Gut microbiota-derived butyrate and the SIRT1/FoxO1 axis: epigenetic-metabolic regulation of ovarian function in premature ovarian insufficiency-a comprehensive review.

Premature ovarian insufficiency (POI) is a chronic condition affecting approximately 1.1-3.7% of women worldwide. Beyond its primary impact on fertility, POI poses significant long-term health risks, including cardiovascular disease, osteoporosis, and neurocognitive decline. Current clinical interventions, largely limited to hormone replacement therapy, are primarily palliative and do not address the underlying depletion of ovarian reserve. Recent research has identified a potential link between gut microbiota and POI pathogenesis, suggesting that gut-ovary axis dysbiosis may play a pivotal role. Systemic depletion of butyrate-producing microbiota has been shown to induce oxidative stress and granulosa cell apoptosis. In this review, we propose the gut-butyrate-SIRT1-FoxO1 axis as a central theoretical framework. This model advances beyond the conventional "leaky gut-LPS inflammation" model to demonstrate that gut-derived butyrate functions as a trans-organ "metabolic messenger." Through epigenetic-metabolic coupling, butyrate orchestrates SIRT1-FoxO1 activation. This pathway may mitigate reactive oxygen species (ROS)-induced calcium overload, restore mitochondrial quality control, and preserve granulosa cell homeostasis. Recent preclinical studies have demonstrated that butyrate supplementation can rescue ovarian function in POI models by enhancing SIRT1-mediated FoxO1 deacetylation, This mechanism may suppress pro-apoptotic signaling and promote follicular survival. Furthermore, fecal microbiota transplantation (FMT) from healthy donors has been shown to mitigate ovarian senescence in mice with dysbiotic intestinal microbiota, further substantiating the therapeutic potential of this axis. This review delineates the pleiotropic effects of butyrate across multiple organ systems and provides a robust biological foundation for future microbiota-based interventions. Although substantial experimental validation remains necessary, a deeper understanding of this signaling axis has the potential to transform POI clinical management. Future approaches may shift from palliative, symptomatic treatment to precise disease-modifying therapy.