Effect of immune cells and plasma metabolites on inflammatory bowel disease: Two-sample Mendelian randomization study and mediation analysis

Inflammatory bowel disease (IBD) represents an immune-related inflammation of the gastrointestinal tract. Current research highlights the significant role of immune mechanisms and metabolic components on its development and progression. Nonetheless, the interplay between these factors remains inadequately explored. This study used Mendelian randomization (MR) to analyze the causality between immune cells, plasma metabolites, and IBD, and to identify potential mediation metabolites. This study used 2-sample MR analysis method to assess the associations between 731 immune cell types, 1400 plasma metabolites, and IBD, and subtypes ulcerative colitis (UC) and Crohn's disease (CD). The inverse-variance weighted, Simple mode, Weighted median, and Weighted mode approaches confirmed the validity of the results. Horizontal pleiotropy was evaluated via MR-Egger regression, heterogeneity through Cochran's Q test, and sensitivity using the leave-one-out method. Mediation analysis pinpointed potential mediation metabolites linking immune cells with IBD and its subtypes. MR analysis identified causal associations involving 17 immune cell phenotypes and 37 metabolites with IBD, 13 immune cell phenotypes and 15 metabolites with UC, and 11 immune cell phenotypes and 19 plasma metabolites with CD (P < .01). Mediation analysis demonstrated that the association between CD25 on IgD+ CD38br and IBD was mediated by the arachidonate (20:4n6) to oleate to vaccenate (18:1) ratio, with a mediation proportion of 7.42%. CD28+ CD45RA+ CD8dim absolute cell and HLA DR on B cells mediated the associations between 3-(4-hydroxyphenyl) lactate, carnitine C14 levels, and UC, with mediation proportions of 6.97% and 8.8%, respectively. CD27 on sw mem and CD3 on EM CD4+ mediated the associations between mannonate levels, 2-hydroxy-4-(methylthio) butanoic acid levels, and CD, with mediation proportions of 10.9% and 5.89%, respectively. The study demonstrates the causal association of immune cells and plasma metabolites with IBD, UC, and CD, providing novel insights in terms of the prevention, diagnosis, and management of these conditions.