From Intestinal Origins to Mammary Targets: Exploring the Potential Role of the Brain‐Gut‐Microbiota Axis in Pre‐Metastatic Conditioning of Breast Tissue in Colorectal Cancer

ABSTRACT

Historically viewed as a localized gastrointestinal malignancy, colorectal cancer (CRC) is increasingly recognized as a systemic pathology that actively programs distant microenvironments. This review delineates a novel mechanistic framework wherein CRC‐driven dysregulation of the brain–gut–microbiota axis (BGMA) acts as a systemic architect of the breast pre‐metastatic niche (PMN). We synthesize how localized intestinal oncogenic stress propagates through three convergent conduits: (1) Immune Reprogramming, where gut‐derived inflammatory mediators and extracellular vesicles (EVs) recruit myeloid‐derived suppressor cells (MDSCs) to the mammary stroma; (2) Neuro‐ecological Conditioning, involving chronic hypothalamic–pituitary–adrenal (HPA) axis activation and sympathetic hyperactivation that drives catecholamine‐mediated remodeling of breast tissue; and (3) Humoral‐Metabolic Convergence, specifically via the “estrobolome” and secondary bile acids that synchronize systemic hormonal levels with local tissue receptivity. By reframing CRC progression as a systemic pathology that potentially preconditions distant, hormone‐sensitive environments, we propose the BGMA as a conceptual framework for prospective “systemic interception”, outlining roadmaps to neutralize metastatic cascades at their incipient, reversible stages.