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Background: Irritable bowel syndrome (IBS) is one of the most common functional bowel disorders and dysmetabolism plays an important role in the pathogenesis of disease. Nevertheless, there remains a lack of information regarding the causal relationship between circulating metabolites and IBS. A two-sample Mendelian randomization (MR) analysis was conducted in order to evaluate the causal relationship between genetically proxied 486 blood metabolites and IBS. Methods: A two-sample MR analysis was implemented to assess the causality of blood metabolites on IBS. The study utilized a genome-wide association study (GWAS) to examine 486 metabolites as the exposure variable while employing a GWAS study with 486,601 individuals of European descent as the outcome variable. The inverse-variance weighted (IVW) method was used to estimate the causal relationship of metabolites on IBS, while several methods were performed to eliminate the pleiotropy and heterogeneity. Another GWAS data was used for replication and meta-analysis. In addition, reverse MR and linkage disequilibrium score regression (LDSC) were employed for additional assessment. Multivariable MR analysis was conducted in order to evaluate the direct impact of metabolites on IBS. Results: Three known and two unknown metabolites were identified as being associated with the development of IBS. Higher levels of butyryl carnitine (OR(95%CI):1.10(1.02–1.18),p = 0.009) and tetradecanedioate (OR(95%CI):1.13(1.04–1.23),p = 0.003)increased susceptibility of IBS and higher levels of stearate(18:0)(OR(95%CI):0.72(0.58–0.89),p = 0.003) decreased susceptibility of IBS. Conclusion: The metabolites implicated in the pathogenesis of IBS possess potential as biomarkers and hold promise for elucidating the underlying biological mechanisms of this condition. [ABSTRACT FROM AUTHOR]