The Role of Gut Microbiota in Tumor Recurrence and Therapy Resistance in Colorectal Cancer: Molecular Mechanisms and Clinical Implications.

Colorectal cancer (CRC) remains a leading cause of cancer-related morbidity and mortality worldwide. Emerging evidence underscores the pivotal role of gut microbiota in influencing CRC initiation, progression, recurrence, and resistance to therapies. This review delves into the complex interactions between gut microbiota and CRC, highlighting the differential microbial profiles in healthy individuals, early-stage CRC, advanced CRC, and recurrent disease. The functional impact of key microbial species, such as Fusobacterium nucleatum and Bacteroides fragilis, is explored, emphasizing their roles in promoting chronic inflammation, genomic instability, and tumor microenvironment remodeling. The review examines microbiota's metabolic and immunological pathways, including short-chain fatty acids, secondary bile acids, and cytokine networks, which collectively shape tumor behavior and therapeutic outcomes. Special attention is given to the influence of microbiota on therapy resistance, including chemotherapy, immunotherapy, and targeted therapies, as well as its role in creating permissive niches for tumor recurrence and metastasis, particularly in the liver. The potential of microbiota-targeted interventions, such as probiotics, prebiotics, and fecal microbiota transplantation, is critically assessed as emerging strategies to improve clinical outcomes. The review also identifies significant research gaps, including the temporal dynamics of microbiota during CRC progression, the relationship between microbiota and molecular subtypes of CRC, and the impact of lifestyle and dietary interventions on microbial composition. This comprehensive synthesis underscores the clinical implications of integrating microbiota-modulating strategies into CRC management and provides a roadmap for future research to leverage microbiota for personalized oncology.