Abstract
BACKGROUND: The prevalence of metabolic syndrome is on the rise globally. Understanding the etiology and discovering potential treatment target have become a priority. Observational data have linked gut microbiota with metabolic syndrome and its comprising traits. However, whether these relations underlie causal effects remains unclear. METHODS: Using Inver Variance Weighted (IVW) as primary analysis method, we performed two-sample Mendelian Randomization (MR) analyses to explore the causal relationship between gut microbiota and metabolic syndrome with its comprising traits. Methods including MR-Egger regression, MR Pleiotropy RESidual Sum and Outlier (MR-PRESSO), Weighted Mode, and Weighted Median were chosen for additional MR analysis to test the robustness of MR results. Cochran's IVW Q test and leave-one-out IVW analysis tested the heterogeneity among instrumental variables (IVs). Steiger filtering was utilized to exclude all IVs with reverse causality. Genome-wide association study (GWAS) data used in this study were all from the largest respective GWAS studies available. RESULTS: Out of 1172 tests, a total of 16 associations with evidence of causality were identified after sensitivity analyses, but only 3 remained after multiple testing correction. Class Melainabacteria (β = 0.02, adjusted P = 0.01) with affiliated order Gastranaerophilales (β = 0.02, adjusted P = 1.20*10(- 3)) and genus Eubacterium hallii (β = 0.03, adjusted P = 0.03) showed a positive effect on abdominal obesity. All effect sizes were small (abs(β) < 0.1). All causal relationships identified were unidirectional. CONCLUSIONS: Given the study's limitations, we found little evidence supporting a large causal effect, i.e. absolute effect size > 0.1, of gut microbial taxa abundance on metabolic syndrome and its comprising traits. This study also suggests that previously reported associations between gut microbiota and metabolic syndrome with its comprising traits may not necessarily lead to causal relations. CLINICAL TRIAL NUMBER: Not applicable.