Immune Cell-Mediated Interactions Between the Gut Microbiome and Endometriosis: A Mendelian Randomization Investigation

The etiology of endometriosis (EM) remains unclear. Evidence indicates a correlation between intestinal microbial communities and immune homeostasis in the pathogenesis of EM. This investigation leverages Mendelian randomization (MR) to delineate causal links connecting gut microbiota composition, specific immune cell phenotypes, and endometriosis, aiming to identify novel therapeutic avenues.

Using publicly available genetic data from genome-wide association study (GWAS) summary datasets that encompass 473 microbial taxa, 731 immunological traits, and endometriosis cases, we executed bidirectional and two-step Mendelian randomization (MR) frameworks to assess causality and quantify mediation effects, aiming to evaluate the associations between intestinal microbial communities and immune homeostasis in the pathogenesis of endometriosis (EM). Utilizing single nucleotide polymorphisms (SNPs) as instrumental variables (IVs), we ensured robustness through sensitivity assessments, specifically Cochran's Q statistic and MR-Egger regression, to mitigate concerns regarding horizontal pleiotropy and heterogeneity.

Our analysis revealed that Actinobacteria exerted an influence on HLA-DR+ CD8+ T cells (total effect: -0.2736; mediated proportion: 6.45%), whereas Actinomycetales regulated DN (CD4-CD8-) NKT cell populations (total effect: -0.1961; mediated proportion: 5.77%). Furthermore, Aneurinibacillaceae demonstrated a 14.30% mediation effect operating through CD28 expression levels on resting regulatory T cells (Tregs) (total effect: 0.4053). Eisenbergiella sp900066775 displayed pleiotropic impacts on markers associated with both Tregs and B cells (total effect: -0.1447). Notably, protective correlations were identified for Actinobacteria (Odds Ratio [OR] = 0.76, 95% Confidence Interval [CI]: 0.65-0.89) and Bifidobacterium angulatum (OR = 0.88, 95% CI: 0.83-0.94). Conversely, Aneurinibacillaceae abundance was linked to elevated endometriosis susceptibility (OR = 1.50, 95% CI: 1.13-1.98).

Dysbiosis within the gut microbiome fosters endometriosis development by modulating immune cell dynamics, predominantly via pathways involving Tregs and NKT cells. These results underscore the microbiota-immune axis as a promising target for intervention, warranting future clinical trials to evaluate probiotic or immunomodulatory strategies.