The Skeletal Muscle as an Endocrine Firewall: Mitigating Metabolic Endotoxemia and Insulin Resistance in Polycystic Ovary Syndrome.

PURPOSE OF REVIEW: Polycystic ovary syndrome (PCOS) is a complex endocrine–metabolic disorder in which insulin resistance and chronic low-grade inflammation contribute to long-term cardiometabolic risk. Emerging evidence suggests that gut microbiota alterations and impaired intestinal barrier function may represent modifiable upstream drivers, particularly in specific patient subsets. RECENT FINDINGS: PCOS has been associated with dysbiosis, increased intestinal permeability, and metabolic endotoxemia, a state of low-grade elevation of circulating lipopolysaccharide (LPS). LPS can activate Toll-like receptor 4 (TLR4) and downstream nuclear factor-κB (NF-κB) signaling, amplifying inflammatory tone and potentially worsening insulin signaling. Clinical studies increasingly report higher circulating markers of endotoxemia in PCOS and links with androgen excess and inflammatory markers, although causality remains unresolved. Conversely, skeletal muscle myokines induced by exercise show potential in counteracting these inflammatory signals. Interactions among diet (especially high saturated-fat meals), sleep disruption, psychosocial stress, and physical inactivity may further shape barrier integrity and postprandial endotoxemia. A gut-barrier–endotoxemia framework offers a metabolically coherent explanation for heterogeneity in PCOS, particularly in phenotypes with obesity and insulin resistance. However, biomarker standardization and well-designed interventions are required to determine which patients derive the greatest benefit from endotoxemia-targeted lifestyle or adjunctive therapies.