Early life stress disrupts intestinal homeostasis via NGF-TrkA signaling

Hoi Leong Xavier Wong, Hong-yan Qin, Siu Wai Tsang, Xiao Zuo, Sijia Che, Chi Fung Willis Chow, Xi Li, Hai-tao Xiao, Ling Zhao, Tao Huang, Cheng Yuan Lin, Hiu Yee Kwan, Tao Yang, Frank M. Longo, Aiping Lyu and Zhao-xiang Bian ()
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Hoi Leong Xavier Wong: Hong Kong Baptist University
Hong-yan Qin: First Hospital of Lanzhou University
Siu Wai Tsang: Hong Kong Baptist University
Xiao Zuo: Lanzhou University
Sijia Che: Hong Kong Baptist University
Chi Fung Willis Chow: Hong Kong Baptist University
Xi Li: Peking University Shenzhen Hospital
Hai-tao Xiao: Shenzhen University
Ling Zhao: Hong Kong Baptist University
Tao Huang: Hong Kong Baptist University
Cheng Yuan Lin: Hong Kong Baptist University
Hiu Yee Kwan: Hong Kong Baptist University
Tao Yang: Stanford University School of Medicine
Frank M. Longo: Stanford University School of Medicine
Aiping Lyu: Hong Kong Baptist University
Zhao-xiang Bian: Hong Kong Baptist University

Nature Communications, 2019, vol. 10, issue 1, 1-14

Abstract: Abstract Early childhood is a critical period for development, and early life stress may increase the risk of gastrointestinal diseases including irritable bowel syndrome (IBS). In rodents, neonatal maternal separation (NMS) induces bowel dysfunctions that resemble IBS. However, the underlying mechanisms remain unclear. Here we show that NMS induces expansion of intestinal stem cells (ISCs) and their differentiation toward secretory lineages including enterochromaffin (EC) and Paneth cells, leading to EC hyperplasia, increased serotonin production, and visceral hyperalgesia. This is reversed by inhibition of nerve growth factor (NGF)-mediated tropomyosin receptor kinase A (TrkA) signalling, and treatment with NGF recapitulates the intestinal phenotype of NMS mice in vivo and in mouse intestinal organoids in vitro. Mechanistically, NGF transactivates Wnt/β-catenin signalling. NGF and serotonin are positively correlated in the sera of diarrhea-predominant IBS patients. Together, our findings provide mechanistic insights into early life stress-induced intestinal changes that may translate into treatments for gastrointestinal diseases.

Date: 2019
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DOI: 10.1038/s41467-019-09744-3

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