The Estrobolome-Epigenetic Inflammatory Axis in Menopause: A Multisystem Mechanistic Link to Chronic Disease

Menopause is characterized by a progressive decline in ovarian estrogen production, resulting in immune dysregulation and a chronic low-grade inflammatory state known as inflammaging. Beyond hormonal deficiency, emerging evidence highlights the role of the Estrobolome-the collection of gut microbial genes involved in estrogen metabolism-in regulating estrogen homeostasis and inflammatory responses. Disruption of the estrobolome may further exacerbate systemic inflammation and contribute to the development of multiple chronic diseases in postmenopausal women. To comprehensively review the molecular mechanisms linking estrogen deficiency, the estrobolome, immune dysregulation, and chronic inflammation during menopause, and to summarize their multisystem effects, current therapeutic strategies, and emerging directions for precision medicine. A comprehensive narrative review of the recent literature was conducted using peer-reviewed publications retrieved from major biomedical databases. Studies investigating estrogen deficiency, inflammatory signaling pathways, immune regulation, oxidative stress, gut microbiota and the estrobolome, menopause-associated diseases, and therapeutic interventions were critically evaluated and synthesized to provide an integrated overview of current evidence. Estrogen deficiency promotes persistent activation of inflammatory pathways, including NF-κB, MAPK, Toll-like receptor signaling, and the NLRP3 inflammasome, resulting in increased production of pro-inflammatory cytokines, oxidative stress, endothelial dysfunction, mitochondrial impairment, and immune dysregulation. Alterations in the estrobolome further disrupt estrogen metabolism, increase intestinal permeability, and amplify systemic inflammation through microbiota-immune interactions. These interconnected mechanisms contribute to cardiovascular disease, osteoporosis, metabolic syndrome, neurodegeneration, hormone-sensitive cancers, and other menopause-associated disorders. Emerging therapeutic approaches-including menopausal hormone therapy, anti-inflammatory lifestyle interventions, microbiome-targeted strategies, and precision medicine based on multi-omics, pharmacogenomics, and artificial intelligence-offer promising opportunities for individualized management. Menopause-associated inflammation is a complex multisystem process driven by interactions among estrogen deficiency, immune dysfunction, oxidative stress, and estrobolome dysregulation. A deeper understanding of these interconnected mechanisms will facilitate the development of personalized preventive and therapeutic strategies that improve healthy aging and long-term outcomes in postmenopausal women.