Abstract
Changes in the gut microenvironment may influence the pathogenesis of autism spectrum disorders (ASD). Here, we investigated the composition of the gut microbiota and metabolites in children with ASD. Ninety-two children with ASD and 42 age-matched children exhibiting typical development (TD) were enrolled in the two-stage study. In the discovery stage, shotgun metagenomic sequencing and liquid chromatography-mass spectrometry (LC-MS) were performed simultaneously on fecal samples obtained from 43 children in the ASD group and 31 children in the TD group. Systematic bioinformatic analyses were performed to identify gut metabolites associated with altered gut microbiota composition. At the validation stage, differential metabolites were tested using LC-MS with an additional 49 and 11 children in the ASD and TD groups, respectively. Altered glutamate metabolites were found in the ASD group, along with a decline in 2-keto-glutaramic acid and an abundance of microbiota associated with glutamate metabolism. These changes in glutamate metabolism were correlated with lower levels of the highly abundant bacteria Bacteroides vulgatus and higher levels of the potentially harmful Eggerthella lenta and Clostridium botulinum. Lower gut cortisol levels have also been identified in the ASD group and associated with changes in gut microbiota glutamate metabolism. Finally, gut 2-keto-glutaramic acid was validated as a potential biomarker for ASD. The significant changes in the gut microenvironment in children with ASD may provide new insight into the cause of ASD and aid in the search for diagnostic and therapeutic approaches. IMPORTANCE Multiple lines of evidence suggest that the gut microbiota may play an important role in the pathogenesis of ASD, but the specific mechanism is still unclear. Through a comprehensive gut metagenomic and metabolome study of children with ASD, alterations in gut metabolite composition were found in children with ASD, and these alterations were linked to changes in gut microbiota composition. This may give us a deeper understanding of the role of gut microbiota in the pathogenesis of ASD.
Highlights
IMPORTANCE Multiple lines of evidence suggest that the gut microbiota may play an important role in the pathogenesis of Autism spectrum disorders (ASD), but the specific mechanism is still unclear
We found that 2-keto-glutaramic acid, L-aspartic acid, and fumaric acid, which are involved in glutamate metabolism, were significantly lower in the guts of children with ASD than in children with typical development (TD)
Our results are consistent with a study by Tebartz van Elst et al, which found significantly lower glutamate signals in the anterior cingulate cortex and cerebellum of patients with ASD compared with healthy controls [9]
Summary
IMPORTANCE Multiple lines of evidence suggest that the gut microbiota may play an important role in the pathogenesis of ASD, but the specific mechanism is still unclear. The ASD mouse model showed a significant increase in the level of the metabolite 4-ethylphenol sulfate, which can be lowered by administration with Bacteroides fragilis [5], whereas other gut metabolites, such as short-chain fatty acids (SCFAs), which originate from microbiota, can regulate blood-brain barrier permeability and affect animal behavior [6]. These studies suggest that changes in the gut microenvironment in patients with ASD may play an important role in the pathogenesis of the disorder. Fecal samples were collected from children with ASD or those exhibiting typical development (TD), and shotgun metagenomic sequencing and liquid chromatography-mass spectrometry (LC-MS)-based metabolomics were performed to identify gut metabolites and microbiota composition associated with ASD
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