Multi-cohort evidence for impaired microbial support of the methionine cycle in children with autism spectrum disorder.

The contribution of gut microbiota to outcomes of autism spectrum disorders (ASD) has been increasingly appreciated in recent years. With the accumulating evidence on ASD-driven alterations of the gut microbiota, heterogeneities arise across different reports. To account for variabilities in gut microbiota, clinical representations of ASD and data processing approaches, as well as limitations in sample sizes among the existing gut microbiota studies for ASD, the present multi-cohort analysis applied a standard bioinformatic and statistical pipeline on the publicly available gut metagenomic sequencing data for 674 samples, including 326 TD and 348 ASD individuals, collected from eight studies across three main geographical regions. Throughout the analysis, we identified taxonomic profiles of the gut microbiota exhibited more pronounced dysbiosis associated with ASD and between-study variations compared to functional profiles. Differentially abundant taxonomic and pathway markers were identified and validated for their consistent response to ASD across different studies. Co-occurring deficits in microbial pathways for salvaging adenosylcobalamin and S-adenosyl-L-methionine and biosynthesis of methionine in children with ASD point to a reduced microbial support for the host methionine cycle. Species from Faecalibacterium, Bacteroides, Blautia and Bifidobacterium were identified as microbial contributors to ASD-deficient microbial pathways, particularly those related to the methionine cycle. Therefore, the generalisable ASD-deficient contributors to the methionine cycle, such as Blautia wexlerae, Bacteroides stercoris and Streptococcus thermophilus, could be further investigated for their role in therapeutic applications for ASD.