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

Guoying Zhang¹, Yannan Lian², Qingguo Li³, Shudi Zhou⁴, Lili Zhang², Liting Chen⁵, Junzhe Tang³, Hailong Liu⁶, Ni Li¹, Qiang Pan¹, Yongqiang Gu², Naiheng Lin², Hanling Wang², Xuege Wang², Jiacheng Guo², Wei Zhang², Zige Jin², Beitao Xu², Xiao Su⁷, Moubin Lin⁸, Qi Han⁹, Jun Qin¹⁰

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.

PMID: 40120585
DOI: 10.1016/j.stem.2025.02.016

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

Guoying Zhang et al. Cell Stem Cell. 2025.

. 2025 May 1;32(5):778-794.e10.

doi: 10.1016/j.stem.2025.02.016. Epub 2025 Mar 21.

Authors

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.

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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Conflict of interest statement

Declaration of interests The authors declare no potential conflicts of interest.

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

Affiliations

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

Authors

Affiliations

Abstract

Conflict of interest statement

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Substances

LinkOut - more resources

Full Text Sources

Medical