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Background Growing evidence suggests a mutual interaction between gut microbiome alterations and ALS pathogenesis. However, previous studies were susceptible to potential confounding factors and reverse causation bias, likely leading to inconsistent and biased results. Objectives To decipher the potentially mutual relationship between gut microbiota and ALS, we used a bidirectional two-sample MR approach to examine the associations between the gut microbiome and ALS. Results Using the inverse variance-weighted method,  OTU10032 unclassified Enterobacteriaceae species-level  OTU and  unclassified Acidaminococcaceae  were associated with a higher risk of ALS (per relative abundance: OR, 1.04; 95% CI, 1.01–1.07;  P  = 0.011 and OR, 1.02; 95% CI, 1.01–1.04;  P  = 0.009, respectively). Importantly, Gamma-Glu-Phe was showed potential deleterious effects on the risk of ALS (genetically predicted per a 1-standard deviation increase in the level of Gamma-Glu-Phe: OR, 1.96; 95% CI, 1.50–2.55;  P  = 0.012). Sensitivity analysis of the two candidate genera and metabolites using the MR-Egger and weighted-median methods produced similar estimates, and no horizontal pleiotropy or outliers were observed. Intriguingly, genetically predicted ALS was associated with an increase in the relative abundance of  OTU4607_Sutterella  (per 1-unit higher log odds: β, 2.23; 95% CI, 1.27–3.18;  P  = 0.020) and  Lactobacillales_ORDER  (per 1-unit higher log odds: β, 0.51; 95% CI, 0.09–0.94;  P  = 0.019). Conclusions Our findings provide novel evidence supporting the bidirectional relationship between the gut microbiota and ALS. These results may contribute to designing microbiome- and microbiome-dependent metabolite interventions in future ALS clinical trials.

bmc neurology

Assessment of bidirectional relationships between 98 genera of the human gut microbiota and amyotrophic lateral sclerosis: a 2-sample Mendelian randomization study