Commensal Dysbiosis Alters Primary Bile Acid Signaling to Drive Mammary Gland Inflammation and Breast Tumor Dissemination

Breast cancer is the most commonly diagnosed malignancy and a leading cause of cancer-related mortality, with hormone receptor-positive (HR+) tumors comprising the majority of metastatic cases. Early dissemination represents a major clinical challenge, yet host-intrinsic factors that promote metastatic progression remain incompletely defined. Previous studies established that commensal dysbiosis, characterized by an inflammatory gut microbiome with reduced biodiversity, enhances HR+ tumor dissemination by inducing mammary gland inflammation. Here, we investigated systemic mechanisms linking dysbiosis to metastatic potential. Using a murine model of HR+ breast cancer, metabolomic profiling revealed marked elevation of primary bile acids (BAs) in dysbiotic hosts. Functional studies employing BA sequestration and dietary supplementation demonstrated that primary BAs are both necessary and sufficient to drive systemic insulin resistance, mammary gland inflammation, and enhanced tumor dissemination. Mechanistically, these effects were mediated by increased synthesis of prostaglandin E2, a pro-inflammatory lipid known to facilitate metastatic progression. Inhibition of BA accumulation or downstream PGE2 signaling mitigated these effects, underscoring a causal relationship between dysbiosis-induced metabolites and tumor cell dissemination. To assess clinical relevance, analyses of The Cancer Genome Atlas (TCGA) revealed that gene signatures associated with BA metabolism, insulin resistance, and PGE2 synthesis correlate with reduced survival in patients with HR+ breast cancer. Complementary retrospective analyses using the Epic Cosmos electronic health record database further demonstrated that bile acid sequestrant use was associated with longer restricted mean survival time among patients with metastatic disease, supporting the translational relevance of BA modulation. Collectively, these findings identify a commensal dysbiosis-driven BA-PGE2 axis that systemically reprograms metabolism and inflammation to promote the dissemination of HR+ breast tumors. This work establishes a mechanistic framework linking the gut microbiome, metabolic dysfunction, and inflammatory signaling to metastatic progression, and highlights microbiome-derived metabolites and eicosanoid pathways as actionable therapeutic targets.