Investigating the causal roles of cholesterol and triglyceride subfractions across lipoproteins in irritable bowel syndrome: a Mendelian randomization study.

Background: Dietary composition and nutrient intake are increasingly recognised as key modulators of symptom onset and severity in a substantial subset of patients with irritable bowel syndrome (IBS). Among dietary lipids, cholesterol and triglycerides have emerged as potential contributors. Nevertheless, the causal relationship remains poorly understood, and evidence in this area remains limited. To address this gap, we conducted a Mendelian randomization (MR) study to dissect the putative causal effects of cholesterol and triglycerides on IBS risk in individuals of European ancestry. Methods: Instrumental variables were constructed for 17 lipid traits-total cholesterol, free cholesterol, triglycerides, and 13 size-specific High-density lipoprotein(HDL), Low-density lipoprotein(LDL), and Very low-density lipoprotein (VLDL) sub-fractions-using summary-level data from the largest available genome-wide association studies (GWAS). Lipid exposures were derived from a meta-analysis of 115,082 European-ancestry individuals. IBS outcomes were ascertained in an independent cohort of 486,601 participants of European descent. Causal estimates were obtained with five complementary MR methods: inverse-variance weighted (IVW), weighted median, MR-Egger, simple mode, and weighted mode. Robustness was further interrogated with leave-one-out permutation, MR-Egger intercept evaluation of directional pleiotropy, and Cochran's Q assessment of heterogeneity. Results: The MR analysis indicated that cholesterol or free cholesterol content of chylomicrons and extremely large VLDL particles were causally associated with an increased risk of developing IBS (β = 0.0679, odds ratios (OR) = 1.070, 95 % CI 1.015-1.128, P = 0.0118; and β = 0.0650, OR = 1.0672, 95 % CI 1.0179-1.1189, P = 0.0007, respectively). Conversely, equivalent increments in cholesterol or free cholesterol carried by very large HDL or very small VLDL conferred protection (β = -0.0626, OR = 0.9392, 95 % CI 0.8992-0.9810, P = 0.0047; and β = -0.0604, OR = 0.9412, 95 % CI 0.9023-0.9819, P = 0.005). Total circulating triglycerides also displayed a positive causal effect on IBS susceptibility (β = 0.0798, OR = 1.083, 95 % CI 1.0268-1.1423, P = 0.0033), with concordant directional estimates observed across the majority of lipoprotein sub-fractions. Conclusion: Whereas triglycerides conveyed a uniformly adverse effect on IBS risk regardless of lipoprotein carrier, cholesterol displayed a net protective signal across most particle classes. This dichotomy implies that lipid-centred interventions should discriminate between the two moieties: dietary or pharmacological strategies that selectively lower triglycerides while preserving-or even augmenting-cholesterol in specific lipoprotein fractions may offer a rational, mechanistically grounded approach to IBS prevention and management.