Prenatal exposure to environmental stressors alters gut macrophage development and gastrointestinal function of male offspring

Gastrointestinal (GI) dysfunction is a frequently reported comorbidity of neurodevelopmental disorders (NDDs). Early-life inflammatory challenges from the environment (e.g., infection, toxicants) can increase risk for NDDs, but the impact of such stressors on the developing GI tract is not well understood. We investigated possible mechanisms by which GI comorbidities arise in response to environmental stressors using our well-characterized model of combined gestational exposure to air pollution (diesel exhaust particles, DEP) and maternal stress (MS), which induces social deficits in male, but not female, offspring. We show that DEP/MS disrupts normal GI development in the first two weeks of postnatal life, leading to altered small intestine morphology in males, but not females. Recent evidence shows that resident macrophages of the gut prune enteric neurons during a precise postnatal window. We found decreased pruning of enteric neurons by the resident macrophages of the muscularis externa in DEP/MS exposed males at postnatal day (P)14. In line with this, we saw the expression of neurotransmission-associated genes (SNAP25, ChAT, nNOS, DBH, VIP, PENK) increased between P4 and P14 in males following DEP/MS exposure. Finally, we assessed small intestinal transit in vivo and observed dysmotility in DEP/MS males only. Taken together, these findings establish intestinal macrophages as probable mediators of GI development that are sensitive to early-life perturbations from the environment, highlighting a potential mechanism connecting NDDs with comorbid GI dysfunction.