Gut microbiota as a hidden modulator of chemotherapy: implications for colorectal cancer treatment

Colorectal cancer (CRC) is a major cause of cancer morbidity and mortality worldwide, with chemotherapy remaining a cornerstone of treatment. Emerging evidence reveals that the gut microbiota significantly influences the metabolism, efficacy, and toxicity of chemotherapeutic agents such as 5-fluorouracil, irinotecan, and oxaliplatin. Microbial enzymes-most notably β-glucuronidases-can reactivate drug metabolites, contributing to adverse effects like mucositis and diarrhea. Additionally, certain bacterial species promote chemoresistance by modulating host immune responses and tumor microenvironments. This review highlights the critical role of the gut microbiota in shaping the efficacy and toxicity of chemotherapy in colorectal cancer, with a focus on microbial metabolism, chemoresistance, and microbiota-targeted therapies. Microbiota-targeted interventions-including probiotics, prebiotics, fecal microbiota transplantation (FMT), and enzyme inhibitors-represent promising strategies to improve treatment outcomes and mitigate toxicity. Enhanced understanding of microbiota-drug interactions is crucial for personalizing chemotherapy regimens, optimizing therapeutic efficacy, and minimizing adverse effects. The gut microbiota thus serves as both a key modulator and a potential therapeutic target in CRC.