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Cited by 181Gut microbiota and healthAutism Spectrum Disorder ResearchChild Nutrition and Feeding Issues

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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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Wang, Mingbang, Wan, Jing, Rong, Han, He, Fusheng, Wang, Hui, Zhou, Jiaxiu, Cai, Chunquan, Wang, Yan, Xu, Ruihuan, Yin, Zhaoqing, Zhou, Wenhao·2019·mSystems
DOI 10.1128/msystems.00321-18PMC PMC6351726
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Abstract

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.

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Crossref · 10.1128/msystems.00321-18

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FIG 1 Altered gut microbiota composition in children with ASD. (a) The Chao 1 value for gut microbiota is significantly lower in the ASD group than in the TD group; this means a lower richness in gut microbiota in children with ASD. ***, P < 0.001 by Wilcoxon rank sum test. (b) Principal-component analysis of the gut microbiota composition at the species level shows that the two principal components (PC1 and PC2) can explain 6.5% and 5.43% of the variation, respectively. Distinctions among the groups are clearer at the PC2 level. (c) The abundance of the phylum Actinobacteria is significantly higher in children with ASD than in children in the TD group. *, P < 0.05 by Wilcoxon rank sum test. (d) PC2 (bacterial species level) is significantly negatively correlated with Eggerthella lenta abundance.
FIG 1 Altered gut microbiota composition in children with ASD. (a) The Chao 1 value for gut microbiota is significantly lower in the ASD group than in the TD group; this means a lower richness in gut microbiota in children with ASD. ***, P < 0.001 by Wilcoxon rank sum test. (b) Principal-component analysis of the gut microbiota composition at the species level shows that the two principal components (PC1 and PC2) can explain 6.5% and 5.43% of the variation, respectively. Distinctions among the groups are clearer at the PC2 level. (c) The abundance of the phylum Actinobacteria is significantly higher in children with ASD than in children in the TD group. *, P < 0.05 by Wilcoxon rank sum test. (d) PC2 (bacterial species level) is significantly negatively correlated with Eggerthella lenta abundance.CC BY · PubMed Central
FIG 2 Changes in the gut metabolome of children with ASD are significantly associated with changes in the gut microbiota. (a) PCA analysis of gut metabolome data. The effect of gut metabolites in children with ASD and TD children is effective. (b) Differential gut metabolites can be significantly enriched in alanine, aspartate, and glutamate metabolism and phenylalanine metabolism pathways. (c) Differential metabolites are related to the gut microbiota functional pathway. The gut metabolites l-2-keto-glutaramic acid and aspartic acid are positively associated with the gut microbiota pathways of d-glutamine and d-glutamate metabolism, and gut metabolites benzaldehyde and l-phenylalanine are negatively correlated with gut microbiota pathways of naphthalene degradation and tyrosine metabolism. A color key is shown to the right of the heatmap to show the size of the correlation coefficient; red represents a positive correlation. The + and − symbols in each lattice represent a significant positive and negative correlation, respectively.
FIG 2 Changes in the gut metabolome of children with ASD are significantly associated with changes in the gut microbiota. (a) PCA analysis of gut metabolome data. The effect of gut metabolites in children with ASD and TD children is effective. (b) Differential gut metabolites can be significantly enriched in alanine, aspartate, and glutamate metabolism and phenylalanine metabolism pathways. (c) Differential metabolites are related to the gut microbiota functional pathway. The gut metabolites l-2-keto-glutaramic acid and aspartic acid are positively associated with the gut microbiota pathways of d-glutamine and d-glutamate metabolism, and gut metabolites benzaldehyde and l-phenylalanine are negatively correlated with gut microbiota pathways of naphthalene degradation and tyrosine metabolism. A color key is shown to the right of the heatmap to show the size of the correlation coefficient; red represents a positive correlation. The + and − symbols in each lattice represent a significant positive and negative correlation, respectively.CC BY · PubMed Central
FIG 3 Gut 2-keto-glutaramic acid is a potential marker of ASD. (a) A higher level of gut 2-keto-glutaramic acid is associated with a lower abundance of gut microbiota involved in the d-glutamine and d-glutamate metabolism pathways. (b) A lower abundance of the usually highly abundant Bacteroides vulgatus is significantly correlated with lower levels of d-glutamine and d-glutamate metabolic pathways in the guts of ASD children. (c and d) Significantly lower levels of gut 2-keto-glutaramic acid at the discovery and validation stages, respectively. Values that are significantly different by the Wilcoxon rank sum test are indicated by bars and asterisks as follows: **, P < 0.01; ***, P < 0.001.
FIG 3 Gut 2-keto-glutaramic acid is a potential marker of ASD. (a) A higher level of gut 2-keto-glutaramic acid is associated with a lower abundance of gut microbiota involved in the d-glutamine and d-glutamate metabolism pathways. (b) A lower abundance of the usually highly abundant Bacteroides vulgatus is significantly correlated with lower levels of d-glutamine and d-glutamate metabolic pathways in the guts of ASD children. (c and d) Significantly lower levels of gut 2-keto-glutaramic acid at the discovery and validation stages, respectively. Values that are significantly different by the Wilcoxon rank sum test are indicated by bars and asterisks as follows: **, P < 0.01; ***, P < 0.001.CC BY · PubMed Central
FIG 4 Schematic diagram of the gut pathway and metabolites involved in the pathogenesis of ASD. The gut microenvironment of children with ASD is characterized by altered glutamate metabolism, which is associated with a lower abundance of bacteria such as Bacteroides vulgatus, a species with glutamate metabolism, which may directly affect neurotransmitter inhibition/excitatory imbalance. Children with ASD also exhibit alterations in gut metabolites, such as lower levels of aromatic compounds and higher levels of bile acids, which are related to higher abundance of Eggerthella lenta and Clostridium botulinum. Children with ASD also show altered levels of the stress hormone cortisol, which implies an impact to the gut microbiota via the hypothalamic-pituitary-adrenal (HPA) axis. Abbreviations: AAT, aspartate aminotransferase; α-KG, α-ketoglutaric acid; GABA, gamma-aminobutyric acid; GABA-T, GABA transaminase; GAD, glutamic acid decarboxylase; GLN, glutamine; GLU, glutamic acid; TCA, tricarboxylic acid.
FIG 4 Schematic diagram of the gut pathway and metabolites involved in the pathogenesis of ASD. The gut microenvironment of children with ASD is characterized by altered glutamate metabolism, which is associated with a lower abundance of bacteria such as Bacteroides vulgatus, a species with glutamate metabolism, which may directly affect neurotransmitter inhibition/excitatory imbalance. Children with ASD also exhibit alterations in gut metabolites, such as lower levels of aromatic compounds and higher levels of bile acids, which are related to higher abundance of Eggerthella lenta and Clostridium botulinum. Children with ASD also show altered levels of the stress hormone cortisol, which implies an impact to the gut microbiota via the hypothalamic-pituitary-adrenal (HPA) axis. Abbreviations: AAT, aspartate aminotransferase; α-KG, α-ketoglutaric acid; GABA, gamma-aminobutyric acid; GABA-T, GABA transaminase; GAD, glutamic acid decarboxylase; GLN, glutamine; GLU, glutamic acid; TCA, tricarboxylic acid.CC BY · PubMed Central

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Metadata

Authors
Wang, M., Wan, J., Rong, H., He, F., Wang, H., Zhou, J., Cai, C., Wang, Y., Xu, R., Yin, Z., & Zhou, W.
Affiliations
  • Fudan University (CN)
  • Division of Neonatology, The People’s Hospital of Dehong Autonomous Prefecture, Mangshi, Yunnan, China
  • Shenzhen KangNing Hospital (CN)
  • Imunobio, Shenzhen, Guangdong, China
  • Children’s Hospital of Fudan University Xiamen Branch (CN)
  • Shenzhen Children's Hospital (CN)
  • Tianjin Children's Hospital (CN)
  • Longgang Central Hospital (CN)
Corresponding author
  • Wang, Mingbang
  • Yin, Zhaoqing
  • Zhou, Wenhao
ORCID
Venue
mSystems
Publisher
American Society for Microbiology
Published
2019-02-26
Volume
4
Issue
1
ISSN
2379-5077 (ISSN-L)
DOI
10.1128/msystems.00321-18
PMC
PMC6351726
OpenAlex
W2914854965
Cited by
181
References
31
Citations by year
2026: 14 · 2025: 20 · 2024: 28 · 2023: 23 · 2022: 29 · 2021: 36 · 2020: 22 · 2019: 9
FWCI
7.94
Type
journal article
Language
en
Open access
Licence
Locations
  • mSystems (publishedVersion, cc-by)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
National Natural Science Foundation of China (81701351, 81720108018)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Gut microbiota and health
  • Life Sciences › Neuroscience › Cognitive Neuroscience › Autism Spectrum Disorder Research
  • Health Sciences › Medicine › Psychiatry and Mental health › Child Nutrition and Feeding Issues
Keywords
autism spectrum disorder, gut microbiota, glutamate metabolism, gut metabolome, gut metagenomics, children, ASD pathogenesis, microbial metabolites

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