Effects of Gut Microbiome and Metabolic Pathways on Obesity: A Two-Sample Mendelian Randomization and Case-Control...

We employed Mendelian randomization (MR) and case-control studies to identify causal associations and validate biological relevance.

Two-sample MR using genome-wide association studies (GWAS) summary statistics prioritized inverse variance-weighted analysis, supplemented by weighted median and MR-Egger regression. Sensitivity analyses included leave-one-out cross-validation, MR-PRESSO global test, and Cochran's Q test for heterogeneity/pleiotropy. False Discovery Rate (FDR) correction identified robust associations. Clinical validation involved 16S rRNA sequencing and untargeted metabolomics in obese and case-control cohorts.

MR identified two microbiota (Streptococcus thermophilus, OR = 0. 98, 95% CI: 0.96-0.99, P < 0.01; Lachnospiraceae bacterium 5_1_63FAA, OR = 0.98, 95% CI: 0.97-0.99, P < 0.001) and two pathways (4-aminobutanoate degradation V, OR = 0.95, 95% CI: 0.92-0.97, P < 0.001; Pyridoxal 5 phosphate biosynthesis I (OR = 0.96, 95% CI: 0.94-0.98, P < 0.001) significantly associated with reduced obesity risk. Sensitivity analyses confirmed no heterogeneity/pleiotropy. Clinical data validated these findings: obese participants exhibited lower abundances of Streptococcus thermophilus and Lachnospiraceae bacterium 5_1_63FAA, reduced serum 4-aminobutanoate and pyridoxal 5-phosphate levels.

Lachnospiraceae bacterium 5_1_63FAA and Streptococcus thermophilus, alongside 4-aminobutanoate degradation and pyridoxal 5-phosphate biosynthesis, represent protective factors against obesity. Targeted modulation of these targets may exert beneficial effects on the prevention and treatment of obesity.