Identification of 1,400 metabolites as mediators of obesity in 473 gut microbiota taxa: a mediation Mendelian randomization study.

Obesity is a global health problem driven by genetic, endocrine, and environmental factors. Gut microbiota significantly influences obesity, yet causal relationships and underlying pathways remain elusive. The objective of the study was to investigate causal relationships between gut microbiota, metabolites, and obesity; elucidate potential pathways mediating obesity onset; identify novel genes; and explore the impact of plasma proteins on obesity risk. Bidirectional and two-sample Mendelian randomization (MR) were used to explore causal relationships. Mediation analyses identified mechanisms linking gut microbiota, metabolites, and obesity. Pathway analyses and protein-protein interaction assessed genetic and protein associations. The MR analysis results identified 11 gut microbiota species with causal associations with obesity, 69 metabolites that were significantly causally related to obesity, and seven bacteria with causal relationships, mediated by metabolites. Single nucleotide polymorphisms (SNP)-related gene set enrichment analysis revealed clustering in a concentration of genes enriched for phosphatidylinositol 3-kinase (PI3K)/protein kinase B (PKB/AKT) and plasma membrane-related signaling pathways. Fms-related receptor tyrosine kinase 1 (FLT1), growth-associated protein 43 (GAP43), and SLIT and NTRK-like family member 1 (SLITRK1) plasma proteins had protective effects against obesity. This study revealed causal links between gut bacteria, metabolites, and obesity, and identified potential therapeutic targets. Findings deepen understanding of obesity's complex mechanisms and suggest novel prevention and treatment strategies, emphasizing the gut microbiota and treatment targets. IMPORTANCE: This study pioneered the use of genetic approaches and mediator analyses to confirm the causal relationship between gut microbiota, metabolites, and obesity, and also explored how these factors work together to promote obesity through specific signaling pathways and protein interactions. This finding provides a theoretical basis and potential targets for precision medicine strategies against obesity, which is of great clinical significance. In addition, the identification of protective plasma proteins as biomarkers for obesity prevention opens up new avenues for tailoring obesity intervention strategies.