Early life stress and the pathogenesis of visceral hypersensitivity: mechanisms and implications for disorders of gut-brain interaction.

Early life stress (ELS) is a major risk factor for disorders of gut-brain interaction (DGBIs), particularly irritable bowel syndrome (IBS), through the induction of persistent visceral hypersensitivity. This review synthesizes evidence from epidemiological studies, clinical observations, and preclinical models to establish ELS-induced visceral hypersensitivity as a core pathophysiological axis. I delineate the multi-level mechanisms underlying this phenomenon, encompassing: (1) central neuroendocrine dysregulation (hypothalamic-pituitary-adrenal axis, corticotropin-releasing factor signaling) with epigenetic modifications (histone acetylation, non-coding RNAs) in limbic circuits; (2) spinal sensitization via brain-derived neurotrophic factor upregulation, glutamate transporter dysfunction, and potassium channel downregulation; (3) peripheral alterations including enterochromaffin cell hyperplasia, mast cell activation, enteric glial phenotypic switching, barrier disruption, and microbiota dysbiosis. I highlight critical modifiers including sexual dimorphism (estrogen-dependent mechanisms) and resilience factors (benevolent childhood experiences, environmental enrichment). Finally, I present a translational roadmap integrating pharmacological, nutritional, and behavioral interventions targeting ELS-programmed dysfunction along the brain-gut axis, emphasizing opportunities for prevention and precision medicine.