Abstract
Ulcerative colitis (UC) involves dysregulated immune responses and metabolic reprogramming, yet the causal mechanisms linking inflammatory mediators to UC via metabolic intermediates remain elusive. This study employs integrated Mendelian randomization (MR) and mediation analysis to dissect the immune-metabolic axis, a novel conceptual framework for UC pathogenesis, where inflammatory factors exert causal effects through metabolite-mediated pathways. Using European genetic data (5931 UC cases; 405,386 controls), we performed bidirectional 2-sample MR to assess causal relationships between 91 inflammatory factors, 1400 plasma metabolites, and UC. Genetic instruments were selected stringently (P < 1 × 10⁻5, r2 < 0.001). Causal estimates were generated via inverse-variance weighted regression, with sensitivity analyses (MR-Egger, weighted median). A 2-stage MR mediation framework quantified metabolite-driven pathways linking inflammatory factors to UC. Six inflammatory factors showed causal effects on UC: IL10RB (odds ratio [OR] = 1.15, P = .011) and CCL4 (OR = 1.12, P = .008) increased risk, while Flt3L, CCL8, CCL11, and PD-L1 were protective (OR range: 0.85-0.90, P < .05). Metabolomic analysis identified 21 causal metabolites, including docosahexaenoic acid-enriched phosphatidylcholines (e.g., 16:0/22:6, OR = 0.858) and linoleate-derived lipids (e.g., 18:0/18:2, OR = 1.262). Crucially, mediation models revealed bidirectional immune-metabolic crosstalk. CCL4 increased UC risk by suppressing protective ether lipids (e.g., p-18:0/20:4; mediation proportion: 8.6%). IL10RB paradoxically offset its direct proinflammatory effect by upregulating tetradecadienoate (14:2), reducing UC risk (mediation proportion: -11.7%). This study establishes genetic evidence for an immune-metabolic axis in UC, wherein inflammatory mediators operate through metabolite-dependent pathways. The identified mediation proportions quantify the contribution of metabolic rewiring to UC pathogenesis, revealing novel targets for therapeutic intervention.