The microbiome-metabolome axis in colorectal cancer therapy resistance: mechanisms, mediators, and therapeutic opportunities

Colorectal cancer (CRC) remains a leading cause of cancer-related morbidity and mortality worldwide, with therapeutic resistance representing a significant barrier to improved patient outcomes. Although tumor-intrinsic genetic alterations are important determinants of treatment resistance, emerging evidence suggests that the gut microbiome and its metabolites may also influence responses to chemotherapy, targeted therapy, and immunotherapy. The microbiome and metabolome function as an interconnected axis that can influence host immunity, microbial drug metabolism, epithelial homeostasis, and tumor-associated signaling pathways, thereby contributing to variation in therapeutic response. Despite advances in microbiome research, the mechanisms by which the microbiome-metabolome axis promotes therapy resistance are not fully elucidated, and clinical translation is limited by the absence of standardized biomarkers and validated therapeutic strategies. This review synthesizes current evidence on the molecular mechanisms through which the microbiome-metabolome axis contributes to CRC therapy resistance, with emphasis on microbial dysbiosis, bacterial metabolites, and host-microbial interactions in modulating treatment efficacy. Emerging microbiome-directed therapeutic approaches, including fecal microbiota transplantation, defined microbial consortia, dietary interventions, microbial metabolites, and engineered microbial therapies, are examined, along with the methodological and translational challenges that must be addressed before their integration into routine clinical practice.