The microbiome-inflammasome axis in endometriosis-associated chronic pelvic pain: mechanisms and therapeutic opportunities from an immunological perspective.

Introduction: Endometriosis (EMs) is increasingly recognized as a chronic inflammatory disease in which innate immune dysregulation plays an important role. Its immunopathological features include macrophage polarization imbalance, with M1-skewed activation in inflamed peritoneal fluid and lesions, reduced natural killer (NK) cell cytotoxicity, adaptive immune alterations including Th2/Treg-skewed profiles reported in some studies, and persistently elevated pro-inflammatory cytokines. The disease affects approximately 10% of women of reproductive age worldwide, and 70%-80% of these patients experience chronic pelvic pain (CPP). Conventional hormonal therapies provide limited relief and are associated with high recurrence rates after withdrawal, yet the immunological drivers of CPP remain incompletely understood. Methods: We conducted a narrative review of peer-reviewed literature identified through PubMed, Web of Science, and Scopus up to August 2026. Search terms covered endometriosis, chronic pelvic pain, microbiota/dysbiosis, Toll-like receptor 4, NF-κB, NLRP3 inflammasome, IL-1β/IL-18, neuroinflammation, and immunotherapy. Reference lists were screened for additional relevant studies, and evidence was synthesized by mechanistic theme and appraised according to study design, directness, and consistency. Results: Convergent preclinical and observational evidence suggests that dysbiosis of the gut and reproductive tract microbiota may activate TLR4 via lipopolysaccharide, triggering NF-κB signaling and promoting NLRP3 inflammasome priming and activation. This cascade may contribute to M1-skewed pelvic inflammation, adaptive immune alterations, pyroptosis, and neuroimmune sensitization that could facilitate CPP chronification. Host-derived damage-associated molecular patterns and metabolic stress appear to be the principal immediate Signal 2 sources, whereas microbiota-derived signals mainly provide priming and indirect contributions. Direct causal evidence in humans remains incomplete, and conflicting microbiome findings may reflect sampling site, disease stage, and methodological differences. Discussion: The microbiome-inflammasome axis represents one potentially important and testable mechanism in EMs-associated CPP rather than a dominant explanatory framework. Promising therapeutic avenues include probiotics/postbiotics, TLR4 antagonists, NF-κB inhibitors, NLRP3 inhibitors, and IL-1β/IL-18-directed therapies, but most remain exploratory and require validation in prospective, mechanism-based trials. Refining this framework may inform immune stratification and precision immunomodulatory therapy for endometriosis-associated pelvic pain.