The 16p11.2 microdeletion exacerbates neurodevelopmental alterations induced by early-life microbiome perturbation

Abstract

Neurodevelopmental disorders (NDDs) arise from interactions between genetic factors and environmental exposures, with infancy representing a critical period of vulnerability. This exploratory, preclinical study investigated whether the 16p11.2 microdeletion (16pDel), a NDD-associated genetic variant, exacerbates the effects of early-life therapeutic antibiotic exposure on the gut microbiome, hippocampal development, and behavior. Cefdinir, selected for its epidemiological association with NDD risk, acutely perturbed the gut microbiome, causing sustained reductions in Lachnospiraceae. These changes were followed by alterations in sociability, risk assessment, and associative learning. Notably, only cefdinir-exposed 16pDel mice exhibited altered hippocampal stem cell dynamics and gene expression, demonstrating genotype-dependent susceptibility. Increased intestinal permeability and alterations in arginine biosynthesis and glycerophospholipid metabolism implicate gut barrier dysfunction as a contributing factor. Our findings suggest that genetic composition can exacerbate neurodevelopmental consequences of early-life microbiome perturbations, identify metabolic pathways for potential interventions, and support cautious antibiotic use during infancy, especially in genetically vulnerable populations.