The association between early-life antibiotic exposure with gut microbiota, metabolite profiles, neurodevelopment and neuroregeneration.

Early-life is a critical period for neurodevelopment and gut microbiota establishment. Both processes are highly susceptible to environmental perturbations. It remains unclear the longitudinal associations between early-life antibiotic exposure and neurodevelopment, spinal cord injury (SCI) repair, as well as gut microbiota and metabolites. Pregnant C57BL/6 dams were administered a broad-spectrum antibiotic cocktail from one week prepartum through one week postpartum. Offspring were assessed at multiple timepoints, with a subset receiving a SCI at postnatal day 7. We employed 16S rRNA sequencing, untargeted metabolomics, and immunofluorescence to characterize the gut environment and neural tissues. Maternal antibiotic exposure was associated with significant alterations in offspring, including increased expression of neuroglial markers (TUJ1, NG2, MBP) in prefrontal cortex and spinal cord after SCI. These neural changes coincided with persistent gut microbiota dysbiosis, characterized by reduced alpha diversity; increased relative abundance of phylum Proteobacteria and genus Enterobacter; decreased relative abundance of phyla Firmicutes, Actinobacteriota, and Bacteroidota, as well as genera Lactobacillus, Rodentibacter, and Streptococcus; and remodeling of the gut metabolome, with 647 differential metabolites identified. Key downregulated metabolites, including 6-hydroxymelatonin glucuronide, were enriched in neuroactive pathways including tryptophan and melatonin metabolism. Integrated correlation network analysis identified a core set of microbes and metabolites strongly associated with the neural biomarkers. Collectively, our multi-omics analyses revealed that early-life antibiotic exposure correlates with altered neuroglial marker in brain and spinal cord, disruption of the gut microbiota and changes in neuroactive metabolites, suggesting candidate microbial and metabolic mediators within the gut-brain/spinal cord axis for future investigation.