Cerebrospinal Fluid Metabolites Mediate the Impact of Gut Microbiota on Amyotrophic Lateral Sclerosis: Novel Insights From Mendelian Randomization

Background Previous studies have noted changes in the gut microbiota of amyotrophic lateral sclerosis patients, with some assessing its impact through metabolites or inflammatory factors. However, most of these are observational, and peripheral systems may not accurately reflect central nervous system pathology. This study uniquely explores the influence of gut microbiota on amyotrophic lateral sclerosis by metabolites in cerebrospinal fluid, which is directly connected to the central nervous system. Methods Data on gut microbiota, cerebrospinal fluid metabolites, and amyotrophic lateral sclerosis were derived from large‐scale genome‐wide association studies. We employed two‐sample and mediation Mendelian randomization to examine the causal effects of gut microbiota and cerebrospinal fluid metabolites on amyotrophic lateral sclerosis, as well as the mediating role of cerebrospinal fluid metabolites between gut microbiota and disease progression. Furthermore, the results were validated through various sensitivity analyses. Results Two‐sample Mendelian randomization analysis revealed significant associations between three gut microbiota and four cerebrospinal fluid metabolites and amyotrophic lateral sclerosis. Notably, mediation Mendelian randomization analysis indicated that cyanobacteria may promote the onset of amyotrophic lateral sclerosis by increasing the levels of 3‐methoxytyramine sulfate in cerebrospinal fluid. Additionally, the sensitivity analysis confirmed the robustness of the Mendelian randomization results. Conclusions This study addresses the gap in causal inference within the research on the relationship between gut microbiota, cerebrospinal fluid metabolomics, and amyotrophic lateral sclerosis, thereby advancing our understanding of the molecular mechanisms underlying the disease. The findings will provide a scientific basis for early intervention and precision treatment of the disease.