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

Area of Science:

• Genetics and Microbiology
• Metabolomics
• Obesity Research

Background:

• Obesity is a complex multifactorial disease with significant public health implications.
• Understanding the interplay between host genetics, gut microbiota, and metabolic pathways is crucial for developing effective interventions.

Purpose of the Study:

• To identify causal associations between specific microbial species, metabolic pathways, and obesity risk using Mendelian randomization (MR).
• To validate the biological relevance of identified associations through clinical case-control studies.

Main Methods:

• Two-sample Mendelian randomization (MR) analysis utilizing genome-wide association studies (GWAS) summary statistics.
• Sensitivity analyses including weighted median, MR-Egger regression, leave-one-out cross-validation, MR-PRESSO, and Cochran's Q test.
• Clinical validation using 16S rRNA sequencing and untargeted metabolomics in obese and control cohorts.

Main Results:

• MR identified two bacterial species, *Streptococcus thermophilus* and *Lachnospiraceae bacterium 5_1_63FAA*, associated with reduced obesity risk (ORs < 1, P < 0.01).
• Two metabolic pathways, 4-aminobutanoate degradation and pyridoxal 5 phosphate biosynthesis, were also significantly associated with lower obesity risk (ORs < 1, P < 0.001).
• Clinical validation confirmed lower abundances of these bacteria and reduced levels of associated metabolites in obese individuals.

Conclusions:

• *Lachnospiraceae bacterium 5_1_63FAA* and *Streptococcus thermophilus*, along with 4-aminobutanoate degradation and pyridoxal 5 phosphate biosynthesis, act as protective factors against obesity.
• Targeted modulation of these identified factors holds promise for the prevention and treatment of obesity.