Is vagus nerve-mediated regulation of immunity an etiological target for therapeutic intervention in endometriosis?

Endometriosis is a complex chronic neuro-inflammatory disorder, affecting roughly 10% of reproductive-age women. It is characterized by the presence of endometrial-like tissue outside the uterus, which induces a chronic inflammatory reaction. This disease can present a wide range of symptoms, including chronic pain and infertility. Despite extensive research, the exact pathogenesis of endometriosis remains incompletely understood. New strategies and paradigms on pathogenesis and treatment are needed. Schematic factors contributing to the development of endometriosis lesions include genetic, hormonal, and immunological factors. Although genetics may contribute to the epidemiologically suggested heritability of endometriosis, epigenetics has gained an increasing consideration in research. Remarkably, microbiota dysbiosis, acting as a catalyst for the main acknowledged epigenetic etiologies (locally produced estradiol, pro-inflammatory cytokines, and hypoxic stress) demands further attention. Indeed, over the past 10 years, it has become clear that the vagus nerve, the fastest component of the microbiota-gut-brain axis, can efficiently control inflammation through the cholinergic anti-inflammatory pathway. Therefore, stimulation of the vagus nerve could be a good candidate for modulating the severity of endometriosis. The detrimental consequences of microbiome dysbiosis and the estrobolome activity on the initiation of the disease as well as counterpart dysfunctions in the central nervous system will be focused on, both supporting a key role of the vagus nerve since the early stage of endometriosis. Consequently, the rationale for using non-invasive vagus nerve stimulation will be discussed, introducing a fruitful shift of paradigm in this still enigmatic disease.