Investigating the causal role of the gut microbiome in Kawasaki disease: mediating effects of immune cells.

Introduction: The etiology of Kawasaki disease (KD), a leading cause of acquired heart disease in children, is unknown, though a link to the gut microbiome is suspected. This study aimed to move beyond association by establishing a causal relationship between gut microbiota and KD, and to explore the immune pathways involved.

Method: We conducted a two-step, two-sample MR study using GWAS summary data from European-ancestry cohorts. Genetic variants for 471 gut microbiota were used as instruments. The primary causal estimate was derived using the inverse-variance weighted (IVW) method, validated with nine sensitivity analyses. A subsequent two-step MR analysis assessed mediation by 731 immune cell phenotypes.

Results: We identified 17 gut microbiota taxa causally associated with KD. Robust analyses consistently supported a protective association for Ensifer (beta = -3.33, P = 0.01) and a risk-increasing association for Lawsonibacter sp900066645 (beta = 3.05, P = 0.02). The protective effect of Ensifer was partially mediated by its influence on CD8dim Natural Killer T %lymphocyte (10.71% mediation). The risk-increasing effect of Coprobacter secundus was mediated through CD27 on CD20- B cells (9.41% mediation).

Conclusion: This study provides the first genetic evidence for a causal link between specific gut microbiota and KD, with effects partially mediated by the immune system. These findings highlight the gut-immune axis in KD pathogenesis and offer genetically validated targets for novel therapeutic strategies. Key Points • This study is the first to use Mendelian Randomization to establish a causal link between specific gut microbiota and Kawasaki disease. • It identifies 17 specific microbial taxa that causally increase or decrease the risk of developing the disease. • The research elucidates the mechanistic pathway, showing that the effects of the gut microbiota on Kawasaki disease are partially mediated by specific immune cell populations. • The findings provide genetically validated targets (specific microbes and immune cells) for developing novel therapies and preventative strategies for Kawasaki disease.