Multivariate Analysis of Plasma Metabolites in Children with Autism Spectrum Disorder and Gastrointestinal Symptoms Before and After Microbiota Transfer Therapy

Adams, James B.; Vargason, Troy; Kang, Dae Wook; Krajmalnik‐Brown, Rosa; Hahn, Juergen

doi:10.3390/pr7110806

Cited by 12 publications

(13 citation statements)

References 47 publications

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“…This suggests that some individuals may respond differently to MTT than others. This finding was similar to the analysis performed on plasma metabolites where a steep decline in median discriminant score was also observed at Week 3 and Week 10 [ 29 ].…”

Section: Discussionsupporting

confidence: 87%

“…None of the metabolites identified as being utilized in the optimum multivariate models were previously identified as being significant for classification in the multivariate plasma models. The general performance of the fecal metabolites when subjected to univariate analysis had generally lower AUROC values than plasma metabolites [ 29 ]. However, despite having lower AUROC scores, multivariate analysis achieved high accuracy in distinguishing ASD and TD children.…”

Section: Discussionmentioning

confidence: 99%

“…Past work in analyzing metabolites prior and subsequent to MTT therapy have also yielded promising results. Children with ASD who underwent MTT presented changes in their plasma metabolite profiles to resemble more closely those of their typically developing peers [ 29 , 30 ]. The work presented in this paper builds on the analysis of this same study [ 25 ], but focuses on fecal metabolites instead of plasma metabolites.…”

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: Discussionsupporting

confidence: 87%

Section: Discussionmentioning

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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“…We previously published a paper on a multivariate analysis of the plasma data from children who participated in our MTT study ( 32 ). This study reports comprehensive metabolite measurements from children who participated in our MTT study ( 28 , 29 ), focusing on a univariate analysis of plasma and fecal metabolite data.…”

Section: Introductionmentioning

confidence: 99%

Distinct Fecal and Plasma Metabolites in Children with Autism Spectrum Disorders and Their Modulation after Microbiota Transfer Therapy

Kang

Adams

Vargason

et al. 2020

mSphere

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Accumulating evidence has strengthened a link between dysbiotic gut microbiota and autism. Fecal microbiota transplant (FMT) is a promising therapy to repair dysbiotic gut microbiota. We previously performed intensive FMT called microbiota transfer therapy (MTT) for children with autism spectrum disorders (ASD) and observed a substantial improvement of gastrointestinal and behavioral symptoms. We also reported modulation of the gut microbiome toward a healthy one. In this study, we report comprehensive metabolite profiles from plasma and fecal samples of the children who participated in the MTT trial. With 619 plasma metabolites detected, we found that the autism group had distinctive metabolic profiles at baseline. Eight metabolites (nicotinamide riboside, IMP, iminodiacetate, methylsuccinate, galactonate, valylglycine, sarcosine, and leucylglycine) were significantly lower in the ASD group at baseline, while caprylate and heptanoate were significantly higher in the ASD group. MTT drove global shifts in plasma profiles across various metabolic features, including nicotinate/nicotinamide and purine metabolism. In contrast, for 669 fecal metabolites detected, when correcting for multiple hypotheses, no metabolite was significantly different at baseline. Although not statistically significant, p-cresol sulfate was relatively higher in the ASD group at baseline, and after MTT, the levels decreased and were similar to levels in typically developing (TD) controls. p-Cresol sulfate levels were inversely correlated with Desulfovibrio, suggesting a potential role of Desulfovibrio on p-cresol sulfate modulation. Further studies of metabolites in a larger ASD cohort, before and after MTT, are warranted, as well as clinical trials of other therapies to address the metabolic changes which MTT was not able to correct. IMPORTANCE Despite the prevalence of autism and its extensive impact on our society, no U.S. Food and Drug Administration-approved treatment is available for this complex neurobiological disorder. Based on mounting evidences that support a link between autism and the gut microbiome, we previously performed a pioneering open-label clinical trial using intensive fecal microbiota transplant. The therapy significantly improved gastrointestinal and behavioral symptoms. Comprehensive metabolomic measurements in this study showed that children with autism spectrum disorder (ASD) had different levels of many plasma metabolites at baseline compared to those in typically developing children. Microbiota transfer therapy (MTT) had a systemic effect, resulting in substantial changes in plasma metabolites, driving a number of metabolites to be more similar to those from typically developing children. Our results provide evidence that changes in metabolites are one mechanism of the gut-brain connection mediated by the gut microbiota and offer plausible clinical evidence for a promising autism treatment and biomarkers.

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“…In humans, intestinal microbiota transplantation has shown very promising results, both against gastrointestinal tract symptoms and ASD symptoms, granting the therapy a 'fast-track' status by the FDA [29]. Among the plasma metabolites showing average to good classification capacity between the treated children and the controls, sarcosine, tyramine O-sulfate and inosine 5'-monophosphate were selected as most discriminant [30]. Many of these studies postulate that microbiota-derived molecules are transported across the blood-brain-barrier, acting as neuroactive metabolites [23].…”

Section: Introductionmentioning

confidence: 99%

Untargeted metabolomic study of autism in newborn screening samples: a pilot study

Courraud

Ernst

et al. 2020

Preprint

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Background The etiopathology of autism spectrum disorder (ASD) is unclear. Main risk factors include both genetic and non-genetic factors, especially prenatal and perinatal events. The Danish Neonatal Screening Biobank in connection with registry data provides unique opportunities to study early signs of disease. Therefore, we aimed to study the metabolomic profiles of dried blood spot (DBS) of newborns later diagnosed with ASD. Methods From the iPsych cohort, we randomly selected 37 subjects born in 2005 and diagnosed with ASD in 2012 (cases) together with 37 matched controls and submitted their biobanked DBS to an LC-MS/MS-based untargeted metabolomics protocol. Raw data were preprocessed using MZmine 2.41.2 and metabolites were subsequently putatively annotated using mzCloud, GNPS feature-based molecular networking and other metabolome mining tools (MolNetEnhancer). Statistical analyses and data visualization included principal coordinates analyses, PERMANOVAs, t-tests, and fold-change analyses. Results 4360 mass spectral features were detected, of which 150 could be putatively annotated at a high confidence level. Chemical structure information at a broad level could be retrieved for a total of 1009 metabolites, covering 31 chemical classes including bile acids, various lipids, nucleotides, amino acids, acylcarnitines and steroids. Although the untargeted analysis revealed no clear distinction between cases and controls, 18 compounds repeatedly reported in the ASD literature could be detected in our study and three mass spectral features were found differentially abundant in cases and controls before FDR correction. In addition, our results pinpointed important other factors influencing chemical profiles of newborn DBS samples such as gestational age, age at sampling and month of birth. Limitations Inherent to pilot studies, our sample size was insufficient to reveal metabolic markers of ASD. Nevertheless, we were able to establish an efficient metabolomic data acquisition and analysis pipeline and flag main confounders to be considered in future studies. Conclusions In this first untargeted DBS metabolomic study, newborns later diagnosed with ASD did not show a significantly different metabolic profile when compared to controls. Nevertheless, our method covered many metabolites associated with ASD in previous studies, suggesting that biochemical markers of ASD are present at birth and may be monitored during newborn screening.

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Multivariate Analysis of Plasma Metabolites in Children with Autism Spectrum Disorder and Gastrointestinal Symptoms Before and After Microbiota Transfer Therapy

Cited by 12 publications

References 47 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

Distinct Fecal and Plasma Metabolites in Children with Autism Spectrum Disorders and Their Modulation after Microbiota Transfer Therapy

Untargeted metabolomic study of autism in newborn screening samples: a pilot study

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