Early life stress disrupts intestinal homeostasis via NGF-TrkA signaling

Hoi Leong Xavier Wong,Cheng Yuan Lin,Ling Zhao,Siu Wai Tsang,Zhao-Xiang Bian,Chi Fung Willis Chow,Hiu Yee Kwan,Hong-Yan Qin,Aiping Lyu,Hai-Tao Xiao,Xiao Zuo,Xi Li,Sijia Che,Frank M Longo,Tao Yang,Tao Huang

doi:10.1038/s41467-019-09744-3

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.

Highlights

Childhood is a critical period for development, and early life stress may increase the risk of gastrointestinal diseases including irritable bowel syndrome (IBS)
Rats treated by intraperitoneal injection of recombinant nerve growth factor (NGF) were found to possess visceral pain thresholds comparable with those of neonatal maternal separation (NMS) rats (Supplementary Fig. 1d), indicating that either NGF treatment or NMS leads to visceral hypersensitivity
Though the majority of NGF functions are mediated via the activation of tropomyosin receptor kinase A (TrkA), NGF is known to interact with the p75 neurotrophin receptor (p75 NTR) at a much lower affinity[28]

Summary

Introduction

Childhood is a critical period for development, and early life stress may increase the risk of gastrointestinal diseases including irritable bowel syndrome (IBS). 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. Emerging evidence reveals that the interplay between the HPA axis and nerve growth factor (NGF) plays a crucial role in the development of early-life stress-associated functional gastrointestinal disorders[9,10]. Understanding how NGF alters intestinal functions will provide insights into ways of reducing the deleterious impact of early-life stress on intestinal integrity

Methods

Results

Conclusion