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Nat Commun. 2019 Apr 15;10(1):1745. doi: 10.1038/s41467-019-09744-3.

Early life stress disrupts intestinal homeostasis via NGF-TrkA signaling.

Author information

1
Institute of Brain and Gut Axis (IBAG), Centre of Clinical Research for Chinese Medicine, School of Chinese Medicine, Hong Kong Baptist University, Kowloon Tong, Hong Kong SAR, China.
2
Department of Pharmacy, First Hospital of Lanzhou University, 730000, Lanzhou, China.
3
School of Chinese Medicine, Hong Kong Baptist University, Kowloon Tong, Hong Kong SAR, China.
4
School of Pharmacy, Lanzhou University, Lanzhou, 730000, China.
5
Department of Gastroenterology, Peking University Shenzhen Hospital, 518035, Shenzhen, China.
6
School of Pharmaceutical Sciences, Health Science Center, Shenzhen University, 518060, Shenzhen, China.
7
Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, CA, 94305, USA.
8
Institute of Brain and Gut Axis (IBAG), Centre of Clinical Research for Chinese Medicine, School of Chinese Medicine, Hong Kong Baptist University, Kowloon Tong, Hong Kong SAR, China. bzxiang@hkbu.edu.hk.

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.

PMID:
30988299
PMCID:
PMC6465335
DOI:
10.1038/s41467-019-09744-3
[Indexed for MEDLINE]
Free PMC Article

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