Butyrate as a Potential Modulator in Gynecological Disease Progression

Abstract

This review investigates the therapeutic potential of butyrate, a short-chain fatty acid (SCFA) produced by gut microbiota, in the prevention and treatment of various gynecological diseases, including polycystic ovary syndrome (PCOS), endometriosis, and gynecologic cancers like cervical and ovarian cancer. These conditions often pose treatment challenges, with conventional therapies offering limited and temporary relief, significant side effects, and a risk of recurrence. Emerging evidence highlights butyrate's unique biological activities, particularly its role as a histone deacetylase (HDAC) inhibitor, which allows it to modulate gene expression, immune responses, and inflammation. In PCOS, butyrate aids in restoring hormonal balance, enhancing insulin sensitivity, and reducing chronic inflammation. For endometriosis, butyrate appears to suppress immune dysregulation and minimize lesion proliferation. Additionally, in cervical and ovarian cancers, butyrate demonstrates anticancer effects through mechanisms such as cell cycle arrest, apoptosis induction, and suppression of tumor progression. Dietary interventions, particularly high-fiber and Mediterranean diets, that increase butyrate production are proposed as complementary approaches, supporting natural microbiota modulation to enhance therapeutic outcomes. However, butyrate's short half-life limits its clinical application, spurring interest in butyrate analogs and probiotics to maintain stable levels and extend its benefits. This review consolidates current findings on butyrate's multifaceted impact across gynecological health, highlighting the potential for microbiota-centered therapies in advancing treatment strategies and improving women's reproductive health.

Keywords: butyrate; cervical cancer; endometrial cancer; endometriosis; gynecological diseases; high-fiber diet; microbiota; ovarian cancer; polycystic ovary syndrome; short-chain fatty acids.

Figure 1

The systemic effects of dietary fiber and SCFAs on health. Dietary fiber, primarily from vegetables, legumes, and whole grains, is fermented by gut microbiota to produce short-chain fatty acids (SCFAs), including acetate, propionate, and butyrate. These SCFAs interact with G-protein-coupled receptors (GPCRs) on host cells, initiating signaling pathways which contribute to various physiological benefits. SCFAs also inhibit histone deacetylase (HDAC) activity, leading to changes in gene expression which support immune regulation, reduce inflammation, and maintain metabolic health. Additionally, the systemic effects of SCFAs play a role in cancer prevention by modulating cellular proliferation and apoptosis, particularly in reproductive systems.

Figure 2

The role of butyrate in modulating cervical cancer cell proliferation and apoptosis. Dysbiosis in the gut microbiota leads to altered microbial composition, which can impact cervical health and increase susceptibility to infections such as HPV. HPV infection promotes histone modification, affecting gene expression and contributing to cancer cell growth. Butyrate exerts anticancer effects on cervical cancer cells by regulating the cell cycle and inducing apoptosis. In the presence of butyrate, cell cycle regulators p21 and p27 are upregulated, leading to G1/S phase arrest, which inhibits cell proliferation. Butyrate also enhances mitochondrial apoptosis by downregulating anti-apoptotic proteins. Butyrate also leads to the release of cytochrome c and the activation of caspase-9, which, in turn, promotes cell death. The therapeutic potential of butyrate is enhanced when combined with treatments like PI3K inhibitors, telomerase inhibitors, or cisplatin. Upward-pointing arrows represent the upregulation of the indicated proteins or cellular processes, while downward-pointing arrows indicate their downregulation.

Figure 3

The role of gut dysbiosis and butyrate in the pathogenesis and potential treatment of polycystic ovary syndrome (PCOS). On the left, lifestyle and environmental factors such as poor diet, obesity, and lack of exercise contribute to gut dysbiosis, which leads to systemic inflammation, insulin resistance, and hormonal imbalance. These interconnected factors drive the development of PCOS, characterized by polycystic ovaries and reproductive dysfunction. On the right, therapeutic approaches to enhance butyrate levels—including dietary modifications, probiotics, prebiotics, and fecal microbiota transplantation—are illustrated in a PCOS animal model. Butyrate exerts beneficial effects on PCOS symptoms through various mechanisms. These findings highlight butyrate’s potential as a therapeutic agent for managing PCOS, targeting both metabolic and reproductive abnormalities associated with the syndrome. Upward-pointing arrows indicate the upregulation of butyrate levels as a result of the three interventions shown.