| الوصف: |
Background: Accumulating clinical evidence demonstrated that gut microbiota (GM) transfer substantially ameliorated autistic symptoms, implying a role of GM in autism spectrum disorder (ASD). Continuous investigation reported GM alteration in ASD individuals, while inconsistency also persists in the abundance of bacterial taxon, as well as their metabolites. Due to deficiencies of stringent study designs, multi-omics assessment, and even animal tests, such data heterogeneity is yet to be addressed, which impedes establishing a causal effect of a specific microbiome-metabolome axis on pathogenesis of ASD.Results: We developed a participant recruitment and sampling procedure that fully considered possible intergroup and intragroup confounders, including age, diet, severity of ASD, and stool consistency. To tease out biological features of ASD from an overarching investigation on metabolome, composition and function of GM, we compared faecal samples collected from 123 children with either mild ASD (n=56) or typical development (TD) (n=67). Metabolite profiling of targeted metabolomics screened and validated a significantly higher ratio of gamma-aminobutyric acid (GABA) to glutamate (Glu) as a metabolic signature of ASD. Linked to autistic symptomatology, the microbial GABA/Glu ratio independently distinguished ASD from TD subjects, particularly at 3-5 years. The 16S rRNA gene sequencing displayed substantially declined GM richness but over-presented genus Escherichia in ASD, which was profoundly associated with the increased GABA/Glu ratio. Metagenomics confirmed both structural and metabolic dysbiosis of GM via revealing consistent changes in microbial components and Escherichia abundance, and highlighting overall hypofunction of the GM and imbalanced GABA/Glu synthesis in ASD. We further identified a series of E. coli-specific adhesins that linked Escherichia colonization with GABA production. Quantitative PCR validation supported increment of Escherichia-specific glutamate decarboxylase, promoting GABA synthesis. Further, challenge of healthy weaning mice with gut commensal E. coli induced significant social deficiency, but not abnormalities in repetitive, locomotor, recognition memory- and anxiety-related behaviors. Conclusions: Our multi-omics study elucidated a microbe-metabolite axis out of GM dysbiosis in mild ASD, characterized by over-presented Escherichia and concomitant GABA/Glu imbalance, which were well-marked features of ASD-linked GM at an early age, and potential causal factors of autistic symptomology. Our study provided insight into importance of microbial excitatory/inhibitory neurotransmitters imbalance in diagnosis and therapeutic treatment of ASD. |
