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Metabolites
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Metabolomics of Autism Spectrum Disorder
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Metabolomics of Autism Spectrum Disorder

A special issue of Metabolites (ISSN 2218-1989). This special issue belongs to the section "Endocrinology and Clinical Metabolic Research".

Deadline for manuscript submissions: closed (15 August 2022) | Viewed by 22895

Special Issue Editors

Dr. Federica Gevi

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Guest Editor
Department of Ecology and Biology, University of Tuscia, 01100 Viterbo, Italy
Interests: metabolomics; UHPLC-mass spectrometry; untargeted metabolomics profiling; multivariate analisys
Prof. Dr. Antonio Persico

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Guest Editor
Department of Biomedical, Metabolic and Neural Sciences, University of Modena and Reggio Emilia, 41125 Modena, Italy
Interests: autism; ADHD; intellectual disability; Phelan-McDermid syndrome; child psychiatry; neurogenetics; neurodevelopment; psychopharmacology
Special Issues, Collections and Topics in MDPI journals
Prof. Dr. Anna Maria Timperio

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Guest Editor
Department of Ecological and Biological Sciences, University of Tuscia, Largo dell\'Università, snc, 01100 Viterbo, Italy
Interests: proteomics; metabolomics; lipidomics; mass spectrometry; red blood cell membranes; food proteomics; MALDI biotype; nucleosides; antarctic cryptoendolithic communities
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Autism spectrum disorder (ASD) is a serious pathology that originates in neurodevelopment anomalies due, in most cases, to a polygenic/oligogenic vulnerability, on which environmental factors can act especially in the prenatal and early postnatal period. This pathology is characterized by social–communicative deficits and cognitive symptoms, such as stereotypes, rigid adherence to routines, fixed and bizarre interests, and sensory hypo- or hyper-sensitivity [1]. Behavioral abnormalities generally begin around 18–24 months of life. According to the Centers for Disease Control and Prevention (CDC) it is estimated that in the United States of America, autism affects 1 in 68 children and is progressively increasing. To date, diagnosis of ASD is still based only on the behavioral observation of the child, and there are no biomarkers to support the autism clinic. It is not feasible to predict whether a newborn growing up develops the disease, and it is difficult to tell if a diagnosed child at the preschool age will develop an expressive language or will remain non-verbal, and finally what their degree of response will be to rehabilitation therapies. Researchers to date have been unable to find a neurological, genetic link or symptom uniquely associated with autism. Blood tests, urinary analysis, brain screening, or other clinical investigations do not allow us to establish the presence or absence of ASD. The metabolomic approach, however, providing a tool to define perturbations in metabolic pathways could be considered a promising tool for clinical diagnosis. Metabolomics by studying and quantifying the metabolites present in biological fluids offers an instantaneous view of the system, providing useful information for interpreting the processes in the analyzed organism. Metabolites, or small molecules, can be considered the final product of gene expression and protein activity, therefore determining the biochemical phenotype of a biological organism. 

Through metabolomics, indeed, it is possible to provide researchers and clinicians with the most up-to-date information on possible biomarkers that can help them to understand how to act on therapeutic strategies for patients. 

This Special Issue will provide comprehensive and critical knowledge of the application of metabolomic approaches to autism disorder and will review progress in this field. Advances across the multitude of metabolomic technologies, including LC–MS, GC–MS, NMR, and Fourier transform infrared spectrometry (FTIR), are significantly expanding our understanding of small molecules. This Special Issue of Metabolites aims to bring together research on the importance of metabolomic application in understanding the mechanisms underlying autism spectrum disorder.

Dr. Federica Gevi
Prof. Antonio Persico
Prof. Dr. Anna Maria Timperio
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Metabolites is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2700 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • metabolomics
  • autism
  • HPLC
  • NMR
  • GC 
  • FT-IR
  • mass spectrometry
  • urine
  • plasma

Published Papers (7 papers)

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Research

21 pages, 803 KiB  
Article
Maternal Serum and Placental Metabolomes in Association with Prenatal Phthalate Exposure and Neurodevelopmental Outcomes in the MARBLES Cohort
by Mariana Parenti, Rebecca J. Schmidt, Sally Ozonoff, Hyeong-Moo Shin, Daniel J. Tancredi, Paula Krakowiak, Irva Hertz-Picciotto, Cheryl K. Walker and Carolyn M. Slupsky
Metabolites 2022, 12(9), 829; https://0-doi-org.brum.beds.ac.uk/10.3390/metabo12090829 - 02 Sep 2022
Cited by 8 | Viewed by 2305
Abstract
Prenatal exposure to phthalates, a family of endocrine-disrupting plasticizers, is associated with disruption of maternal metabolism and impaired neurodevelopment. We investigated associations between prenatal phthalate exposure and alterations of both the maternal third trimester serum metabolome and the placental metabolome at birth, and [...] Read more.
Prenatal exposure to phthalates, a family of endocrine-disrupting plasticizers, is associated with disruption of maternal metabolism and impaired neurodevelopment. We investigated associations between prenatal phthalate exposure and alterations of both the maternal third trimester serum metabolome and the placental metabolome at birth, and associations of these with child neurodevelopmental outcomes using data and samples from the Markers of Autism Risk in Babies Learning Early Signs (MARBLES) cohort. The third trimester serum (n = 106) and placental (n = 132) metabolomes were investigated using 1H nuclear magnetic resonance spectroscopy. Children were assessed clinically for autism spectrum disorder (ASD) and cognitive development. Although none of the urinary phthalate metabolite concentrations were associated with maternal serum metabolites after adjustment for covariates, mixture analysis using quantile g-computation revealed alterations in placental metabolites with increasing concentrations of phthalate metabolites that included reduced concentrations of 2-hydoxybutyrate, carnitine, O-acetylcarnitine, glucitol, and N-acetylneuraminate. Child neurodevelopmental outcome was not associated with the third trimester serum metabolome, but it was correlated with the placental metabolome in male children only. Maternal phthalate exposure during pregnancy is associated with differences in the placental metabolome at delivery, and the placental metabolome is associated with neurodevelopmental outcomes in males in a cohort with high familial ASD risk. Full article
(This article belongs to the Special Issue Metabolomics of Autism Spectrum Disorder)
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15 pages, 2640 KiB  
Article
Urinary Untargeted Metabolic Profile Differentiates Children with Autism from Their Unaffected Siblings
by Anna Maria Timperio, Federica Gevi, Francesca Cucinotta, Arianna Ricciardello, Laura Turriziani, Maria Luisa Scattoni and Antonio M. Persico
Metabolites 2022, 12(9), 797; https://0-doi-org.brum.beds.ac.uk/10.3390/metabo12090797 - 26 Aug 2022
Cited by 7 | Viewed by 2279
Abstract
Autism Spectrum Disorder (ASD) encompasses a clinical spectrum of neurodevelopmental conditions that display significant heterogeneity in etiology, symptomatology, and severity. We previously compared 30 young children with idiopathic ASD and 30 unrelated typically-developing controls, detecting an imbalance in several compounds belonging mainly to [...] Read more.
Autism Spectrum Disorder (ASD) encompasses a clinical spectrum of neurodevelopmental conditions that display significant heterogeneity in etiology, symptomatology, and severity. We previously compared 30 young children with idiopathic ASD and 30 unrelated typically-developing controls, detecting an imbalance in several compounds belonging mainly to the metabolism of purines, tryptophan and other amino acids, as well as compounds derived from the intestinal flora, and reduced levels of vitamins B6, B12 and folic acid. The present study describes significant urinary metabolomic differences within 14 pairs, including one child with idiopathic ASD and his/her typically-developing sibling, tightly matched by sex and age to minimize confounding factors, allowing a more reliable identification of the metabolic fingerprint related to ASD. By using a highly sensitive, accurate and unbiased approach, suitable for ensuring broad metabolite detection coverage on human urine, and by applying multivariate statistical analysis, we largely replicate our previous results, demonstrating a significant perturbation of the purine and tryptophan pathways, and further highlight abnormalities in the “phenylalanine, tyrosine and tryptophan” pathway, essentially involving increased phenylalanine and decreased tyrosine levels, as well as enhanced concentrations of bacterial degradation products, including phenylpyruvic acid, phenylacetic acid and 4-ethylphenyl-sulfate. The outcome of these within-family contrasts consolidates and extends our previous results obtained from unrelated individuals, adding further evidence that these metabolic imbalances may be linked to ASD rather than to environmental differences between cases and controls. It further underscores the excess of some gut microbiota-derived compounds in ASD, which could have diagnostic value in a network model differentiating the metabolome of autistic and unaffected siblings. Finally, it points toward the existence of a “metabolic autism spectrum” distributed as an endophenotype, with unaffected siblings possibly displaying a metabolic profile intermediate between their autistic siblings and unrelated typically-developing controls. Full article
(This article belongs to the Special Issue Metabolomics of Autism Spectrum Disorder)
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19 pages, 3256 KiB  
Article
Impact of Maternal Obesity on the Gestational Metabolome and Infant Metabolome, Brain, and Behavioral Development in Rhesus Macaques
by Yu Hasegawa, Zhichao Zhang, Ameer Y. Taha, John P. Capitanio, Melissa D. Bauman, Mari S. Golub, Judy Van de Water, Catherine A. VandeVoort, Cheryl K. Walker and Carolyn M. Slupsky
Metabolites 2022, 12(8), 764; https://0-doi-org.brum.beds.ac.uk/10.3390/metabo12080764 - 19 Aug 2022
Cited by 4 | Viewed by 1913
Abstract
Maternal gestational obesity is associated with elevated risks for neurodevelopmental disorder, including autism spectrum disorder. However, the mechanisms by which maternal adiposity influences fetal developmental programming remain to be elucidated. We aimed to understand the impact of maternal obesity on the metabolism of [...] Read more.
Maternal gestational obesity is associated with elevated risks for neurodevelopmental disorder, including autism spectrum disorder. However, the mechanisms by which maternal adiposity influences fetal developmental programming remain to be elucidated. We aimed to understand the impact of maternal obesity on the metabolism of both pregnant mothers and their offspring, as well as on metabolic, brain, and behavioral development of offspring by utilizing metabolomics, protein, and behavioral assays in a non-human primate model. We found that maternal obesity was associated with elevated inflammation and significant alterations in metabolites of energy metabolism and one-carbon metabolism in maternal plasma and urine, as well as in the placenta. Infants that were born to obese mothers were significantly larger at birth compared to those that were born to lean mothers. Additionally, they exhibited significantly reduced novelty preference and significant alterations in their emotional response to stress situations. These changes coincided with differences in the phosphorylation of enzymes in the brain mTOR signaling pathway between infants that were born to obese and lean mothers and correlated with the concentration of maternal plasma betaine during pregnancy. In summary, gestational obesity significantly impacted the infant systemic and brain metabolome and adaptive behaviors. Full article
(This article belongs to the Special Issue Metabolomics of Autism Spectrum Disorder)
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19 pages, 2884 KiB  
Article
Effect of Supplementation on Levels of Homovanillic and Vanillylmandelic Acids in Children with Autism Spectrum Disorders
by Paulina Gątarek and Joanna Kałużna-Czaplińska
Metabolites 2022, 12(5), 423; https://0-doi-org.brum.beds.ac.uk/10.3390/metabo12050423 - 09 May 2022
Cited by 5 | Viewed by 3826
Abstract
Autism Spectrum Disorders (ASD) are characterized by numerous comorbidities, including various metabolic and nutritional abnormalities. In many children with ASD, problems with proper nutrition can often lead to inadequate nutrient intake and some disturbances in metabolic profiles, which subsequently correlate with impaired neurobehavioural [...] Read more.
Autism Spectrum Disorders (ASD) are characterized by numerous comorbidities, including various metabolic and nutritional abnormalities. In many children with ASD, problems with proper nutrition can often lead to inadequate nutrient intake and some disturbances in metabolic profiles, which subsequently correlate with impaired neurobehavioural function. The purpose of this study was to investigate and compare the relationship between supplementation, levels of homovanillic acid (HVA) and vanillylmandelic acid (VMA) and the behaviour of children with ASD using quantitative urinary acid determination and questionnaires provided by parents/caregivers. The study was carried out on 129 children between 3 and 18 years of age. HVA and VMA were extracted and derivatized from urinary samples and simultaneously analyzed by gas chromatography-mass spectrometry (GC-MS). In addition, parents/caregivers of children with ASD were asked to complete questionnaires containing information about their diet and intake/non-intake of supplements. The application of the Mann–Whitney U test showed a statistically significant difference between the level of HVA and vitamin B supplementation (p = 1.64 × 10−2) and also omega-6 fatty acids supplementation and the levels of HVA (p = 1.50 × 10−3) and VMA (p = 2.50 × 10−3). In some children, a reduction in the severity of autistic symptoms (better response to own name or better reaction to change) was also observed. These results suggest that supplementation affects the levels of HVA and VMA and might also affect the children’s behaviour. Further research on these metabolites and the effects of supplementation on their levels, as well as the effects on the behaviour and physical symptoms among children with ASD is needed. Full article
(This article belongs to the Special Issue Metabolomics of Autism Spectrum Disorder)
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19 pages, 3113 KiB  
Article
Central Nervous System Metabolism in Autism, Epilepsy and Developmental Delays: A Cerebrospinal Fluid Analysis
by Danielle Brister, Brianna A. Werner, Geoffrey Gideon, Patrick J. McCarty, Alison Lane, Brian T. Burrows, Sallie McLees, P. David Adelson, Jorge I. Arango, William Marsh, Angelea Flores, Matthew T. Pankratz, Ngoc Han Ly, Madison Flood, Danni Brown, David Carpentieri, Yan Jin, Haiwei Gu and Richard E. Frye
Metabolites 2022, 12(5), 371; https://0-doi-org.brum.beds.ac.uk/10.3390/metabo12050371 - 20 Apr 2022
Cited by 9 | Viewed by 2815
Abstract
Neurodevelopmental disorders are associated with metabolic pathway imbalances; however, most metabolic measurements are made peripherally, leaving central metabolic disturbances under-investigated. Cerebrospinal fluid obtained intraoperatively from children with autism spectrum disorder (ASD, n = 34), developmental delays (DD, n = 20), and those without [...] Read more.
Neurodevelopmental disorders are associated with metabolic pathway imbalances; however, most metabolic measurements are made peripherally, leaving central metabolic disturbances under-investigated. Cerebrospinal fluid obtained intraoperatively from children with autism spectrum disorder (ASD, n = 34), developmental delays (DD, n = 20), and those without known DD/ASD (n = 34) was analyzed using large-scale targeted mass spectrometry. Eighteen also had epilepsy (EPI). Metabolites significantly related to ASD, DD and EPI were identified by linear models and entered into metabolite–metabolite network pathway analysis. Common disrupted pathways were analyzed for each group of interest. Central metabolites most involved in metabolic pathways were L-cysteine, adenine, and dodecanoic acid for ASD; nicotinamide adenine dinucleotide phosphate, L-aspartic acid, and glycine for EPI; and adenosine triphosphate, L-glutamine, ornithine, L-arginine, L-lysine, citrulline, and L-homoserine for DD. Amino acid and energy metabolism pathways were most disrupted in all disorders, but the source of the disruption was different for each disorder. Disruption in vitamin and one-carbon metabolism was associated with DD and EPI, lipid pathway disruption was associated with EPI and redox metabolism disruption was related to ASD. Two microbiome metabolites were also detected in the CSF: shikimic and cis-cis-muconic acid. Overall, this study provides increased insight into unique metabolic disruptions in distinct but overlapping neurodevelopmental disorders. Full article
(This article belongs to the Special Issue Metabolomics of Autism Spectrum Disorder)
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15 pages, 2500 KiB  
Article
Are Fecal Metabolome and Microbiota Profiles Correlated with Autism Severity? A Cross-Sectional Study on ASD Preschoolers
by Luca Laghi, Paola Mastromarino, Margherita Prosperi, Maria Aurora Morales, Sara Calderoni, Elisa Santocchi, Filippo Muratori and Letizia Guiducci
Metabolites 2021, 11(10), 654; https://0-doi-org.brum.beds.ac.uk/10.3390/metabo11100654 - 26 Sep 2021
Cited by 6 | Viewed by 2584
Abstract
Autism spectrum disorders (ASD) make up a heterogeneous group of neurodevelopmental disorders characterized by social and communication difficulties associated with repetitive and restrictive behaviors. Besides core features, metabolic imbalances, inflammation, gastrointestinal (GI) symptoms, and altered gut microbiota composition were often described in association [...] Read more.
Autism spectrum disorders (ASD) make up a heterogeneous group of neurodevelopmental disorders characterized by social and communication difficulties associated with repetitive and restrictive behaviors. Besides core features, metabolic imbalances, inflammation, gastrointestinal (GI) symptoms, and altered gut microbiota composition were often described in association with ASD, but their connection with the severity of autism (SA) remains unexplored. In this study, fecal metabolome, microbiota, and calprotectin levels of 80 ASD preschoolers were quantified and correlated with SA. Twelve of the fifty-nine molecules that were quantified by fecal metabolome analysis were significantly associated with SA. No links between SA or GI symptoms and microorganisms’ relative abundance were highlighted. Significant correlations between bifidobacteria, Sutterella, lactobacilli relative abundance, and metabolomics profiles were found. These results suggest that fecal metabolome discriminates the SA and intestinal microorganisms mediate the link between metabolome and SA regardless of GI symptomatology. The study raises the possibility that grouping ASD populations through metabolomics and fecal microbiota could aid the identification of specific ASD endophenotypes, on the basis of the SA. Mechanistic studies focusing on detected biomarkers might be an option for future studies. Full article
(This article belongs to the Special Issue Metabolomics of Autism Spectrum Disorder)
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20 pages, 798 KiB  
Article
Maternal Plasma Metabolic Profile Demarcates a Role for Neuroinflammation in Non-Typical Development of Children
by Rebecca J. Schmidt, Donghai Liang, Stefanie A. Busgang, Paul Curtin and Cecilia Giulivi
Metabolites 2021, 11(8), 545; https://0-doi-org.brum.beds.ac.uk/10.3390/metabo11080545 - 18 Aug 2021
Cited by 6 | Viewed by 3617
Abstract
Maternal and cord plasma metabolomics were used to elucidate biological pathways associated with increased diagnosis risk for autism spectrum disorders (ASD). Metabolome-wide associations were assessed in both maternal and umbilical cord plasma in relation to diagnoses of ASD and other non-typical development (Non-TD) [...] Read more.
Maternal and cord plasma metabolomics were used to elucidate biological pathways associated with increased diagnosis risk for autism spectrum disorders (ASD). Metabolome-wide associations were assessed in both maternal and umbilical cord plasma in relation to diagnoses of ASD and other non-typical development (Non-TD) compared to typical development (TD) in the Markers of Autism risk in Babies: Learning Early Signs (MARBLES) cohort study of children born to mothers who already have at least one child with ASD. Analyses were stratified by sample matrix type, machine mode, and annotation confidence level. Dimensionality reduction techniques were used [i.e, principal component analysis (PCA) and random subset weighted quantile sum regression (WQSRS)] to minimize the high multiple comparison burden. With WQSRS, a metabolite mixture obtained from the negative mode of maternal plasma decreased the odds of Non-TD compared to TD. These metabolites, all related to the prostaglandin pathway, underscored the relevance of neuroinflammation status. No other significant findings were observed. Dimensionality reduction strategies provided confirming evidence that a set of maternal plasma metabolites are important in distinguishing Non-TD compared to TD diagnosis. A lower risk for Non-TD was linked to anti-inflammatory elements, thereby linking neuroinflammation to detrimental brain function consistent with studies ranging from neurodevelopment to neurodegeneration. Full article
(This article belongs to the Special Issue Metabolomics of Autism Spectrum Disorder)
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