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, Zhao Xiang Bian*

*Corresponding author for this work

Research output: Contribution to journalJournal articlepeer-review

38 Citations (Scopus)


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.

Original languageEnglish
Article number1745
JournalNature Communications
Publication statusPublished - Dec 2019

Scopus Subject Areas

  • Chemistry(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Physics and Astronomy(all)


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