OBJECTIVE: This study investigates the causal relationship between gut microbiota, inflammatory cytokines, and Kawasaki disease (KD), and whether cytokines mediate the effect of gut microbiota on KD. METHODS: A Mendelian randomization analysis using the inverse-variance weighted method assessed the causal effects of gut microbiota and inflammatory cytokines on KD and explored potential mediation. RESULTS: The study found causal links between 20 types of gut microbiota and KD. Ten types increased KD risk, notably Francisellales (OR = 27.82, P = 0.0309). Ten types provided protection, with Fusobacteriaceae showing the strongest effect (OR = 0.0424, P = 0.002). Five inflammatory cytokines were significantly associated with KD
adenosine deaminase was most protective (OR = 0.7447, P = 0.0037), while Fractalkine indicated higher risk (OR = 2.0448, P = 0.0315). Mediation analysis revealed that the Interleukin-10 receptor subunit beta mediates the effect of Bifidobacterium adolescentis on KD, with a mediation effect of -0.0237 (4.75% ratio). Interleukin-20 mediates the effect of Faecalicatena lactaris on KD, with a mediation effect of -0.1168 (15.30% ratio). CONCLUSION: The findings indicate a causal relationship among gut microbiota, inflammatory cytokines, and KD, suggesting that the gut microbiome influences KD through specific cytokines. IMPACT: The study confirmed a causal relationship between 20 types of gut microbiota and Kawasaki disease, finding that 10 types increase the risk of Kawasaki disease, particularly Francisellales. Five inflammatory cytokines were significantly associated with Kawasaki disease, with adenosine deaminase showing a protective effect, while Fractalkine increased the risk. Mediation analysis indicated that specific inflammatory cytokines (such as Interleukin-10 receptor subunit beta and Interleukin-20) play a significant mediating role between gut microbiota and Kawasaki disease.