Medical Sciences, Dalian Medical University, Dalian, China.
  • 6. Department of Pathology, College of Medicine and Department of Animal Sciences, College of ACES, University of Illinois at Urbana-Champaign, Urbana, IL, USA.
  • 7. Department of Oncology, the Second Affiliated Hospital, Dalian Medical University, Dalian, China. [email protected].
  • 8. Institute of Cancer Stem Cell, Dalian Medical University, Dalian, China. [email protected].
  • 9. State Key Laboratory of Oncology in South China, Cancer Center, Sun Yat-sen University, Guangzhou, China. [email protected].
  • 10. Institute of Cancer Stem Cell, Dalian Medical University, Dalian, China. [email protected].
  • # Contributed equally.
PMID: 40038255 DOI: 10.1038/s41392-025-02159-1
Abstract

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.

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