Enteric and sympathetic nervous system pathways mediate early life stress effects on gut motility and pain: mechanistic findings with human correlation

Adverse experiences during early life can disrupt the development of the gut-brain axis, yet the mechanisms linking early life stress (ELS) to persistent gastrointestinal dysmotility and pain remain poorly understood. This research utilized a maternal separation (MS) mouse model of ELS to evaluate visceral pain sensitivity, intestinal motility, and the composition of the enteric nervous system (ENS). Additionally, two large human pediatric population cohorts were analyzed to explore associations between ELS and the risk of disorders of gut-brain interaction (DGBI).

The results indicated that MS in mice led to visceral hypersensitivity and sex-specific motility defects, alongside alterations in ENS composition, including increased serotonergic innervation and shifts in the proportions of neuronal subtypes. Notably, the suppression of gonadal hormones via Degarelix reversed the visceral pain and motility defects induced by MS, highlighting the role of sex hormones in persistent gut alterations. Furthermore, MS was associated with enhanced sympathetic innervation of the ENS, and chemical sympathectomy was found to restore normal motility, suggesting a state of sympathetic overactivity in ELS-related gut dysfunction.

In human cohorts, significant correlations were identified between maternal mental health issues and pediatric DGBI, echoing the findings from preclinical studies. These results elucidate ELS-driven modifications in the enteric, sensory, and sympathetic pathways that contribute to the risk of DGBI, providing valuable insights for potential therapeutic interventions. [NPID: Gastrointestinal, early life stress, visceral pain, gut alterations]

Year: 2026

Reference: Najjar, S. A., Kildegaard, H., Talati, A., Goncalves, P. D., Del Colle, A., Huang, Z., Tong, Y., Juarez, D., Shah, R., Barati, E., Woo, T., Medina, M., Israelyan, N., Bernard, M., Tonea, R., Ovchinsky, M., Pesner, N., Ringel, R., Valdetaro, L., Bliddal, M., … Margolis, K. G. (2026). Enteric and Sympathetic Nervous System Pathways Mediate Early Life Stress Effects on Gut Motility and Pain: Mechanistic Findings With Human Correlation. Gastroenterology, S0016-5085(26)00205-2. Advance online publication. https://doi.org/10.1053/j.gastro.2026.02.030

Related Studies

Evidence for the presence of non-celiac gluten sensitivity in patients with functional gastrointestinal symptoms: Results from a multicenter randomized double-blind placebo-controlled gluten challenge

This multicenter double-blind placebo-controlled trial published in 2016 involved placing participants with functional gastrointestinal symptoms on a 3-week gluten-free diet (GFD) before randomly assigning the responsive patients to gluten intake (5.6g per day) or placebo for 7 days, and subsequently switching the subjects into the other group (crossover). Symptoms and quality of life were monitored […]

Attention deficit and hyperactivity disorder symptoms respond to gluten-free diet in patients with coeliac disease

Since patients with coeliac disease commonly suffer from what is called “brain fog”, Kiristensen et al. (2019) set out to assess symptoms of impaired concentration in patients with coeliac disease before and after treatment with gluten-free diet and compared the data to that of healthy (healthcare personnel) and patient controls [those with inflammatory bowel disease(IBD)]. […]