Causal genetic link between gut microbiome, metabolites, and autism spectrum disorder in a European cohort.

This study used genetic analysis to explore whether gut bacteria might cause autism. Researchers found that certain types of gut bacteria may increase autism risk, while others might be protective. When they looked at brain chemicals and nutrients produced by gut bacteria, most connections became weaker, but two bacteria families still showed strong links to higher autism risk. The study suggests gut bacteria changes might contribute to autism development, not the other way around.

This Mendelian randomization study investigated causal relationships between gut microbiota, metabolites, and autism spectrum disorder (ASD) using genetic data from 18,340 individuals for microbiota exposure and 14,759 ASD cases with 155,327 controls. The analysis identified nine bacterial taxa as potential risk factors for ASD, including Methanobacteria, Prevotellaceae, and Lachnospiraceae families, while two taxa (Eisenbergiella and Ruminococcaceae) showed protective effects. When adjusting for neurotransmitter and amino acid metabolites, most associations diminished except for Prevotellaceae and Lachnospiraceae, which remained significant risk factors. Reverse analysis found no evidence that ASD causes gut microbiota changes, suggesting the relationship is unidirectional from microbiota to ASD risk.

Findings suggest specific gut bacteria may causally influence ASD risk through metabolic pathways. This supports development of targeted microbiome interventions and highlights the importance of gut health in autism. However, clinical translation requires validation in diverse populations and functional studies to understand mechanisms.

Study limited to European cohort, restricting generalizability to other populations. Mendelian randomization relies on genetic instruments which may not capture all microbiota variation. Metabolite adjustments were limited to neurotransmitter and amino acid pathways, potentially missing other relevant metabolic mechanisms.

Recent studies have illuminated a significant relationship between the gut microbiota and the development and progression of autism spectrum disorder (ASD), mediated through the complex gut-brain axis, where metabolic pathways are crucial. Nevertheless, the exact causal link remains to be elucidated. This study aims to assess the potential causal relationship between the gut microbiota, metabolites, and ASD, utilizing Mendelian randomization methodology. The exposure variable of gut microbiota was ascertained using instrumental variables derived from a genome-wide association study that included a cohort of 18,340 individuals.

The outcome variable comprised genome-wide association study data from 14,759 individuals diagnosed with ASD and 1,55,327 controls. The primary method of analysis was the inverse-variance weighted method. Multivariable multiple regression analysis was conducted to examine the impact of gut microbial metabolites on the established correlations. Inverse-variance weighted analyses revealed that Methanobacteria[c] (odds ratio [OR] = 1.17 [1.03-1.33]), Methanobacteriaceae[f] (OR = 1.17 [1.03-1.33]), Prevotellaceae[f] (OR = 1.29 [1.04-1.60]), Holdemania[g] (OR = 1.23 [1.03-1.45]), Lachnospiraceae[g] (OR = 1.29 [1.06-1.57]), Ruminiclostridium[g] (OR = 1.63 [1.27-2.10]), Terrisporobacter[g] (OR = 1.28 [1.00-1.63]), Methanobacteriales[o] (OR = 1.17 [1.03-1.33]), and Euryarchaeota[p] (OR = 1.16 [1.02-1.32]) serve as risk factors for ASD, while Eisenbergiella[g] (OR = 0.80 [0.68-0.94]) and Ruminococcaceae[g] (OR = 0.79 [0.63-1.00]) exhibit protective roles against ASD.

Adjustments for neurotransmitter and amino acid metabolites effects diminished these associations. However, Prevotellaceae and Lachnospiraceae remained significantly associated with increased ASD risk. Reverse Mendelian randomization analyses did not establish a causal relationship between ASD and gut microbiota composition. Sensitivity tests showed no evidence of heterogeneity or pleiotropy.

Alterations in metabolites induced by the gut microbiota may contribute to ASD susceptibility. Prevotellaceae and Lachnospiraceae are implicated as potential risk factors. Investigating these associations further could unveil novel therapeutic targets and provide deeper insights into ASD's etiological mechanisms.