Autism spectrum disorder (ASD) is characterized by impaired social interaction and repetitive stereotyped behavior, and effective interventions for the core autistic symptoms are currently limited. This study examines the protective role of L-tyrosine in alleviating ASD-like behavioral disorders in a valproic acid (VPA)-induced ASD mouse model and explores the underlying mechanisms via integrated multi-omics. We first investigated the potential of dietary L-tyrosine in mitigating autistic behavior. Subsequently, 16S rRNA sequencing, hippocampal transcriptomics, and neurotransmitter metabolome were employed to elucidate the underlying mechanism. Further, we conducted transplantation of the L-tyrosine-regulated microbiota in VPA-induced ASD mice. The results showed that L-tyrosine supplementation significantly mitigates ASD-like behavioral disorders, alleviates social communication deficits, and reduces repetitive behavior in autistic mice. L-tyrosine also attenuates the neuronal loss caused by VPA treatment in the DG and CA1 hippocampal regions in mice. The hippocampi of the L-tyrosine-treated mouse model for ASD displays modified gene expression profiles and different neurotransmitter levels. L-tyrosine also mitigates colonic barrier damage and amends the gut microbial composition and function. The integrative transcriptomic, metabolomic, and microbiome analysis shows strong connections between the hippocampal genes, neurotransmitters, and gut microbiota affected by L-tyrosine. The transplantation of microbiota from L-tyrosine-treated mice to VPA-induced ASD mice recipients recapitulated the preventive and protective effects of L-tyrosine on autistic behavior disorders. These findings suggest that dietary L-tyrosine may represent a viable, effective treatment option for managing the physiological and behavioral deficits associated with ASD.
