Gut Microbiotas, Plasma Metabolites, and Autism Spectrum Disorder: A Bidirectional Mendelian Randomization Analysis

Area of Science:

• Genetics
• Microbiology
• Metabolomics
• Neuroscience

Background:

• Autism spectrum disorder (ASD) is increasingly linked to gut microbiome and plasma metabolite alterations.
• The precise causal relationships between these factors and ASD remain largely undetermined.
• Advanced genetic methods are needed to elucidate these complex interactions.

Purpose of the Study:

• To investigate the genetic causality between the gut microbiome and ASD.
• To explore the mediating role of plasma metabolites in the gut microbiome-ASD axis.
• To identify specific microbial taxa and metabolites influencing ASD risk.

Main Methods:

• Utilized linkage disequilibrium score regression (LDSC) and bidirectional Mendelian randomization (MR) analyses.
• Employed large-scale genome-wide association study (GWAS) summary statistics from diverse cohorts.
• Performed mediation MR to assess metabolite-mediated effects of gut microbes on ASD.

Main Results:

• Identified significant genetic correlations between specific gut bacteria (e.g., Lachnospiraceae NK4A136 group, Sellimonas) and ASD.
• Demonstrated causal effects of five gut microbial genera on ASD risk via MR.
• Revealed causal links between 58 plasma metabolites and ASD, with some mediating microbial effects on ASD.

Conclusions:

• Established a causal relationship between the gut microbiome and ASD, mediated by plasma metabolites.
• Highlighted specific microbial pathways (e.g., Ruminiclostridium5, Ruminococcaceae UCG005, Sutterella) influencing ASD via metabolite modulation.
• Provided a foundation for developing microbiome-targeted therapeutic strategies for ASD.