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

Mar 18, 2026Gastroenterology

Early Life Stress May Affect Gut Movement and Pain Through Digestive and Stress-Related Nerve Systems, with Similar Patterns Seen in Humans

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Abstract

Maternal separation in mice resulted in visceral hypersensitivity and sex-specific motility defects.

Early life stress in mice caused changes in the composition of the enteric nervous system.
Increased serotonergic innervation and alterations in neuronal proportions were observed after maternal separation.
Suppression of gonadal hormones reversed visceral pain and motility defects associated with early life stress.
Enhanced sympathetic innervation of the enteric nervous system was linked to gut dysfunction due to early life stress.
Significant associations were found between maternal mental health issues and pediatric disorders of gut-brain interaction in human cohorts.

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BACKGROUND & AIMS: Adverse experiences during early life can disrupt gut-brain axis development, but the mechanisms linking early life stress (ELS) to long-term gastrointestinal (GI) dysmotility and pain remain unclear.

METHODS: 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 early life stress and DGBI risk.

RESULTS: 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 disorders of gut-brain interaction (DGBI) were observed in both cohorts, mirroring preclinical findings.

CONCLUSION: These results identify ELS-driven changes in enteric, sensory, and sympathetic pathways as contributors to DGBI risk and offer insight into potential therapeutic targets.

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

Abstract

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