Early life stress disrupts intestinal homeostasis via NGF-TrkA signaling

Area of Science:

• Neurogastroenterology
• Developmental Biology
• Gastroenterology

Background:

• Early childhood stress is linked to increased risk of gastrointestinal diseases like irritable bowel syndrome (IBS).
• Neonatal maternal separation (NMS) in rodents models early life stress and causes IBS-like bowel dysfunction, but mechanisms are unknown.

Purpose of the Study:

• To elucidate the mechanisms by which NMS induces intestinal changes resembling IBS.
• To investigate the role of nerve growth factor (NGF) signaling in NMS-induced gut alterations.

Main Methods:

• Rodent models of neonatal maternal separation (NMS).
• Analysis of intestinal stem cells (ISCs), enterochromaffin (EC) cells, and serotonin production.
• Pharmacological inhibition/activation of nerve growth factor (NGF) and TrkA signaling.
• In vivo and in vitro studies using mouse intestinal organoids.
• Analysis of human patient sera for NGF and serotonin correlation.

Main Results:

• NMS led to expansion of ISCs and differentiation into EC and Paneth cells, causing EC hyperplasia and increased serotonin.
• Inhibition of NGF-TrkA signaling reversed NMS-induced intestinal changes.
• NGF treatment alone mimicked NMS phenotype in vivo and in vitro.
• NGF activated Wnt/β-catenin signaling, linking stress to cellular changes.
• Elevated NGF and serotonin levels were observed in diarrhea-predominant IBS patients.

Conclusions:

• Early life stress via NMS induces gut dysfunction through ISC expansion and altered cell differentiation, mediated by NGF-TrkA and Wnt/β-catenin signaling.
• NGF and serotonin pathways are key players in the pathophysiology of stress-induced gastrointestinal disorders.
• Targeting NGF signaling presents a potential therapeutic strategy for IBS and related conditions stemming from early life stress.