Objective  To investigate the causal relationship between gut microbiota and functional dyspepsia (FD) and the potential mediating effects of blood metabolites using Mendelian randomization (MR).

Methods  Summary-level data were obtained from publicly available genome-wide association studies (GWAS) databases. Genetic instruments were extracted for 473 gut microbial taxa and 233 blood metabolites, and FD GWAS data were sourced from a Finnish database. Two-sample MR was performed to assess the potential associations of gut microbiota and blood metabolites with FD. Sensitivity analyses were conducted to evaluate the robustness of the MR results. Mediation MR was used to explore the potential mediating effects of blood metabolites.

Results  A total of 29 gut microbial taxa and 2 blood metabolites showed reliable causal relationships with FD (P<0.05). Mediation analysis indicated that the proportion of total cholesterol in high-density lipoprotein (HDL) mediated the causal relationship between Lawsonibacter and FD risk.

Conclusion  Lawsonibacter was positively correlated with FD, and the proportion of total cholesterol in HDL played a mediating role in this  relationship.

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