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

UNLABELLED: Breast cancer is the most commonly diagnosed malignancy and a leading cause of cancer-related mortality. Hormone receptor-positive (HR+) tumors represent the most prevalent metastatic subtype, and early dissemination remains a major clinical challenge. Commensal dysbiosis, defined as an inflammatory gut microbiome with low biodiversity, promotes metastasis by inducing mammary gland inflammation. In this study, we investigated systemic mechanisms governing dysbiosis-induced metastasis. Metabolomic profiling revealed elevated primary bile acids (BA) in the dysbiotic fecal microbiome. Sequestration and supplementation approaches demonstrated that beyond driving metabolic disease and mammary gland inflammation, primary BAs orchestrated enhanced HR+ tumor dissemination via a prostaglandin E2 (PGE2)-dependent pathway. Analysis of The Cancer Genome Atlas showed that BA, insulin resistance, and PGE2 gene signatures are associated with reduced survival in patients with HR+ tumors. In complementary analyses using the Epic Cosmos electronic health record database, BA sequestrant use was associated with longer restricted mean survival time among patients with metastatic disease. Together, these findings reveal that commensal dysbiosis-associated loss of microbial BA metabolism elevates primary BAs and promotes HR+ metastatic progression through PGE2 signaling.

SIGNIFICANCE: Dysbiosis-induced bile acids drive systemic and mammary tissue-specific inflammation that promotes HR+ breast tumor metastasis, supporting the development of strategies targeting microbiome-derived metabolites to reduce metastatic risk in vulnerable populations.