The 16p11.2 microdeletion influences how early-life microbiota perturbations affect hippocampal development and behavior throughout the lifespan.

Neurodevelopmental disorders result from interactions between genetic predisposition and environmental risk factors, with infancy being the most vulnerable period. We designed a longitudinal study to determine how short-term antibiotic exposure during early postnatal life impacts the gut microbiome, neurodevelopment, and behavior, and whether these alterations were exacerbated by the neurodevelopmental disorder-associated 16p11.2 microdeletion (16pDel) mutation. The cephalosporin antibiotic, cefdinir, broadly altered the gut microbiome acutely, with persistent reductions in several Lachnospiraceae genera despite overall recovery. These alterations preceded long-term behavioral changes, including reduced juvenile sociability, compromised risk assessment, and deficits in associative learning. Remarkably, only cefdinir-exposed 16pDel mice had changes in hippocampal stem cell proliferation, subsequent adolescent cell numbers, and gene expression compared to other groups, demonstrating that genetic predisposition can modulate the effects of early-life antibiotic exposure on neurodevelopment. These alterations may be mediated by gastrointestinal disturbances, as cefdinir-exposed 16pDel males had increased intestinal permeability and shifted metabolite profiles including arginine biosynthesis and glycerophospholipid metabolism. Taken together, this study highlights how early-life microbial alterations affect behavior and reveals that genetic predisposition influences antibiotic-induced changes in hippocampal development. Further, these insights identify metabolic mechanisms as potential targets for intervention and may raise concerns regarding antibiotic use during infancy.