Abstract
Alterations in the microbiota-gut-brain axis are associated with the onset of autism spectrum disorder (ASD). Numerous studies have reported that the gut microbiota (GM) is significantly altered in individuals with ASD and animal models of ASD. However, few studies have focused on sex-specific differences in the GM and fecal metabolites of ASD. In this study, we performed 16S rRNA gene sequencing and untargeted metabolomics in parallel on fecal samples from a valproic acid (VPA)-induced rat model of autism (VPA rats). Based on these data, we analyzed differentially abundant metabolites in the Kyoto Encyclopedia of Genes and Genomes (KEGG) database to reveal the possible mechanism of ASD. Data derived from male and female rats were analyzed separately. Finally, we analyzed the correlation between characteristic genera and characteristic fecal metabolites in VPA rats of both sexes. The results showed that VPA rats of both sexes presented remarkable alterations in the GM and fecal metabolites. Sex-specific differences were noticeably detected. We identified 51 annotated differentially abundant fecal metabolites and 1 differentially enriched KEGG pathway between the male VPA and male control groups. Ruminococcus_2, Candidatus_Soleaferrea, Desulfovibrio, Candidatus_Saccharimonas, Intestinimonas, [Eubacterium]_xylanophilum_group, [Eubacterium]_brachy_group and [Bacteroides]_pectinophilus_group were the characteristic genera of male VPA rats. Between the female VPA and female control groups, 124 annotated differentially abundant fecal metabolites were identified without differentially enriched KEGG pathways. Ruminiclostridium, Acetatifactor, Desulfovibrio, [Eubacterium]_xylanophilum_group and Candidatus_Saccharimonas were the characteristic genera of female VPA rats. Correlation analysis revealed a tight relationship between the GM and fecal metabolites in VPA rats of both sexes. In conclusion, alterations in the GM and fecal metabolites in VPA rats showed sex-specific differences. The therapy for ASD might be different between sexes in the future.
Highlights
Autism spectrum disorder (ASD) is an intractable neurodevelopmental disability caused by multiple genetic and environmental factors [1,2,3]
We used 16S rRNA gene sequencing and untargeted metabolomics to explore the characteristics of fecal metabolites and the gut microbiota (GM) in male and female Valproic acid (VPA) rats
Dysbacteriosis existed in the fecal samples of both male and female VPA rats, with sex-specific differences
Summary
Autism spectrum disorder (ASD) is an intractable neurodevelopmental disability caused by multiple genetic and environmental factors [1,2,3]. The characteristic symptoms of ASD include social deficits and repetitive behaviors [4]. The prevalence of ASD has grown very rapidly in industrialized countries [5]. The mechanism of ASD remains unclear with no effective medications. The morbidity of ASD is typically male biased, with a male-to-female ratio of approximately 4 to 1 [6, 7]. A previous study reported that the mechanism of ASD is different between sexes [8]. Sex-specific studies may help better illuminate the mechanisms of ASD
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