Causal relationship between blood metabolites and inflammatory bowel disease: a metabolome-wide mendelian randomization study

Abstract

Abstract Background Prior investigations have indicated a link between metabolic disorders and immune-mediated bowel disease (IBD). Nevertheless, a conclusive causal relationship between metabolites and the facilitation or prevention of IBD remains elusive. Therefore, the primary aim of this study is to evaluate the causal association between 486 blood metabolites and IBD using a two-sample multivariable Mendelian randomization analysis. Method This research employed a genome-wide association study (GWAS) of 486 metabolites as the exposure, with inflammatory bowel disease (IBD), Crohn's disease (CD), and ulcerative colitis (UC) as the outcomes. Causal analysis predominantly utilized the inverse variance-weighted (IVW) method, complemented by MR-Egger and weighted median analysis methods. Rigorous sensitivity analyses, including Cochran's Q test, MR-Egger intercept test, MR-presso, and leave-one-out analysis, were conducted to ensure the robustness of the results. Moreover, reverse MR and LD score regression (LDSC) analyses were performed to address concerns related to reverse causation, genetic correlation, and linkage disequilibrium (LD). To directly assess the impact of metabolites on IBD, a multivariable MR approach was employed. Additionally, metabolic pathway analysis was carried out using the web-based tool MetaboAnalyst 5.0. All statistical analyses were executed using R software, guaranteeing the rigor and accuracy of the study's findings. Result In this comprehensive MR analysis, we identified a total of 45 metabolites showing significant associations with various IBD phenotypes. By conducting complementary and sensitivity analyses, we identified 4, 8, and 4 metabolites that demonstrated noteworthy correlations with IBD, CD, and UC, respectively. Furthermore, our metabolic pathway analysis unveiled 8 essential metabolic pathways shared between IBD and CD phenotypes. These findings offer valuable insights into the potential contribution of specific metabolites and pathways to the development of IBD and its subtypes, providing potential targets for further research and therapeutic interventions. Conclusion Our study findings indicate that the identified metabolites and metabolic pathways hold promise as reliable circulating metabolic biomarkers for clinical screening and prevention of IBD. Additionally, they represent potential candidate molecules for further mechanistic investigations in future research.