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Urinary metabolomics of young Italian autistic children supports abnormal tryptophan and purine metabolism

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ABSTRACT

Background: Autism spectrum disorder (ASD) is still diagnosed through behavioral observation, due to a lack of laboratory biomarkers, which could greatly aid clinicians in providing earlier and more reliable diagnoses. Metabolomics on human biofluids provides a sensitive tool to identify metabolite profiles potentially usable as biomarkers for ASD. Initial metabolomic studies, analyzing urines and plasma of ASD and control individuals, suggested that autistic patients may share some metabolic abnormalities, despite several inconsistencies stemming from differences in technology, ethnicity, age range, and definition of “control” status.

Methods: ASD-specific urinary metabolomic patterns were explored at an early age in 30 ASD children and 30 matched controls (age range 2–7, M:F = 22:8) using hydrophilic interaction chromatography (HILIC)-UHPLC and mass spectrometry, a highly sensitive, accurate, and unbiased approach. Metabolites were then subjected to multivariate statistical analysis and grouped by metabolic pathway.

Results: Urinary metabolites displaying the largest differences between young ASD and control children belonged to the tryptophan and purine metabolic pathways. Also, vitamin B6, riboflavin, phenylalanine-tyrosine-tryptophan biosynthesis, pantothenate and CoA, and pyrimidine metabolism differed significantly. ASD children preferentially transform tryptophan into xanthurenic acid and quinolinic acid (two catabolites of the kynurenine pathway), at the expense of kynurenic acid and especially of melatonin. Also, the gut microbiome contributes to altered tryptophan metabolism, yielding increased levels of indolyl 3-acetic acid and indolyl lactate.

Conclusions: The metabolic pathways most distinctive of young Italian autistic children largely overlap with those found in rodent models of ASD following maternal immune activation or genetic manipulations. These results are consistent with the proposal of a purine-driven cell danger response, accompanied by overproduction of epileptogenic and excitotoxic quinolinic acid, large reductions in melatonin synthesis, and gut dysbiosis. These metabolic abnormalities could underlie several comorbidities frequently associated to ASD, such as seizures, sleep disorders, and gastrointestinal symptoms, and could contribute to autism severity. Their diagnostic sensitivity, disease-specificity, and interethnic variability will merit further investigation.

Electronic supplementary material: The online version of this article (doi:10.1186/s13229-016-0109-5) contains supplementary material, which is available to authorized users.

No MeSH data available.


Quantification of tryptophan metabolites: a kynurenine pathway; b serotonin/melatonin pathway; c–d bacterial degradation products. Peak areas for each metabolite were normalized by urinary specific gravity. Nominal P values: *P < 0.05, **P < 0.0.1, ***P < 0.001
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Fig4: Quantification of tryptophan metabolites: a kynurenine pathway; b serotonin/melatonin pathway; c–d bacterial degradation products. Peak areas for each metabolite were normalized by urinary specific gravity. Nominal P values: *P < 0.05, **P < 0.0.1, ***P < 0.001

Mentions: Given the relevance of tryptophan-derived compounds in many neural functions, tryptophan metabolism was assessed in greater detail at the level of specific intermediates (Fig. 4):


Urinary metabolomics of young Italian autistic children supports abnormal tryptophan and purine metabolism
Quantification of tryptophan metabolites: a kynurenine pathway; b serotonin/melatonin pathway; c–d bacterial degradation products. Peak areas for each metabolite were normalized by urinary specific gravity. Nominal P values: *P < 0.05, **P < 0.0.1, ***P < 0.001
© Copyright Policy - OpenAccess
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC5121959&req=5

Fig4: Quantification of tryptophan metabolites: a kynurenine pathway; b serotonin/melatonin pathway; c–d bacterial degradation products. Peak areas for each metabolite were normalized by urinary specific gravity. Nominal P values: *P < 0.05, **P < 0.0.1, ***P < 0.001
Mentions: Given the relevance of tryptophan-derived compounds in many neural functions, tryptophan metabolism was assessed in greater detail at the level of specific intermediates (Fig. 4):

View Article: PubMed Central - PubMed

ABSTRACT

Background: Autism spectrum disorder (ASD) is still diagnosed through behavioral observation, due to a lack of laboratory biomarkers, which could greatly aid clinicians in providing earlier and more reliable diagnoses. Metabolomics on human biofluids provides a sensitive tool to identify metabolite profiles potentially usable as biomarkers for ASD. Initial metabolomic studies, analyzing urines and plasma of ASD and control individuals, suggested that autistic patients may share some metabolic abnormalities, despite several inconsistencies stemming from differences in technology, ethnicity, age range, and definition of &ldquo;control&rdquo; status.

Methods: ASD-specific urinary metabolomic patterns were explored at an early age in 30 ASD children and 30 matched controls (age range 2&ndash;7, M:F&thinsp;=&thinsp;22:8) using hydrophilic interaction chromatography (HILIC)-UHPLC and mass spectrometry, a highly sensitive, accurate, and unbiased approach. Metabolites were then subjected to multivariate statistical analysis and grouped by metabolic pathway.

Results: Urinary metabolites displaying the largest differences between young ASD and control children belonged to the tryptophan and purine metabolic pathways. Also, vitamin B6, riboflavin, phenylalanine-tyrosine-tryptophan biosynthesis, pantothenate and CoA, and pyrimidine metabolism differed significantly. ASD children preferentially transform tryptophan into xanthurenic acid and quinolinic acid (two catabolites of the kynurenine pathway), at the expense of kynurenic acid and especially of melatonin. Also, the gut microbiome contributes to altered tryptophan metabolism, yielding increased levels of indolyl 3-acetic acid and indolyl lactate.

Conclusions: The metabolic pathways most distinctive of young Italian autistic children largely overlap with those found in rodent models of ASD following maternal immune activation or genetic manipulations. These results are consistent with the proposal of a purine-driven cell danger response, accompanied by overproduction of epileptogenic and excitotoxic quinolinic acid, large reductions in melatonin synthesis, and gut dysbiosis. These metabolic abnormalities could underlie several comorbidities frequently associated to ASD, such as seizures, sleep disorders, and gastrointestinal symptoms, and could contribute to autism severity. Their diagnostic sensitivity, disease-specificity, and interethnic variability will merit further investigation.

Electronic supplementary material: The online version of this article (doi:10.1186/s13229-016-0109-5) contains supplementary material, which is available to authorized users.

No MeSH data available.