1. Academic Validation
  2. Vagal pathway activation links chronic stress to decline in intestinal stem cell function

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

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: xsu@ips.ac.cn.
  • 8 Department of General Surgery, Yangpu Hospital, School of Medicine, Tongji University, Shanghai, China. Electronic address: lmbin@hotmail.com.
  • 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: qihan8@shsmu.edu.cn.
  • 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: qinjun@sibs.ac.cn.
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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