From psychology to physicality: how nerve growth factor transduces early life stress into gastrointestinal motility disorders later in life.

Environmental stressors in early childhood can have a detrimental impact later in life, manifesting in functional gastrointestinal disorders including irritable bowel syndrome (IBS). The phenomenon is also observed in rodents, where neonatal-maternal separation, a model of early life stress, induces phenotypes similar to IBS; however, the underlying mechanisms remain unelucidated. Our recent study provided a mechanism for the pathogenesis in the gut, demonstrating that increased visceral hyperalgesia resulted from the expansion of the intestinal stem cell compartment leading to increased differentiation and proliferation of serotonin (5-hydroxytryptamine/5-HT)-producing enterochromaffin cells. Moreover, it identified nerve growth factor (NGF) as a key mediator of the pathogenesis; surprisingly, it exerts its effect via cross talk with Wnt/ß-catenin signaling. This article addresses the roles of NGF in driving IBS and its potential clinical implications, outstanding questions in how psychological stimuli are transduced into physical phenotypes, as well as future directions of our findings. Abbreviations: 5-HT: 5-hydroxytryptamine/serotonin; BDNF: brain-derived neurotrophic factor; CRF: corticotrophin-releasing factor; EC: enterochromaffin; ENS: enteric nervous system; GI: gastrointestinal; GPCR: G-protein-coupled receptor; IBS (-D): irritable bowel syndrome (diarrhea predominant); LRP5/6: low-density lipoprotein receptor-related protein 5/6; MAPK: mitogen-activated protein kinase; NGF: nerve growth factor; NMS: neonatal-maternal separation; PI3K: phosphoinositode3-kinase; PLCγ: phospholipase c, gamma subtype; TrkA: tropomyosin receptor kinase A.

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

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/ß-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.