Objective:

To assess the causal effects of circulating metabolites, gut microbiota traits, and immune cell phenotypes on the risk of deep infiltrating endometriosis (DIE), emphasizing the significance of understanding the gut-immune-pelvic axis.

Key Findings:

• Causal associations identified between circulating metabolites, gut microbiota, and immune phenotypes with DIE susceptibility.
• 324 protein-coding genes were identified, with 42 differentially expressed between DIE and controls, highlighting potential molecular targets.
• A five-gene panel (HDC, GADD45B, CDK5, AHNAK, RASGRP2) showed high discrimination between DIE lesions and normal endometrium (AUC = 0.999), indicating its diagnostic potential.
• Immunohistochemistry confirmed upregulation of HDC, GADD45B, AHNAK, RASGRP2 and downregulation of CDK5 in DIE lesions, supporting the relevance of these genes.

Interpretation:

The findings support a gut-immune-pelvic pathway in DIE, highlighting the role of metabolic, microbial, and immune factors in its pathogenesis and suggesting avenues for future research.

Limitations:

• The study primarily relies on genetic proxies, which may not capture all relevant environmental factors, potentially limiting the scope of findings.
• The generalizability of findings may be limited to specific populations represented in the GWAS data, necessitating further validation in diverse cohorts.

Conclusion:

This study provides evidence for a biologically plausible five-gene signature associated with DIE, suggesting potential targets for therapeutic intervention and further exploration in clinical settings.