Abstract
BACKGROUND: Autism Spectrum Disorders (ASD) are defined as a group of pervasive neurodevelopmental disorders, and the heterogeneity in the symptomology and etiology of ASD has long been recognized. Altered immune function and gut microbiota have been found in ASD populations. Immune dysfunction has been hypothesized to involve in the pathophysiology of a subtype of ASD. METHODS: A cohort of 105 ASD children were recruited and grouped based on IFN-γ levels derived from ex vivo stimulated γδT cells. Fecal samples were collected and analyzed with a metagenomic approach. Comparison of autistic symptoms and gut microbiota composition was made between subgroups. Enriched KEGG orthologues markers and pathogen-host interactions based on metagenome were also analyzed to reveal the differences in functional features. RESULTS: The autistic behavioral symptoms were more severe for children in the IFN-γ-high group, especially in the body and object use, social and self-help, and expressive language performance domains. LEfSe analysis of gut microbiota revealed an overrepresentation of Selenomonadales, Negatiyicutes, Veillonellaceae and Verrucomicrobiaceae and underrepresentation of Bacteroides xylanisolvens and Bifidobacterium longum in children with higher IFN-γ level. Decreased metabolism function of carbohydrate, amino acid and lipid in gut microbiota were found in the IFN-γ-high group. Additional functional profiles analyses revealed significant differences in the abundances of genes encoding carbohydrate-active enzymes between the two groups. And enriched phenotypes related to infection and gastroenteritis and underrepresentation of one gut-brain module associated with histamine degradation were also found in the IFN-γ-High group. Results of multivariate analyses revealed relatively good separation between the two groups. CONCLUSIONS: Levels of IFN-γ derived from γδT cell could serve as one of the potential candidate biomarkers to subtype ASD individuals to reduce the heterogeneity associated with ASD and produce subgroups which are more likely to share a more similar phenotype and etiology. A better understanding of the associations among immune function, gut microbiota composition and metabolism abnormalities in ASD would facilitate the development of individualized biomedical treatment for this complex neurodevelopmental disorder.