Impact of gut microbiome, plasma metabolites, peripheral immune cells, and circulating inflammatory protein on chronic spontaneous urticaria: Bidirectional 2-sample Mendelian randomization study and mediation analysis

Background
Growing evidence links gut microbiota to chronic spontaneous urticaria (CSU), yet causality and underlying mediators remain unclear.
Objective
To investigate causal relationships and potential mediators-specifically plasma metabolites, immune cells, and inflammatory proteins-through which gut microbes influence CSU risk.
Methods
We applied two-sample Mendelian randomization (MR) to genome-wide association study (GWAS) data on 430 gut microbial taxa, 1,400 plasma metabolites, 731 immune cell traits, and 91 inflammatory proteins. Analyses used inverse-variance weighted (IVW), MR-Egger, weighted median, and weighted mode estimators, complemented by sensitivity, mediation, multivariable MR, and Bayesian colocalisation tests for shared causal variants.
Results
8 gut taxa, 79 metabolites, 25 immune-cell phenotypes, and 3 inflammatory proteins showed suggestive associated with CSU (all FDR > 0.05). Galactonate mediated the effect of Paraprevotella on CSU, while N-acetylleucine mediated the protective effect of Bacteroides; only the latter remained significant in multivariable MR. Immune cells and inflammatory proteins showed no significant mediation. Bayesian colocalisation provided no evidence of shared causal variants between CSU and any of the four trait categories.
Conclusion
Gut microbiota may suggestively influence CSU risk via specific metabolite pathways, particularly N-acetylleucine, though colocalisation did not support shared genetic causality and no association survived multiple testing correction at FDR < 0.05. These findings offer hypothesis-generating insights and candidate targets for further functional validation.