Inflammatory bowel diseases (IBDs), including Crohn’s disease (CD) and ulcerative colitis (UC),
have become a global health problem with a rapid growth of incidence in newly industrialized countries.
Observational studies have recognized associations between blood lipid traits and IBDs, but the causality
still remains unclear. To determine the causal effects of blood lipid traits, including triglycerides (TG),
total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C), and low-density lipoprotein cholesterol
(LDL-C) on IBDs, two-sample Mendelian randomization (MR) analyses were conducted using the summary-level genome-wide
association study (GWAS) statistics of blood lipid traits and IBDs. Our univariable MR using multiplicative random-effect
inverse-variance weight (IVW) method identified TC (OR: 0.674; 95% CI: 0.554, 0.820;p< 0.00625)
and LDL-C (OR: 0.685; 95% CI: 0.546, 0.858;p< 0.00625) as protective factors of UC. The result of
our multivariable MR analysis further provided suggestive evidence of the protective effect of TC on UC risk
(OR: 0.147; 95% CI: 0.025, 0.883;p< 0.05). Finally, our MR-BMA analysis prioritized TG
(MIP: 0.336;θ^MACE: −0.025; PP: 0.31;θ^λ: −0.072) and HDL-C (MIP: 0.254;θ^MACE: −0.011; PP: 0.232;θ^λ: −0.04) for CD and TC (MIP: 0.721;θ^MACE: −0.257; PP: 0.648;θ^λ: −0.356) and LDL-C (MIP: 0.31;θ^MACE: −0.095; PP: 0.256;θ^λ: −0.344) for UC as the top-ranked protective factors. In conclusion, the causal effect of TC for UC prevention was robust across all of our MR approaches, which provide the first evidence that genetically determined TC is causally associated with reduced risk of UC. The finding of this study provides important insights into the metabolic regulation of IBDs and potential metabolites targeting strategies for IBDs intervention.