Vagal pathway activation links chronic stress to decline in intestinal stem cell function

  • Cell Stem Cell. 2025 May 1;32(5):778-794.e10. doi: 10.1016/j.stem.2025.02.016.
Guoying Zhang  1 ,  Yannan Lian  2 ,  Qingguo Li  3 ,  Shudi Zhou  4 ,  Lili Zhang  2 ,  Liting Chen  5 ,  Junzhe Tang  3 ,  Hailong Liu  6 ,  Ni Li  1 ,  Qiang Pan  1 ,  Yongqiang Gu  2 ,  Naiheng Lin  2 ,  Hanling Wang  2 ,  Xuege Wang  2 ,  Jiacheng Guo  2 ,  Wei Zhang  2 ,  Zige Jin  2 ,  Beitao Xu  2 ,  Xiao Su  7 ,  Moubin Lin  8 ,  Qi Han  9 ,  Jun Qin  10
Affiliations
  • 1. CAS Key Laboratory of Tissue Microenvironment and Tumor, Shanghai Institute of Nutrition and Health, Chinese Academy of Sciences, 320 Yueyang Road, Shanghai 200031, China; Jinfeng Laboratory, Chongqing 401329, China.
  • 2. CAS Key Laboratory of Tissue Microenvironment and Tumor, Shanghai Institute of Nutrition and Health, Chinese Academy of Sciences, 320 Yueyang Road, Shanghai 200031, China.
  • 3. Department of Colorectal Surgery, Fudan University Shanghai Cancer Center, Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, Shanghai 200032, China.
  • 4. Department of Endocrinology, Shanghai Children's Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200062, China.
  • 5. Department of Emergency and Critical Disease, Songjiang Hospital and Songjiang Research Institute, Shanghai Key Laboratory of Emotions and Affective Disorders, Shanghai Jiao Tong University School of Medicine, Shanghai 201600, China; Department of Anatomy and Physiology, Key Laboratory of Cell Differentiation and Apoptosis of Chinese Ministry of Education, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China.
  • 6. Department of General Surgery, Yangpu Hospital, School of Medicine, Tongji University, Shanghai, China.
  • 7. Shanghai Institute of Immunity and Infection, Chinese Academy of Sciences, 320 Yueyang Road, Shanghai 200031, China. Electronic address: [email protected].
  • 8. Department of General Surgery, Yangpu Hospital, School of Medicine, Tongji University, Shanghai, China. Electronic address: [email protected].
  • 9. Department of Emergency and Critical Disease, Songjiang Hospital and Songjiang Research Institute, Shanghai Key Laboratory of Emotions and Affective Disorders, Shanghai Jiao Tong University School of Medicine, Shanghai 201600, China; Department of Anatomy and Physiology, Key Laboratory of Cell Differentiation and Apoptosis of Chinese Ministry of Education, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China. Electronic address: [email protected].
  • 10. CAS Key Laboratory of Tissue Microenvironment and Tumor, Shanghai Institute of Nutrition and Health, Chinese Academy of Sciences, 320 Yueyang Road, Shanghai 200031, China; Jinfeng Laboratory, Chongqing 401329, China. Electronic address: [email protected].
PMID: 40120585 DOI: 10.1016/j.stem.2025.02.016
Abstract

Chronic stress adversely affects intestinal health, but the specific neural pathways linking the brain to intestinal tissue are not fully understood. Here, we show that chronic stress-induced activation of the central amygdala-dorsal motor nucleus of the vagus (CeA-DMV) pathway accelerates premature aging and impairs the stemness of intestinal stem cells (ISCs). This pathway influences ISC function independently of the microbiota, the hypothalamic-pituitary-adrenal (HPA) axis, the immune response, and the sympathetic nervous system (SNS). Under chronic stress, DMV-mediated vagal activation prompts cholinergic enteric neurons to release acetylcholine (ACh), which engages ISCs via the M3 Muscarinic Acetylcholine Receptor (CHRM3). This interaction activates the p38 mitogen-activated protein kinase (MAPK) pathway, triggering growth arrest and mitochondrial fragmentation, thereby accelerating an aging-like decline in ISCs. Together, our findings provide insights into an alternative neural mechanism that links stress to intestinal dysfunction. Strategies targeting the DMV-associated vagal pathway represent potential therapeutic approaches for stress-induced intestinal diseases.

Keywords
aging; chronic stress; intestinal stem cells; p38; the brain-gut axis; vagus.
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