Early-life antibiotic exposure leads to gut microbial dysbiosis associated with neurodevelopment and neuroregeneration

Early-life is a critical period for neurodevelopment and establishment of gut microbiota, which are highly susceptible to antibiotic exposure. Here, we aimed to investigate association between gut microbiota and metabolites with neurodevelopment and neuroregeneration in early-life after antibiotic exposure. To induce microbial dysbiosis in offspring, a broad-spectrum antibiotic cocktail was administered to mice dams. The prefrontal lobe, spinal cord tissues and gut sample of offspring were collected at different time with or without spinal cord crush injury. 16S rRNA sequencing and metabolomics were performed to analyze the gut microbiota and metabolites. NG2 glia were cultured and treated by mitochondrial fusion and fission compounds and metabolites. Maternal antibiotic exposure significantly affected neuronal maturation, NG2 glia proliferation, prefrontal cortex myelination and injured spinal cord neuroregeneration of offspring. Mice in antibiotic exposure group exhibited disruption of gut microbiota and metabolites, along with lower Ace, Chao and Shannon indexes, higher relative abundance of Enterobacter and Escherichia_Shigella, lower lactobacillus and Streptococcus genus, and downregulated Cyclo(Arg-Gly-Asp-D-Phe-Val), Ampicilloyl, DG(8:0/i-19:0/0:0), Petasinine and 6-Hydroxymelatonin glucuronide. These metabolites were enriched in alpha-Linolenic acid metabolism, phenylalanine, tyrosine and tryptophan biosynthesis, linoleic acid metabolism. 6-Hydroxymelatonin glucuronide, PC(20:3/0:0), PC(20:2/0:0), Ameltolide, DG(8:0/i-19:0/0:0), Inproquone, and Chorismate were the cores of networks between gut microbiota and metabolites and negatively associated with neurodevelopment and neuroregeneration. Additionally, gut microbiota metabolites promoted NG2 glia differentiation, partly through reversing the effects of mitochondrial fusion/fission compounds. Totally, antibiotic exposure in early-life changed the composition, abundance, and metabolites of gut microbiota in offspring, which was associated with neurodevelopment and neuroregeneration.