From local lesion to multisystem disease: integrated crosstalk among the gut microbiota, immune system, and host metabolism in endometriosis.

Endometriosis (EMs) is a common estrogen-dependent inflammatory disease characterized by pelvic pain and infertility. Despite its substantial clinical burden, its etiology and pathogenesis remain incompletely resolved, and current management continues to be constrained by delayed diagnosis, limited therapeutic efficacy, and frequent disease recurrence. Growing evidence indicates that EMs is not merely a localized gynecological disorder but a disease state with multisystem pathophysiological features, a condition defined by crosstalk among the gut microbiota, the immune system, and host metabolism. This review synthesizes current evidence to establish a systems biology framework in which gut dysbiosis, immune dysfunction, and metabolic reprogramming are integrated as interconnected drivers of disease initiation, progression, and persistence. We first examine alterations in gut microbial composition and function, including estrogen metabolism dysregulation, expansion of opportunistic pathogens, and impaired intestinal barrier integrity, and discuss how these changes influence estrogen homeostasis, inflammatory signaling, and host-microbe interactions. We then explore how aberrations in innate and adaptive immunity promote immune evasion, chronic inflammation, angiogenesis, and ectopic lesion survival. Furthermore, we highlight the multifaceted remodeling of carbohydrate, lipid, and amino acid metabolism, and its link to cell proliferation and the immunosuppressive microenvironment. Particular emphasis is placed on the bidirectional interplay among microbial metabolites, immunometabolic signaling, oxidative stress, and tricarboxylic acid cycle (TCA) intermediates, all of which coalesce into a self-reinforcing pathological network. By integrating these domains, This review advances a unifying "microbiome-immune-metabolic" framework to elucidate the multisystem pathophysiological features of EMs, aiming to inspire the discovery of non-invasive biomarkers and the development of precision therapeutic strategies that target microbial, immune, and metabolic pathways.