Metabolome signature of autism in the human prefrontal cortex

Kurochkin, Ilia; Khrameeva, Ekaterina E.; Tkachev, Anna; Stepanova, Vita; Vanyushkina, Anna; Stekolshchikova, Elena; Li, Qian; Zubkov, Dmitry; Shichkova, Polina; Halene, Tobias B.; Willmitzer, Lothar; Giavalisco, Patrick; Akbarian, Schahram; Khaitovich, Philipp

doi:10.1038/s42003-019-0485-4

Cited by 50 publications

(44 citation statements)

References 61 publications

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“…Amino acid signatures of oxidative stress and mitochondrial function are also present in our dataset. Dysregulated amino acid degradation, homeostasis, and import into the brain have been implicated as a cause of neuronal stress in ASD, and supporting metabolomic data has shown perturbations of various amino acid pathways, such as glutamate, methionine, glutathione, and gamma-glutamyl metabolites (10,17,24,26,29,33,49,52,76), which exhibit differences as well ( Figure 4E). We also demonstrate correlations between pathways of oxidative stress (cysteine, methionine, SAM and glutathione pathways) with the ADOS-SS ( Figure 4F).…”

Section: Asd Correlates With Cellular Energy and Oxidative Stress Metsupporting

confidence: 55%

“…These most discriminatory metabolites were primarily from the lipid, amino acid, xenobiotic, and cofactor/vitamin super pathways ( Figures 1E-1F). Several of these metabolites have been previously linked to ASD, such as steroids, bile acids, acyl-carnitines, and nicotinamide metabolites (46)(47)(48)(49). Further, multiple molecules known to be produced or manipulated by the gut microbiota also featured prominently, including 4-ethylphenyl sulfate (4EPS), which is elevated in an ASD mouse model, and indolelactate, a microbe-derived tryptophan metabolite ( Figure 1E) (50,51).…”

Section: Plasma and Fecal Metabolomes Differ Between Asd And Tdmentioning

confidence: 97%

“…Additionally, the 5 plasma metabolites most positively correlated with ADOS-SS are all involved in these cellular energy pathways ( Figure S4D, Table S1). These observed differences in energy markers and lipids could have a neurodevelopmental effect during periods when the high lipid and energy requirement in the brain is crucial (73)(74)(75), and alterations to levels of tricarboxylic acid (TCA) cycle intermediates have been observed in human ASD prefrontal cortex samples (49). Such defects in cellular metabolism support the theory that mitochondrial dysfunction may not only be comorbid with ASD but also a potential contributing factor, as suggested by numerous previous reports (6,13,67,69,72).…”

Section: Asd Correlates With Cellular Energy and Oxidative Stress Metmentioning

confidence: 99%

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Plasma and Fecal Metabolite Profiles in Autism Spectrum Disorder

Needham

Adame

Serena

et al. 2020

Preprint

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Autism Spectrum Disorder (ASD) is a neurodevelopmental condition with hallmark behavioral manifestations including impaired social communication and restricted repetitive behavior. In addition, many affected individuals display metabolic imbalances, immune dysregulation, gastrointestinal (GI) dysfunction, and altered gut microbiome compositions. We sought to better understand non-behavioral features of ASD by determining molecular signatures in peripheral tissues. Herein, we present the untargeted metabolome of 231 plasma and 97 fecal samples from a large cohort of children with ASD and typically developing (TD) controls. Differences in lipid, amino acid, and xenobiotic metabolism discriminate ASD and TD samples. We reveal correlations between specific metabolite profiles and clinical behavior scores, and identify metabolites particularly associated with GI dysfunction in ASD. These findings support a connection between GI physiology, metabolism, and complex behavioral traits, and may advance discovery and development of molecular biomarkers for ASD. Sterol 1 1 1 Gly, Ser, Thr 0 1 1

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Section: Asd Correlates With Cellular Energy and Oxidative Stress Metsupporting

confidence: 55%

Section: Plasma and Fecal Metabolomes Differ Between Asd And Tdmentioning

confidence: 97%

Section: Asd Correlates With Cellular Energy and Oxidative Stress Metmentioning

confidence: 99%

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Plasma and Fecal Metabolite Profiles in Autism Spectrum Disorder

Needham

Adame

Serena

et al. 2020

Preprint

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“…One of the functions of CysGly is a prooxidant that reduces ferric iron to ferrous iron [50]. Kurochkin et al (2019) observed that within the glutathione pathway, in addition to the decrease in the glutathione intensity, two metabolites, such as L-cysteinylglycine and L-γ-glutamyl-L-cysteine, display intensity differences in ASD [51]. Enzymes catalyzing reactions involving glutathione, L-cysteinylglycine, and L-γ-glutamyl-L-cysteine were shown to contain genetic variants connected with ASD (polymorphisms in genes such as GPX1, GSTM1, GGT1, and GSS51-53).…”

Section: Discussionmentioning

confidence: 99%

Higher Levels of Low Molecular Weight Sulfur Compounds and Homocysteine Thiolactone in the Urine of Autistic Children

et al. 2020

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In this study, the levels of concentration of homocysteine thiolactone (HTL), cysteine (Cys), and cysteinylglycine (CysGly) in the urine of autistic and non-autistic children were investigated and compared. HTL has never been analyzed in autistic children. The levels of low molecular weight sulfur compounds in the urine of both groups were determined by validated methods based on high-performance liquid chromatography with spectrofluorometric and diode-array detectors. The statistical data show a significant difference between the examined groups. Children with autism were characterized by a significantly higher level of HTL (p = 5.86 × 10−8), Cys (p = 1.49 × 10−10) and CysGly (p = 1.06 × 10−8) in urine compared with the control group. A difference in the p-value of <0.05 is statistically significant. Higher levels of HTL, Cys, and CysGly in the urine of 41 children with autism, aged 3 to 17, were observed. The obtained results may indicate disturbances in the metabolism of methionine, Cys, and glutathione in some autistic patients. These preliminary results suggest that further research with more rigorous designs and a large number of subjects is needed.

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“…Metabolomics perturbations associated to ASD cannot be only detected in blood, urine or saliva, but even in cerebellum or cortex samples of affected patients. In the study of Kurochin et al, 1366 metabolites were compared in the prefrontal cortex grey matter of ASD patients and healthy controls, revealing different profiles and metabolic pathways and opening the way to different analysis strategies [113].…”

Section: Metabolomics and Neuropsychiatric Disordersmentioning

confidence: 99%

How could metabolomics change pediatric health?

Bardanzellu

Fanos

2020

Ital J Pediatr

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In the last years, 'omics' technologies, and especially metabolomics, emerged as expanding scientific disciplines and promising technologies in the characterization of several pathophysiological processes. In detail, metabolomics, able to detect in a dynamic way the whole set of molecules of low molecular weight in cells, tissues, organs, and biological fluids, can provide a detailed phenotypic portray, representing a metabolic "snapshot." Thanks to its numerous strength points, metabolomics could become a fundamental tool in human health, allowing the exact evaluation of individual metabolic responses to pathophysiological stimuli including drugs, environmental changes, lifestyle, a great number of diseases and other epigenetics factors. Moreover, if current metabolomics data will be confirmed on larger samples, such technology could become useful in the early diagnosis of diseases, maybe even before the clinical onset, allowing a clinical monitoring of disease progression and helping in performing the best therapeutic approach, potentially predicting the therapy response and avoiding overtreatments. Moreover, the application of metabolomics in nutrition could provide significant information on the best nutrition regimen, optimal infantile growth and even in the characterization and improvement of commercial products' composition. These are only some of the fields in which metabolomics was applied, in the perspective of a precision-based, personalized care of human health. In this review, we discuss the available literature on such topic and provide some evidence regarding clinical application of metabolomics in heart diseases, auditory disturbance, nephrouropathies, adult and pediatric cancer, obstetrics, perinatal conditions like asphyxia, neonatal nutrition, neonatal sepsis and even some neuropsychiatric disorders, including autism. Our research group has been interested in metabolomics since several years, performing a wide spectrum of experimental and clinical studies, including the first metabolomics analysis of human breast milk. In the future, it is reasonable to predict that the current knowledge could be applied in daily clinical practice, and that sensible metabolomics biomarkers could be easily detected through cheap and accurate sticks, evaluating biofluids at the patient's bed, improving diagnosis, management and prognosis of sick patients and allowing a personalized medicine. A dream? May be I am a dreamer, but I am not the only one.

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Metabolome signature of autism in the human prefrontal cortex

Cited by 50 publications

References 61 publications

Plasma and Fecal Metabolite Profiles in Autism Spectrum Disorder

Plasma and Fecal Metabolite Profiles in Autism Spectrum Disorder

Higher Levels of Low Molecular Weight Sulfur Compounds and Homocysteine Thiolactone in the Urine of Autistic Children

How could metabolomics change pediatric health?

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