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Alterations in Gut Glutamate Metabolism Associated with Changes in Gut Microbiota Composition in Children with Autism Spectrum Disorder.

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.

SUBMITTER: Wang M

PROVIDER: S-EPMC6351726 | biostudies-literature | 2019 Jan-Feb

REPOSITORIES: biostudies-literature

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Project description:Diet is one of the most influential environmental factors in determining the composition of the gastrointestinal microbiota. Microbial dysbiosis in children with Autism Spectrum Disorder (ASD) and the impact of some bacterial taxa on symptoms of ASD has been recognized. Children with ASD are often described as picky eaters with low intake of fiber-rich foods, including fruits and vegetables. However, the impact of diet on the microbiota composition in children with ASD is largely unknown. Herein, fecal samples, 3 day food diaries and the Youth and Adolescence Food Frequency questionnaire (YAQ) were collected from children with ASD (ASD; n = 26) and unaffected controls (CONT; n = 32). Children's ASD symptoms were determined using the Pervasive Developmental Disorder Behavior Inventory Screening Version (PDDBI-SV). Differences in the microbiota composition at the phyla, order, family, and genus level between ASD and CONT were observed. Microbiota composition of children with ASD was investigated in relation to feeding behavior, nutrient and food group intake as well as dietary patterns derived from the YAQ. In children with ASD, two distinct dietary patterns (DP) were associated with unique microbial profiles. DP1, characterized by higher intakes of vegetables, legumes, nuts and seeds, fruit, refined carbohydrates, and starchy vegetables, but lower intakes of sweets, was associated with lower abundance of Enterobacteriaceae, Lactococcus, Roseburia, Leuconostoc, and Ruminococcus. DP2, characterized by low intakes of vegetables, legumes, nuts and seeds and starchy vegetables, was associated with higher Barnesiellaceae and Alistipes and lower Streptophyta, as well as higher levels of propionate, isobutyrate, valerate, and isovalerate. Peptostreptococcaceae and Faecalibacterium predicted social deficit scores in children with ASD as measured by the PDDBI-SV. Diet-associated microbial profiles were related to GI symptoms, but no significant interaction between nutrition and microbiota in predicting social deficit scores were observed. In conclusion, dietary patterns associated with fecal microbiota composition and VFA concentrations in children with ASD were identified. Future studies using a larger sample size and measuring other behaviors associated with ASD are needed to investigate whether dietary intake may be a modifiable moderator of ASD symptoms.

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Alterations in Gut Glutamate Metabolism Associated with Changes in Gut Microbiota Composition in Children with Autism Spectrum Disorder.

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