OBJECTIVE: Asthma is a prevalent chronic respiratory condition with multifactorial pathogenesis. Emerging evidence suggests that gut microbiota and their metabolites influence asthma risk. This study explores the mediation effects of plasma metabolites between gut microbiota and asthma using Mendelian randomization (MR) analysis. METHODS: Publicly available genome-wide association study (GWAS) data were analyzed, comprising 5,959 individuals for gut microbiota, 8,299 for plasma metabolites, and 543,586 (86,923 cases and 456,663 controls) for asthma outcomes. MR analyses were conducted to evaluate causal relationships between gut microbiota, plasma metabolites, and asthma. Mediation effects were assessed using the product of coefficients approach, and statistical significance was determined with Bonferroni correction. RESULTS: The MR analysis identified 24 gut microbiomes and 88 plasma metabolites with suggestive associations with asthma. Notably, mediation analysis revealed that the phylum CONCLUSION: This study underscores the significant role of the gut microbiota-lung axis in asthma pathogenesis. By identifying specific gut microbiota and metabolite pathways, the findings pave the way for innovative biomarkers and therapeutic strategies targeting gut microbiota and its metabolites to manage and prevent asthma.