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

Researchers studied the genetic links between gut bacteria, blood chemicals, and autism using data from over 18,000 people. They found that certain gut bacteria may influence autism risk through specific chemicals in the blood. Some bacteria appear to reduce autism risk through beneficial metabolites, while the gut-brain connection may work through serotonin and other chemical pathways.

This Mendelian randomization study investigated genetic relationships between gut microbiome, plasma metabolites, and autism spectrum disorder using large-scale genomic data. Researchers analyzed data from 18,340 individuals for gut microbiome, 18,382 for ASD, and 8,299 for plasma metabolites. The study found significant genetic correlations between specific gut bacteria (NK4A136 group) and ASD. Five gut microbial genera showed causal effects on ASD risk, while 58 plasma metabolites demonstrated causal relationships with ASD.

Mediation analysis revealed that specific bacteria may reduce ASD occurrence through metabolites Delta-CEHC and Docosadioate, while others modulate ASD by affecting serotonin and N-acetyl-L-glutamine pathways.

Findings support gut-brain axis involvement in autism and suggest microbiome-based interventions may be beneficial. Specific metabolic pathways identified could guide targeted therapies. However, clinical validation needed before therapeutic applications.

Study relies on genetic associations which may not reflect actual biological causation. Cross-population generalizability unclear. Mediation pathways require validation in clinical studies. Sample sizes varied across datasets, potentially affecting statistical power for some analyses.

: Previous studies have indicated that the gut microbiome and plasma metabolites play key roles in autism spectrum disorder (ASD), but their causal relationships remain unclear. Linkage disequilibrium score regression (LDSC) and Mendelian randomization (MR) are powerful tools for assessing genetic causality. This study uses LDSC and MR to investigate the genetic links between the gut microbiome and ASD and explore the mediating role of plasma metabolites.: To explore the genetic relationships between the gut microbiome, plasma metabolites, and ASD, we obtained summary statistics from large-scale genome-wide association studies (GWAS). Gut microbiome data came from a MiBioGen consortium meta-analysis (= 18,340), ASD data from the Danish Psychiatric Central Research Register (DPCRR) (= 18,382), and plasma metabolite data from the Canadian Longitudinal Study of Aging (CLSA)= 8299).

We applied LDSC and bidirectional MR to analyze the genetic associations between the gut microbiome and ASD and plasma metabolites and ASD. Mediation MR was used to assess the mediating role of plasma metabolites in the gut microbiome-ASD relationship.: LDSC analysis revealed significant genetic correlations between the gut microbiotaNK4A136 group andwith ASD. Moreover, bidirectional MR demonstrated causal effects of five gut microbial genera on ASD risk, as indicated by inverse variance weighted (IVW) methods. Similarly, we identified 49 plasma metabolites that exhibited genetic correlations with ASD, and 58 metabolites had causal effects on ASD in MR analysis.

Mediation analysis revealed that specific bacteria,, reduce the occurrence of ASD through metabolites Delta-CEHC and Docosadioate (C22-DC). Furthermore,andmodulate ASD by inhibiting Serotonin and N-acetyl-L-glutamine, respectively.: This study provides evidence of a causal relationship between the gut microbiome and ASD, with plasma metabolites acting as a potential mediator. Our findings offer new insights into the causal mechanisms linking the gut microbiome and ASD and provide a theoretical foundation for microbiome-based therapeutic strategies.