Integrated analysis of metabolome and microbiome in a mouse model of sodium valproate-induced autism

Background: Sodium valproate (SV) can induce autism in animals. The aim of this study is to investigate the potential correlations between gut microbiota compositions and metabolomic disorders in SV-induced autism in mice.Methods: A autism mouse model induced by SV was established. Open field test, elevated plus-maze test and water maze test were performed to assess the anxiety like-behaviors and the learning and memory performance of mice. Hematoxylin & eosin staining showed the histological changes of hippocampus. Gas chromatography-mass spectrometry and 16S ribosomal RNA gene sequencing were integrated to evaluate the influences of SV on metabolic profiles and gut microbiota in autism mice. Based on Spearman correlation coefficient, the correlations between metabolites and gut microbiota were calculated.Results: Open field test, elevated plus-maze test and water maze test all indicated that SV treatment aggravated anxiety like-behaviors, and impeded spatial learning and memory capabilities. SV disrupted metabolic and biosynthesis pathways in hippocampus, cortex, intestine and serum samples, mainly including glycine, serine and threonine metabolism, glycerophospholipid metabolism and aminoacyl-tRNA biosynthesis and so on. SV could decrease the abundances of Dubosiella, Faecalibaculum, norank_f__norank_o__Clostridia_UCG-014, Bifidobacterium, Alloprevotella, Prevotellaceae_NK3B31_group, norank_f__Oscillospiraceae, Muribaculum, Erysipelatoclostridium, norank_f__Eubacterium_coprostanoligenes_group, Parabacteroides, norank_f__norank_o__Gastranaerophilales,norank_f__Desulfovibrionaceae, norank_f__Mitochondria, Rikenellaceae_RC9_gut_group and Eubacterium_nodatum_group, while increase the abundances of Candidatus_Saccharimonas, Lachnoclostridium, norank_f__Ruminococcaceae, Streptococcus,norank_f__Erysipelotrichaceae,norank_f__norank_o__Clostridia_vadinBB60_group,unclassified_f__Ruminococcaceae, Candidatus_Arthromitus and Novosphingobium in intestine. The results of correlation analysis showed that in hippocampus and cortex, Bifidobacterium and Parabacteroides were positively correlated with serine and glycine, while Streptococcus was negatively correlated with them.Conclusion: These findings evidenced that SV can induce neurotoxicity to promote autism progression by altering the gut microbiota abundances and brain metabolite profiles. This may provide new direction for the management of SV-induced autism.