Background: Childhood with obesity is characterized by metabolic dysregulation and unique gut microbiota profiles. Nevertheless, the comprehensive understanding of gut microbiota and metabolic dysregulation of Childhood with obesity remains unclear. Objectives: This study aimed to investigate the causal relationship of gut microbiota and Childhood with obesity and identify the blood metabolites as potential mediators. Methods: The exposure genome-wide association studies (GWAS) data were sourced from the GWAS Catalog, while the outcome GWAS data were obtained from the Early Growth Genetics (EGG) Consortium. The study used 473 types of gut microbiota, 233 types of blood metabolites, and Childhood with obesity from GWAS. We then performed two-sample Mendelian randomization (TSMR) and bidirectional Mendelian randomization (BDMR) analyses to explore the causal relationships between gut microbiota, blood metabolites, and Childhood with obesity. Additionally, we conducted multivariable Mendelian randomization (MVMR) and two-step Mendelian randomization (2SMR) to identify potential mediating blood metabolites in this process. Results: MR analysis identified 13 types of gut microbiota and 12 types of blood metabolites that were causally associated with Childhood with obesity. Furthermore, there was no strong evidence that genetically predicted Childhood with obesity had an effect on these gut microbiota and blood metabolites. Further, 2SMR analysis revealed that the association between K10 sp001941205 and Childhood with obesity was mediated by the Total cholesterol to total lipids ratio in medium VLDL, accounting for 2.53% (95%CI; 2.14%-2.92%) of the association. Similarly, the relationship between SM23-33 and Childhood with obesity was mediated by the Ratio of 22:6 docosahexaenoic acid to total fatty acids, which accounted for 4.07% (95%CI; 2.70%-5.44%) of the association. Conclusions: The present study is the first to investigate the causal relationships among 473 gut microbiota phenotypes, 233 blood metabolites, and Childhood with obesity through Mendelian randomization analysis, identifying 13 gut microbiota types with potential causal links to Childhood with obesity and suggesting that 2 blood metabolites may mediate these associations, thereby providing valuable insights for future intervention strategies aimed at addressing Childhood with obesity. Keywords gut microbiota, blood metabolites, mendelian randomization, Childhood with obesity

The authors have declared no competing interest.

This work was supported by Shanghai Pudong New District Health Commission Health Science and Technology Project (Grant numbers PW2021A-76).

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