Urinary metabolomics of young Italian autistic children supports abnormal tryptophan and purine metabolism
Open accessAbstract
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: , 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.
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Increases in an alternative branch of the kynurenine pathway led to reduced kynurenic acid and elevated quinolinic acid, an excitotoxic NMDA receptor agonist, in children with ASD.
“Increases in an alternative branch of the kynurenine pathway led to reduced kynurenic acid and elevated quinolinic acid (QA), a compound known to be an excitotoxic N-methyl-D-aspartate (NMDA) receptor agonist, in children with ASD [68] (Fig. 1).”
From The Gut Microbiota and Dysbiosis in Autism Spectrum Disorders (2018) · cites this paper as [68]
Metabolome studies have repeatedly shown evidence of alterations in tryptophan, kynurenine, and serotonin pathways in children with ASD, including increased urinary excretion of tryptophan and associated metabolites.
“Metabolome studies have repeatedly shown evidence of alterations in tryptophan, kynurenine, and serotonin pathways in children with ASD, including reports of increased urinary excretion of tryptophan and associated metabolites [63, 67, 68, 72, 105].”
From The Gut Microbiota and Dysbiosis in Autism Spectrum Disorders (2018) · cites this paper as [68]
Dysregulation of the kynurenine pathway has been linked to several brain disorders, including depression, schizophrenia, and autism spectrum disorder.
“Dysregulation of the kynurenine pathway has been linked to several brain disorders, including depression (395), schizophrenia (396, 397), and ASD (398).”
From Diet and the Microbiota–Gut–Brain Axis: Sowing the Seeds of Good Mental Health (2021) · cites this paper as [398]
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- Authors
- Gevi, F., Zolla, L., Gabriele, S., & Persico, A. M.
- Affiliations
- Università degli Studi della Tuscia (IT)
- Università Campus Bio-Medico (IT)
- University of Messina (IT)
- Corresponding author
- Zolla, Lello
- Persico, Antonio M.
- Venue
- Molecular Autism
- Published
- 2016-11-24
- Volume
- 7
- Issue
- 1
- Pages
- 47-47
- ISSN
- 2040-2392 (ISSN-L)
- PMC
- PMC5121959
- OpenAlex
- W2555361771
- Cited by
- 251
- References
- 72
- Citations by year
- 2026: 26 · 2025: 26 · 2024: 21 · 2023: 32 · 2022: 35 · 2021: 30 · 2020: 35 · 2019: 27 · 2018: 13 · 2017: 6
- FWCI
- 9.76
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- cc-by
- Locations
- Molecular Autism (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- IRIS UNIMORE (University of Modena and Reggio Emilia) (submittedVersion, cc-by)
- UnitusOpen (Tuscia University) (submittedVersion)
- Funders
- Italian Ministry for University, Scientific Research and Technology (PRIN n.2006058195)
- Italian Ministry of Health (CCM2012)
- Fondazione Gaetano e Mafalda Luce (Milan, Italy)
- Autism Research Institute
- Innovative Medicines Initiative Joint Undertaking (EU-AIMS 115300)
- Interuniversity Consortium for Biotechnologies (mobility studentship funds and post-doctoral research grant)
- Topics
- Life Sciences › Neuroscience › Cognitive Neuroscience › Autism Spectrum Disorder Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolomics and Mass Spectrometry Studies
- Life Sciences › Neuroscience › Biological Psychiatry › Tryptophan and brain disorders
- Keywords
- autism spectrum disorder, urine metabolomics, tryptophan metabolism, purine metabolism, kynurenine pathway, quinolinic acid, melatonin, xanthurenic acid, gut microbiota, indole-3-acetic acid, biomarkers, early diagnosis, children, seizures, sleep disorders, gastrointestinal symptoms
- MeSH terms
- Autism Spectrum Disorder, Child, Child, Preschool, Chromatography, High Pressure Liquid, Coenzyme A, Female, Humans, Indoleacetic Acids, Italy, Kynurenic Acid, Male, Melatonin, Pantothenic Acid, Purines, Pyrimidines, Riboflavin, Tryptophan, Xanthurenates, Biomarkers, Case-Control Studies, Quinolinic Acid, Vitamin B 6, Metabolomics, Hydrophobic and Hydrophilic Interactions, Dysbiosis
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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