Enteric and Sympathetic Nervous System Pathways Mediate Early Life Stress Effects on Gut Motility and Pain: Mechanistic Findings With Human Correlation.

Abstract

Adverse experiences during early life can disrupt gut-brain axis development, but the mechanisms linking early life stress (ELS) to long-term gastrointestinal dysmotility and pain remain unclear. We used a maternal separation (MS) mouse model of ELS and assessed visceral pain sensitivity, intestinal motility, and enteric nervous system (ENS) composition. Two large human pediatric population cohorts were also analyzed for associations between ELS and disorders of gut-brain interaction (DGBI) risk. MS in mice led to visceral hypersensitivity, sex-specific motility defects, and altered ENS composition, including increased serotonergic innervation and changes in subtype-specific neuronal proportions. Degarelix-mediated suppression of gonadal hormones reversed MS-induced visceral pain and motility defects, implicating sex hormones in long-term gut changes. MS led to enhanced sympathetic innervation of the ENS and chemical sympathectomy restored normal motility, suggesting sympathetic overactivity in ELS-related gut dysfunction. In humans, significant associations between maternal mental health problems and pediatric DGBI were observed in both cohorts, mirroring preclinical findings. These results identify ELS-driven changes in enteric, sensory, and sympathetic pathways as contributors to DGBI risk and offer insight into potential therapeutic targets.