Causal Effect Between Gut Microbiota, Gut Bacterial Pathway, and Chronic Spontaneous Urticaria: A Large-Scale Bidirectional Mendelian Randomization Analysis

Background: To analyze causality between gut microbiota and chronic spontaneous urticaria (CSU) and to investigate the mediating effect of metabolic pathways. Methods: We extracted genome-wide association study summary statistics for 211 microbiota taxa from the MiBioGen consortium (N=18 340), 205 microbiota metabolic pathways from the Dutch Microbiome Project (N=7738), and CSU from the FinnGen genomics initiative (N=450). Bidirectional Mendelian randomization (MR) was performed to detect genetic causality between gut microbiota, gut bacterial pathways, and CSU. Sensitivity analyses were performed to validate the robustness of the results. Mediation MR investigated mediators in the association between gut microbiota and CSU. Results: MR analysis suggested that the family Peptococcaceae and its child taxon, the genus Peptococcus, were risk factors for CSU. In addition, the genera Collinsella, Lachnospiraceae UCG004, Ruminococcaceae UCG004, and Sellimonas were also risk factors for CSU, whereas Family XIII UCG001, Lachnospiraceae UCG010, and Methanobrevibacter had protective effects on CSU. As for metabolic pathways, NONMEVIPP-PWY, PWY-5022, and PWY-7221 were positively associated with CSU, although others, such as KDO-NAGLIPASYN-PWY, PWY- 6353, and PWY-7400 presented a suggestive association with CSU. Moreover, PWY-7400 was a mediator in causality between the family Peptococcaceae and CSU. These results were based on nominal significance (P<.05). None of the Bonferroni-corrected P values were <.05. Conclusions: Our study confirmed a causal association between gut microbiota and CSU, with the metabolic pathway being a potential mediator. Our findings provide new insights for further mechanistic and clinical studies in CSU.