Abstract
BACKGROUND: Dyspepsia is a prevalent gastrointestinal disorder with complex pathogenesis involving the gut-brain axis. While alterations in gut microbiota have been linked to dyspepsia, the role of central nervous system metabolites, particularly those in cerebrospinal fluid (CSF), remains unexplored. OBJECTIVE: To investigate the potential causal relationship between CSF metabolites and dyspepsia using a two-sample Mendelian randomization (MR) approach. METHODS: We conducted a two-sample MR analysis using genome-wide association study (GWAS) summary statistics. CSF metabolite data were derived from 532 individuals across two cohorts, and dyspepsia outcome data were obtained from the UK Biobank (7586 cases and 353 608 controls). Instrumental variables (SNPs) were selected based on genome-wide significance (p < 5 × 10(-8)), with clumping to eliminate linkage disequilibrium. The inverse-variance weighted (IVW) method was the primary analytical approach, supplemented by MR-Egger, weighted median, and weighted mode methods. Sensitivity analyses, including heterogeneity tests and MR-PRESSO, were used to assess the robustness of the findings. RESULTS: Among 71 CSF metabolites tested, only butyrate (4:0) showed a significant inverse causal association with dyspepsia (IVW OR = 0.997, 95% CI: 0.996-0.998, p < 0.001; P (FDR) = 0.007). Sensitivity analyses indicated no evidence of heterogeneity or pleiotropy. Additional enrichment analysis revealed involvement of genes associated with serine-type peptidase and protein catabolic processes. CONCLUSIONS: Our study provides the first genetic evidence linking elevated CSF butyrate levels to a reduced risk of dyspepsia, highlighting a potential neuroprotective role within the gut-brain axis.