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

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.