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

Abstract

BackgroundAutism 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.MethodsASD-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.ResultsUrinary 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.ConclusionsThe 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 materialThe online version of this article (doi:10.1186/s13229-016-0109-5) contains supplementary material, which is available to authorized users.

A quasi-paired cohort strategy reveals the impaired detoxifying function of microbes in the gut of autistic children

“…Among the 39 ASD-enriched pathways, 17 are from yeast and one of them synthesizes 2-amino-3-carboxymuconate semialdehyde (Table S3), the intermediate to generate an excitotoxin—quinolinic acid—through the subsequent kynurenine pathway. This result is consistent with the previous findings in ASD patients of overproduction of quinolinic acid( 31 ) and overgrowth of yeast in the intestine( 32 ). The consistency of the ASD-associated pathways we identified with previously reported metabolic alterations in ASD supported the reliability of our novel analysis strategy of quasi-paired cohort, and further confirmed the contributions of gut microbial metabolism to hosts.…”

Serum Tryptophan, Tryptophan Catabolites and Brain-derived Neurotrophic Factor in Subgroups of Youngsters with Autism Spectrum Disorders

“…Croonenberghs and co-workers (53) found lower plasma tryptophan concentrations in 26 autistic subjects (aged 12-18 years) than in normal volunteers. Gevi et al (54) showed differences in TRYCATs including KA, KYN, QA, 5-HT levels, in 30 ASD patients (aged 3-7 years) when compared to controls. There is a partial overlap between both childhood autism and IDD, namely in our study 16 of the 25 IDD patients showed childhood autism and the 9 others not.…”

Characterization of LC-MS Based Urine Metabolomics in Healthy Subjects Across the Life Span

“…These metabolic characteristics correspond to the physiological characteristics during this life stage, high metabolism activity for rapid growth and development demands [4]. Research on children aged from 2-7 years old suggested that pantothenate and CoA biosynthesis, pyrimidine metabolism and vitamin B6 metabolism were signi cantly related to autism spectrum disorder (ASD) [22]. These results highlight the importance for these pathways to maintain homeostasis during preschool.…”