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.
Individuals with autism spectrum disorder (ASD) are frequently affected by co-occurring medical conditions (COCs), which vary in severity, age of onset, and pathophysiological characteristics. The presence of COCs contributes to significant heterogeneity in the clinical presentation of ASD between individuals and a better understanding of COCs may offer greater insight into the etiology of ASD in specific subgroups while also providing guidance for diagnostic and treatment protocols. This study retrospectively analyzed medical claims data from a private United States health plan between years 2000 and 2015 to investigate patterns of COC diagnoses in a cohort of 3,278 children with ASD throughout their first 5 years of enrollment compared to 279,693 children from the general population without ASD diagnoses (POP cohort). Three subgroups of children with ASD were identified by k-means clustering using these COC patterns. The first cluster was characterized by generally high rates of COC diagnosis and comprised 23.7% (n = 776) of the cohort. Diagnoses of developmental delays were dominant in the second cluster containing 26.5% (n = 870) of the cohort. Children in the third cluster, making up 49.8% (n = 1,632) of the cohort, had the lowest rates of COC diagnosis, which were slightly higher than rates observed in the POP cohort. A secondary analysis using these data found that gastrointestinal and immune disorders showed similar longitudinal patterns of prevalence, as did seizure and sleep disorders. These findings may help to better inform the development of diagnostic workup and treatment protocols for COCs in children with ASD.Lay Summary: Medical conditions that co-occur with autism spectrum disorder (ASD) vary significantly from person to person. This study analyzed patterns in diagnosis of co-occurring conditions from medical claims data and observed three subtypes of children with ASD. These results may aid with screening for co-occurring conditions in children with ASD and with understanding ASD subtypes.
Autism spectrum disorder (ASD) is a developmental disorder which is currently only diagnosed through behavioral testing. Impaired folate‐dependent one carbon metabolism (FOCM) and transsulfuration (TS) pathways have been implicated in ASD, and recently a study involving multivariate analysis based upon Fisher Discriminant Analysis returned very promising results for predicting an ASD diagnosis. This article takes another step toward the goal of developing a biochemical diagnostic for ASD by comparing five classification algorithms on existing data of FOCM/TS metabolites, and also validating the classification results with new data from an ASD cohort. The comparison results indicate a high sensitivity and specificity for the original data set and up to a 88% correct classification of the ASD cohort at an expected 5% misclassification rate for typically‐developing controls. These results form the foundation for the development of a biochemical test for ASD which promises to aid diagnosis of ASD and provide biochemical understanding of the disease, applicable to at least a subset of the ASD population.
A retrospective analysis of administrative claims data from a large U.S. health insurer was performed to study a potential association between oral antibiotic use during early childhood and occurrence of later gastrointestinal (GI) symptoms in children with autism spectrum disorder (ASD). Among 3253 children with ASD, 37.0% had a GI-related diagnosis during the last 2 years of their 5-year health coverage enrollment period, compared to 20.0% of 278,370 children from the general population without an ASD diagnosis. Greater numbers of oral antibiotic fills during the first 3 years of enrollment were found to significantly increase the hazard rate of having a later GI-related diagnosis (adjusted hazard ratio 1.48; 95% confidence interval 1.34, 1.63) in children both with and without ASD.
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