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. <Table Float="No" ID="Taba"> <tgroup cols="2"> <colspec align="left" colname="c1" colnum="1" /> <colspec align="left" colname="c2" colnum="2" /> <tbody> <row> <entry align="left" nameend="c2" namest="c1"> 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. </entry> </row> </tbody> </tgroup> </Table>

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

期刊论文
发表日期：

2025年9月22日

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Youfei Fan,
Shuo Zhang,
Feng Guo

摘要

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.