TY - JOUR
T1 - Early life stress disrupts intestinal homeostasis via NGF-TrkA signaling
AU - Wong, Hoi Leong Xavier
AU - Qin, Hong Yan
AU - Tsang, Siu Wai
AU - Zuo, Xiao
AU - Che, Sijia
AU - Chow, Chi Fung Willis
AU - Li, Xi
AU - Xiao, Hai Tao
AU - Zhao, Ling
AU - Huang, Tao
AU - Lin, Cheng Yuan
AU - Kwan, Hiu Yee
AU - Yang, Tao
AU - Longo, Frank M.
AU - Lyu, Aiping
AU - Bian, Zhao Xiang
N1 - Funding Information:
This work was gratefully supported by RGC (260010), HKBU Faculty Research Grant (FRG1/16-17/021), Innovation and Technology Fund (ITS/148/14FP), the National Science Foundation of China (81400596), and Scientific Research Starting Foundation for the Returned Overseas Chinese Scholars from Ministry of Human Resources and Social Security of China. We thank Prof. Zhou Zhongjun for providing us with the Lgr5-EGFP-IRES-CreERT2 mice.
Publisher copyright:
© The Author(s) 2019
PY - 2019/12
Y1 - 2019/12
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85064330346&partnerID=8YFLogxK
U2 - 10.1038/s41467-019-09744-3
DO - 10.1038/s41467-019-09744-3
M3 - Article
C2 - 30988299
AN - SCOPUS:85064330346
SN - 2041-1723
VL - 10
JO - Nature Communications
JF - Nature Communications
M1 - 1745
ER -
