Abstract
BACKGROUND: Despite prior observational studies suggesting a link between gut microbiota to Kawasaki disease (KD), these findings remain debated. This study aimed to assess the association between gut microbiota and KD on a genetic level using a two-sample Mendelian randomization (MR) analysis. METHODS: This two-sample MR analysis utilized summary statistics from the largest genome-wide association study meta-analysis on gut microbiota conducted by the MiBioGen consortium. The causal relationship between gut microbiota and KD evaluated using multiple methods, including inverse variance weighted (IVW), MR Egger, weighted median, simple mode, weighted mode, and MR-PRESSO. Reverse MR analysis was conducted on bacteria identified as causally linked to KD in the initial MR study. Cochran's Q and Rucker's Q tests assessed the heterogeneity among instrumental variables. RESULTS: The IVW estimates indicated no significant genetic causal relationship with KD for various taxa, including genus Bifidobacterium (p = 0.774, OR 95% CI = 0.876 [0.355-2.163]), genus FamilyXIIIAD3011group (p = 0.945, OR 95% CI = 0.979 [0.539-1.780]), genus LachnospiraceaeUCG004 (p = 0.987, OR 95%CI = 1.005 [0.542-1.863]), genus RuminococcaceaeNK4A214group (p = 0.453, OR 95%CI = 1.469 [0.538-4.009]), genus RuminococcaceaeUCG002 (p = 0.835, OR 95% CI = 1.092 [0.478-2.494]), genus LachnospiraceaeUCG001 (p = 0.996, OR 95%CI = 0.998 [0.482-2.066]), genus Bacteroides (p = 0.595, OR 95%CI = 0.831 [0.419-1.648]), genus Olsenella (p = 0.414, OR 95%CI = 1.312 [0.684-2.516]), genus Lactococcus (p = 0.870, OR 95%CI = 0.962 [0.600-1.541]), family Rhodospirillaceae (p = 0.995, OR 95%CI = 1.002 [0.550-1.827]), family FamilyXIII (p = 0.894, OR 95%CI = 1.093 [0.298-4.009]), family BacteroidalesS24 (p = 0.604, OR 95%CI = 0.849 [0.456-1.578]), family Ruminococcaceae (p = 0.524, OR 95%CI = 0.692 [0.223-2.148]), and class Bacilli (p = 0.905, OR 95%CI = 0.967 [0.561-1.667]). The reverse MR analysis revealed no significant causal effect of KD on gut microbiota. No significant heterogeneity of instrumental variables or horizontal pleiotropy was observed. CONCLUSION: This bidirectional causal inference analysis did not reveal a genetic causal relationship between gut microbiota and KD. Confounding factors may have influenced the observed associations in previous observational studies. Further research with advanced MR methods and larger GWAS datasets is needed to confirm these findings. IMPACT: This study employs Mendelian randomization to investigate the causal relationship between gut microbiota and Kawasaki disease, and finds no evidence of a genetic association between them. This represents the first Mendelian randomization study to examine the causal link between gut microbiota and Kawasaki disease, offering valuable insights into the potential mechanisms underlying previous observational findings. The study challenges existing observational findings by suggesting that the association between gut microbiota and Kawasaki disease may be confounded by other factors, thereby highlighting the necessity for further genetic studies to elucidate the role of gut microbiota in the disease.