Sleep disturbance triggers aberrant activation of vagus circuitry and induces intestinal stem cell dysfunction

Mingxin Zhang; Xi Wu; Di Liu; Huaxing Li; Xulin Li; Wuqi Yang; Jialin Ye; Liyuan Hou; Shiyang Wang; Ning Ning; Hanfu Zhang; Yuhua Tian; Lu Yu; Kaichun Wu; Liping Wang; Maksim V Plikus; Cong Lv; Feng Wang; Zhengquan Yu

doi:10.1016/j.stem.2026.01.002

Sleep disturbance triggers aberrant activation of vagus circuitry and induces intestinal stem cell dysfunction

Cell Stem Cell. 2026 Feb 5;33(2):306-324.e8. doi: 10.1016/j.stem.2026.01.002.

Authors

Mingxin Zhang¹, Xi Wu², Di Liu², Huaxing Li², Xulin Li³, Wuqi Yang⁴, Jialin Ye⁵, Liyuan Hou⁴, Shiyang Wang², Ning Ning², Hanfu Zhang², Yuhua Tian⁶, Lu Yu², Kaichun Wu⁷, Liping Wang³, Maksim V Plikus⁸, Cong Lv⁹, Feng Wang¹⁰, Zhengquan Yu¹¹

Affiliations

¹ State Key Laboratory of Metabolic Dysregulation, Prevention and Treatment of Esophageal Cancer, School of Life Sciences, Zhengzhou University, Zhengzhou 450052, Henan, China; State Key Laboratory of Animal Biotech Breeding, College of Biological Sciences, China Agricultural University, Beijing 100193, China.
² State Key Laboratory of Animal Biotech Breeding, College of Biological Sciences, China Agricultural University, Beijing 100193, China.
³ Shenzhen Key Laboratory of Neuropsychiatric Modulation, Guangdong Provincial Key Laboratory of Brain Connectome and Behavior, the Brain Cognition and Brain Disease Institute, Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences, Shenzhen-Hong Kong Institute of Brain Science, Shenzhen 518055, China; University of Chinese Academy of Sciences, Beijing 101408, China.
⁴ Key Laboratory of Precision Nutrition and Food Quality, Ministry of Education, Department of Nutrition and Health, China Agricultural University, Beijing 100193, China.
⁵ Shenzhen Key Laboratory of Neuropsychiatric Modulation, Guangdong Provincial Key Laboratory of Brain Connectome and Behavior, the Brain Cognition and Brain Disease Institute, Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences, Shenzhen-Hong Kong Institute of Brain Science, Shenzhen 518055, China.
⁶ State Key Laboratory of Metabolic Dysregulation, Prevention and Treatment of Esophageal Cancer, School of Life Sciences, Zhengzhou University, Zhengzhou 450052, Henan, China; Tianjian Laboratory of Advanced Biomedical Sciences, Academy of Medical Sciences, Zhengzhou University, Zhengzhou 450052, Henan, China.
⁷ State Key Laboratory of Holistic Integrative Management of Gastrointestinal Cancers and Xijing Hospital of Digestive Diseases, Fourth Military Medical University, Xi'an 710032, China.
⁸ Department of Developmental and Cell Biology, Sue and Bill Gross Stem Cell Research Center, Center for Complex Biological Systems, University of California, Irvine, Irvine, CA 92697, USA. Electronic address: plikus@uci.edu.
⁹ Key Laboratory of Precision Nutrition and Food Quality, Ministry of Education, Department of Nutrition and Health, China Agricultural University, Beijing 100193, China. Electronic address: lvc@cau.edu.cn.
¹⁰ Shenzhen Key Laboratory of Neuropsychiatric Modulation, Guangdong Provincial Key Laboratory of Brain Connectome and Behavior, the Brain Cognition and Brain Disease Institute, Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences, Shenzhen-Hong Kong Institute of Brain Science, Shenzhen 518055, China; University of Chinese Academy of Sciences, Beijing 101408, China. Electronic address: feng.wang@siat.ac.cn.
¹¹ State Key Laboratory of Metabolic Dysregulation, Prevention and Treatment of Esophageal Cancer, School of Life Sciences, Zhengzhou University, Zhengzhou 450052, Henan, China; State Key Laboratory of Animal Biotech Breeding, College of Biological Sciences, China Agricultural University, Beijing 100193, China; Tianjian Laboratory of Advanced Biomedical Sciences, Academy of Medical Sciences, Zhengzhou University, Zhengzhou 450052, Henan, China; The First Affiliated Hospital of Zhengzhou University, Academy of Medical Sciences, Zhengzhou University, Zhengzhou 450052, Henan, China. Electronic address: zyu@cau.edu.cn.

PMID: 41650935
DOI: 10.1016/j.stem.2026.01.002

Abstract

Sleep disturbances are associated with pathogenesis of numerous chronic disorders, including chronic gastrointestinal diseases. However, the mechanism that transmits sleep disturbance-induced aberrant neural signaling from the brain to the gut remains elusive. We show that acute sleep deprivation (SD) impairs intestinal stem cell (ISC) function, leading to shortening of crypt-villus architecture and Paneth cell loss. We identified the dorsal motor nucleus of vagus (DMV) as the SD-sensitive central nervous system center that transmits sleep effects to the gut. SD aberrantly activates DMV neurons, driving excessive acetylcholine release from the vagus nerve into the gut. Acetylcholine triggers 5-hydroxytryptamine (5-HT) release by enterochromaffin cells and suppresses its reuptake via muscarinic receptors, thereby causing a spike in 5-HT levels. Elevated 5-HT induces excessive oxidative stress in ISCs through its receptor HTR4, promoting gut pathologies. Overall, we reveal an SD-responsive neural circuit that controls ISCs and identify therapeutic strategies for mitigating SD-related gut diseases.

Keywords: 5-hydroxytryptamine; acetylcholine; brain-gut communications; intestinal stem cells; oxidative stress; sleep disturbance; the dorsal motor nucleus of vagus; translation stress response.

MeSH terms

Acetylcholine / metabolism
Animals
Intestines* / pathology
Mice
Mice, Inbred C57BL
Oxidative Stress
Serotonin / metabolism
Sleep Wake Disorders* / pathology
Sleep Wake Disorders* / physiopathology
Stem Cells* / metabolism
Stem Cells* / pathology
Vagus Nerve* / pathology
Vagus Nerve* / physiopathology

Substances

Serotonin
Acetylcholine