Causal Relationship between Branched-Chain Amino Acids and Inflammatory Bowel Disease: A Bidirectional and Multivariable Mendelian Randomization Study

Aims/Background The relationship between dysregulated branched-chain amino acid (BCAA) and inflammatory bowel disease (IBD) is not fully understood. This study applied a bidirectional, two- sample Mendelian randomization (MR) approach to explore the potential causal relationship between circulating BCAA levels and IBD. Methods Genome-wide association studies (GWAS) data on total BCAA levels, comprising leucine, valine, and isoleucine, were utilized. Data on IBD and its subtypes were sourced from the FinnGen study. The primary analytical method was the inverse-variance weighted (IVW) MR. To determine the direct causal effect of BCAA levels on IBD risk while accounting for confounders, we employed multivariable Mendelian randomization (MVMR). Results IVW analysis revealed a positive correlation between circulating total BCAA levels, including valine, leucine, and isoleucine, and an increased risk of Crohn's disease (CD). No causal link was detected between BCAA levels and overall IBD or ulcerative colitis (UC). In the MVMR analysis, adjusting for common risk factors further validated a direct causal effect of elevated BCAA levels on CD risk. Conclusion Our findings suggest that elevated circulating BCAA levels are associated with an increased risk of CD. Further research is warranted to explore the potential implications of these findings for CD risk management.