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 occur 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, leading to altered small intestine morphology in neonatal 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 gut enteric neurons by the resident macrophages of the muscularis externa in DEP/MS exposed males at postnatal day 14. In line with this, we saw the expression of motor neuron-associated genes spike in males at the same postnatal time point following DEP/MS exposure. Finally, we assessed the motor function of the GI tract of these animals and observed dysmotility in DEP/MS males only. Taken together, these findings establish intestinal macrophages as a mediator of GI development that is sensitive to early-life perturbations from the environment, highlighting a potential mechanism connecting NDDs with comorbid GI dysfunction.