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Urinary metabolomics of young Italian autistic children supports abnormal tryptophan and purine metabolism / F. GEVI in Molecular Autism, 7 (2016)
[article]
Titre : Urinary metabolomics of young Italian autistic children supports abnormal tryptophan and purine metabolism Type de document : Texte imprimé et/ou numérique Auteurs : F. GEVI, Auteur ; L. ZOLLA, Auteur ; S. GABRIELE, Auteur ; A. M. PERSICO, Auteur Article en page(s) : 47p. Langues : Anglais (eng) Mots-clés : Autism Spectrum Disorder/complications/diagnosis/urine Biomarkers/urine Case-Control Studies Child Child, Preschool Chromatography, High Pressure Liquid Coenzyme A/urine Dysbiosis/complications/diagnosis/urine Female Humans Hydrophobic and Hydrophilic Interactions Indoleacetic Acids/urine Italy Kynurenic Acid/urine Male Melatonin/urine Metabolomics/methods Pantothenic Acid/urine Purines/urine Pyrimidines/urine Quinolinic Acid/urine Riboflavin/urine Tryptophan/urine Vitamin B 6/urine Xanthurenates/urine Autism Autism spectrum disorder Kynurenine Melatonin Metabolomics Purinergic signaling Quinolinic acid Serotonin Tryptophan Index. décimale : PER Périodiques Résumé : 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. En ligne : http://dx.doi.org/10.1186/s13229-016-0109-5 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=328
in Molecular Autism > 7 (2016) . - 47p.[article] Urinary metabolomics of young Italian autistic children supports abnormal tryptophan and purine metabolism [Texte imprimé et/ou numérique] / F. GEVI, Auteur ; L. ZOLLA, Auteur ; S. GABRIELE, Auteur ; A. M. PERSICO, Auteur . - 47p.
Langues : Anglais (eng)
in Molecular Autism > 7 (2016) . - 47p.
Mots-clés : Autism Spectrum Disorder/complications/diagnosis/urine Biomarkers/urine Case-Control Studies Child Child, Preschool Chromatography, High Pressure Liquid Coenzyme A/urine Dysbiosis/complications/diagnosis/urine Female Humans Hydrophobic and Hydrophilic Interactions Indoleacetic Acids/urine Italy Kynurenic Acid/urine Male Melatonin/urine Metabolomics/methods Pantothenic Acid/urine Purines/urine Pyrimidines/urine Quinolinic Acid/urine Riboflavin/urine Tryptophan/urine Vitamin B 6/urine Xanthurenates/urine Autism Autism spectrum disorder Kynurenine Melatonin Metabolomics Purinergic signaling Quinolinic acid Serotonin Tryptophan Index. décimale : PER Périodiques Résumé : 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. En ligne : http://dx.doi.org/10.1186/s13229-016-0109-5 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=328 Identification of urinary metabolites that correlate with clinical improvements in children with autism treated with sulforaphane from broccoli / Stephen BENT in Molecular Autism, 9 (2018)
[article]
Titre : Identification of urinary metabolites that correlate with clinical improvements in children with autism treated with sulforaphane from broccoli Type de document : Texte imprimé et/ou numérique Auteurs : Stephen BENT, Auteur ; B. LAWTON, Auteur ; T. WARREN, Auteur ; F. WIDJAJA, Auteur ; K. DANG, Auteur ; J. W. FAHEY, Auteur ; Brian CORNBLATT, Auteur ; J. M. KINCHEN, Auteur ; K. DELUCCHI, Auteur ; R. L. HENDREN, Auteur Article en page(s) : 35p. Langues : Anglais (eng) Mots-clés : Adolescent Antioxidants/administration & dosage/analysis/therapeutic use Autistic Disorder/drug therapy/urine Biomarkers/urine Brassica/chemistry Child Female Humans Isothiocyanates/administration & dosage/analysis/therapeutic use Male Metabolome Social Behavior Young Adult Antioxidant Autism Biomarker Metabolomics Index. décimale : PER Périodiques Résumé : Background: Children with autism spectrum disorder (ASD) have urinary metabolites suggesting impairments in several pathways, including oxidative stress, inflammation, mitochondrial dysfunction, and gut microbiome alterations. Sulforaphane, a supplement with indirect antioxidant effects that are derived from broccoli sprouts and seeds, was recently shown to lead to improvements in behavior and social responsiveness in children with ASD. We conducted the current open-label study to determine if we could identify changes in urinary metabolites that were associated with clinical improvements with the goal of identifying a potential mechanism of action. Methods: Children and young adults enrolled in a school for children with ASD and related neurodevelopmental disorders were recruited to participate in a 12-week, open-label study of sulforaphane. Fasting urinary metabolites and measures of behavior (Aberrant Behavior Checklist-ABC) and social responsiveness (Social Responsiveness Scale-SRS) were measured at baseline and at the end of the study. Pearson's correlation coefficient was calculated for the pre- to post-intervention change in each of the two clinical scales (ABS and SRS) versus the change in each metabolite. Results: Fifteen children completed the 12-week study. Mean scores on both symptom measures showed improvements (decreases) over the study period, but only the change in the SRS was significant. The ABC improved - 7.1 points (95% CI - 17.4 to 3.2), and the SRS improved - 9.7 points (95% CI - 18.7 to - 0.8). We identified 77 urinary metabolites that were correlated with changes in symptoms, and they clustered into pathways of oxidative stress, amino acid/gut microbiome, neurotransmitters, hormones, and sphingomyelin metabolism. Conclusions: Urinary metabolomics analysis is a useful tool to identify pathways that may be involved in the mechanism of action of treatments targeting abnormal physiology in ASD. Trial registration: This study was prospectively registered at clinicaltrials.gov (NCT02654743) on January 11, 2016. En ligne : https://dx.doi.org/10.1186/s13229-018-0218-4 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=371
in Molecular Autism > 9 (2018) . - 35p.[article] Identification of urinary metabolites that correlate with clinical improvements in children with autism treated with sulforaphane from broccoli [Texte imprimé et/ou numérique] / Stephen BENT, Auteur ; B. LAWTON, Auteur ; T. WARREN, Auteur ; F. WIDJAJA, Auteur ; K. DANG, Auteur ; J. W. FAHEY, Auteur ; Brian CORNBLATT, Auteur ; J. M. KINCHEN, Auteur ; K. DELUCCHI, Auteur ; R. L. HENDREN, Auteur . - 35p.
Langues : Anglais (eng)
in Molecular Autism > 9 (2018) . - 35p.
Mots-clés : Adolescent Antioxidants/administration & dosage/analysis/therapeutic use Autistic Disorder/drug therapy/urine Biomarkers/urine Brassica/chemistry Child Female Humans Isothiocyanates/administration & dosage/analysis/therapeutic use Male Metabolome Social Behavior Young Adult Antioxidant Autism Biomarker Metabolomics Index. décimale : PER Périodiques Résumé : Background: Children with autism spectrum disorder (ASD) have urinary metabolites suggesting impairments in several pathways, including oxidative stress, inflammation, mitochondrial dysfunction, and gut microbiome alterations. Sulforaphane, a supplement with indirect antioxidant effects that are derived from broccoli sprouts and seeds, was recently shown to lead to improvements in behavior and social responsiveness in children with ASD. We conducted the current open-label study to determine if we could identify changes in urinary metabolites that were associated with clinical improvements with the goal of identifying a potential mechanism of action. Methods: Children and young adults enrolled in a school for children with ASD and related neurodevelopmental disorders were recruited to participate in a 12-week, open-label study of sulforaphane. Fasting urinary metabolites and measures of behavior (Aberrant Behavior Checklist-ABC) and social responsiveness (Social Responsiveness Scale-SRS) were measured at baseline and at the end of the study. Pearson's correlation coefficient was calculated for the pre- to post-intervention change in each of the two clinical scales (ABS and SRS) versus the change in each metabolite. Results: Fifteen children completed the 12-week study. Mean scores on both symptom measures showed improvements (decreases) over the study period, but only the change in the SRS was significant. The ABC improved - 7.1 points (95% CI - 17.4 to 3.2), and the SRS improved - 9.7 points (95% CI - 18.7 to - 0.8). We identified 77 urinary metabolites that were correlated with changes in symptoms, and they clustered into pathways of oxidative stress, amino acid/gut microbiome, neurotransmitters, hormones, and sphingomyelin metabolism. Conclusions: Urinary metabolomics analysis is a useful tool to identify pathways that may be involved in the mechanism of action of treatments targeting abnormal physiology in ASD. Trial registration: This study was prospectively registered at clinicaltrials.gov (NCT02654743) on January 11, 2016. En ligne : https://dx.doi.org/10.1186/s13229-018-0218-4 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=371