Plasma and Fecal Metabolite Profiles in Autism Spectrum Disorder

Needham, Brittany D.; Adame, Mark D.; Serena, Gloria; Rose, Destanie R.; Preston, Gregory M.; Conrad, Mary C.; Campbell, Stewart; Donabedian, David H.; Fasano, Alessio; Ashwood, Paul; Mazmanian, Sarkis K.

doi:10.1016/j.biopsych.2020.09.025

Cited by 145 publications

(148 citation statements)

References 97 publications

(105 reference statements)

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“…While there are several metabolic pathways that are related to the top 50 metabolites identified, about 45% of the top metabolites were connected to phenylalanine and tyrosine metabolism, fatty acid metabolism or sphingolipid metabolism. Differences in tyrosine metabolites such as decreased concentration of phenylalanine and increased concentration of p-cresol have been previously observed in studies examining the gut metabolite composition in TD and ASD children [ 14 , 44 ]. The role of the microbiota in this pathway is also very significant.…”

Section: Discussionmentioning

confidence: 87%

“…Many of the metabolites identified as being differentially expressed between the ASD and TD cohorts have also been previously examined for their relationship to ASD. Specifically, among the top five metabolites ranked by their AUROC value, carnitine, indole and sphingosine have all been found to be differentially expressed in some capacity among individuals with ASD [ 14 , 17 , 18 , 36 ]. In a meta-analysis, 10–20% of individuals with ASD were found to have disorders with synthesizing carnitine, which was the metabolite that had achieved the largest AUROC value [ 36 ].…”

Section: Discussionmentioning

confidence: 99%

“…Certain genera such as Prevotella and Coprococcus have been shown to be significantly less prevalent in the gut of children with ASD [ 12 , 13 ]. Furthermore, it has been proposed that the microbiota differences in children with ASD give rise to metabolomic differences that can be quantitatively evaluated to distinguish them from their TD peers [ 14 , 15 ].…”

Section: Introductionmentioning

confidence: 99%

“…Some previous work involving fecal metabolites identified isopropanol, p-cresol, acetyl-carnitine, free carnitine and neurotransmitters-gamma-Aminobutyrate (GABA) as metabolites that have significantly different concentrations between the ASD and TD cohorts [ 14 , 16 , 17 ]. There have also been mixed results regarding the fecal concentrations of short chain fatty acids.…”

Section: Introductionmentioning

confidence: 99%

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Multivariate Analysis of Fecal Metabolites from Children with Autism Spectrum Disorder and Gastrointestinal Symptoms before and after Microbiota Transfer Therapy

Qureshi

Adams

Hanagan

et al. 2020

JPM

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Fecal microbiota transplant (FMT) holds significant promise for patients with Autism Spectrum Disorder (ASD) and gastrointestinal (GI) symptoms. Prior work has demonstrated that plasma metabolite profiles of children with ASD become more similar to those of their typically developing (TD) peers following this treatment. This work measures the concentration of 669 biochemical compounds in feces of a cohort of 18 ASD and 20 TD children using ultrahigh performance liquid chromatography-tandem mass spectroscopy. Subsequent measurements were taken from the ASD cohort over the course of 10-week Microbiota Transfer Therapy (MTT) and 8 weeks after completion of this treatment. Univariate and multivariate statistical analysis techniques were used to characterize differences in metabolites before, during, and after treatment. Using Fisher Discriminant Analysis (FDA), it was possible to attain multivariate metabolite models capable of achieving a sensitivity of 94% and a specificity of 95% after cross-validation. Observations made following MTT indicate that the fecal metabolite profiles become more like those of the TD cohort. There was an 82–88% decrease in the median difference of the ASD and TD group for the panel metabolites, and among the top fifty most discriminating individual metabolites, 96% report more comparable values following treatment. Thus, these findings are similar, although less pronounced, as those determined using plasma metabolites.

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Section: Discussionmentioning

confidence: 87%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Multivariate Analysis of Fecal Metabolites from Children with Autism Spectrum Disorder and Gastrointestinal Symptoms before and after Microbiota Transfer Therapy

Qureshi

Adams

Hanagan

et al. 2020

JPM

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“…Moreover, glycine serves as the precursor to one-carbon metabolism (cysteine, methionine, and glutathione pathways). These are essential regulators of oxidative state which have been implicated in the metabolomic profile associated with ASD severity in two independent cohorts (78,79) and have been identified as a link between DNA methylation and mitochondrial dysfunction (80,81). In addition, both PGC-1α methylation and mtDNA copy number correlate significantly with metabolites derived from BCAA catabolism.…”

Section: Discussionmentioning

confidence: 99%

DNA methylation of PGC-1α is associated with elevated mtDNA copy number and altered urinary metabolites in Autism Spectrum Disorder

Bam

Buchanan

Mahony

et al. 2021

Preprint

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BackgroundAutism Spectrum Disorder (ASD) is a complex disorder that is underpinned by numerous dysregulated biological pathways, including canonical mitochondrial pathways. Epigenetic mechanisms contribute to this dysregulation and DNA methylation is an important factor in the aetiology of ASD. We examined the relationship between DNA methylation of peroxisome proliferator-activated receptor gamma coactivator-1 alpha (PGC-1α), an essential transcriptional regulator of mitochondrial homeostasis, and mitochondrial dysfunction in an ASD cohort of South African children.ResultsUsing targeted Next Generation bisulfite sequencing, we found 12 highly variable CpG sites in PGC-1α that were significantly differentially methylated (p<0.05) between ASD (n = 55) and controls (n = 44). In ASD, eight CpG sites were hypermethylated in the PGC-1α promotor with a putative binding site for CAMP response binding element 1 (CREB1) spanning one of these CpG sites (p = 1 × 10−6). Mitochondrial DNA (mtDNA) copy number, a marker of mitochondrial function, was elevated (p = 0.002) in ASD compared to controls and correlated significantly with DNA methylation at the PGC-1α promoter. There was a positive correlation between methylation at PGC-1α at CpG#1 and mtDNA copy number (Spearman’s r = 0.2, n = 49, p = 0.04) in ASD, but a negative correlation between methylation at PGC-1α at CpG#4 promoter and mtDNA copy number in controls (Spearman’s r = −0.4, n = 42, p = 0.045). While there was no relationship between mtDNA deletions and PGC-1α methylation in ASD, mtDNA deletions correlated negatively with methylation at PGC-1α at CpG#4 (Spearman’s r = −0.4, n = 42, p = 0.032) in controls. Furthermore, levels of urinary organic acids associated with mitochondrial dysfunction correlated significantly (p<0.05) with DNA methylation at PGC-1α CpG#1 and mtDNA copy number in ASD (n= 20) and controls (n= 13) with many of these metabolites involved in altered redox homeostasis and neuroendocrinology.ConclusionsThese data show an association between PGC-1α promoter methylation, elevated mtDNA copy number and metabolomic evidence of mitochondrial dysfunction in ASD. This highlights an unexplored link between DNA methylation and mitochondrial dysfunction in ASD.

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Analysis of mitochondrial DNA replisome in autism spectrum disorder: Exploring the role of replisome genes

Rojas,

Carrasco‐Gallardo,

Tenorio

et al. 2024

Autism Research

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Autism spectrum disorder (ASD) is a neurodevelopmental condition often associated with mitochondrial dysfunction, including increased mitochondrial DNA (mtDNA) copy number and impaired energy production. This study investigates the role of the mitochondrial replisome—specifically, the genes TFAM, TWNK, POLG, and TOP1MT—in mtDNA replication and its potential contribution to ASD pathophysiology. We analyzed samples from the oral mucosa of children with ASD and typically developing (TD) controls, assessing mtDNA copy number, gene expression, and protein levels. Our findings revealed a significant increase in mtDNA copy number in the oral mucosa of ASD children, along with partially deleted mtDNA molecules. However, there were no significant changes in the expression of TFAM, TWNK, POLG, or MT‐TL1 genes between ASD and TD samples. Additionally, TFAM protein levels, including monomeric, dimeric, and trimeric forms, did not differ significantly. We also observed increased oxidative stress and inflammatory markers in the oral mucosa of ASD children, suggesting that mitochondrial alterations may be linked to inflammation and oxidative damage in ASD. To further investigate the functional impact of TFAM, we overexpressed it in human HEK293 cells and cortical neurons (CN1.4). TFAM overexpression led to increased mtDNA copy number, cell proliferation, and ATP production in HEK293 cells, but did not significantly alter mitochondrial gene expression, protein oxidation, or mtDNA integrity. In CN1.4 neurons, TFAM overexpression increased mitochondrial membrane potential and length, indicating potential changes in mitochondrial dynamics. Overall, our study suggests that while mtDNA alterations are present in ASD, they are not directly driven by changes in mitochondrial replisome gene expression. These findings highlight the complexity of mitochondrial dysfunction in ASD and suggest the need for further investigation into the underlying molecular mechanisms.

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Plasma and Fecal Metabolite Profiles in Autism Spectrum Disorder

Cited by 145 publications

References 97 publications

Multivariate Analysis of Fecal Metabolites from Children with Autism Spectrum Disorder and Gastrointestinal Symptoms before and after Microbiota Transfer Therapy

Multivariate Analysis of Fecal Metabolites from Children with Autism Spectrum Disorder and Gastrointestinal Symptoms before and after Microbiota Transfer Therapy

DNA methylation of PGC-1α is associated with elevated mtDNA copy number and altered urinary metabolites in Autism Spectrum Disorder

Analysis of mitochondrial DNA replisome in autism spectrum disorder: Exploring the role of replisome genes

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