Studies have reported the effects of the gut microbiota on colorectal cancer (CRC) chemotherapy, but few studies have investigated the association between gut microbiota and targeted therapy. This study investigated the role of the gut microbiota in the treatment outcomes of patients with metastatic CRC (mCRC). We enrolled 110 patients with mCRC and treated them with standard cancer therapy. Stool samples were collected before administering a combination of chemotherapy and targeted therapy. Patients who had a progressive disease (PD) or partial response (PR) for at least 12 cycles of therapy were included in the study. We further divided these patients into anti-epidermal growth factor receptor (cetuximab) and anti-vascular endothelial growth factor (bevacizumab) subgroups. The gut microbiota of the PR group and bevacizumab-PR subgroup exhibited significantly higher α-diversity. The β-diversity of bacterial species significantly differed between the bevacizumab-PR and bevacizumab-PD groups (P = 0.029). Klebsiella quasipneumoniae exhibited the greatest fold change in abundance in the PD group than in the PR group. Lactobacillus and Bifidobacterium species exhibited higher abundance in the PD group. The abundance of Fusobacterium nucleatum was approximately 32 times higher in the PD group than in the PR group. A higher gut microbiota diversity was associated with more favorable treatment outcomes in the patients with mCRC. Bacterial species analysis of stool samples yielded heterogenous results. K. quasipneumoniae exhibited the greatest fold change in abundance among all bacterial species in the PD group. This result warrants further investigation especially in a Taiwanese population.
Colorectal cancer (CRC), a highly prevalent malignant disease globally, is the third most common cancer and the fourth leading cause of cancer-related deaths . In Asia, the incidence and mortality rates of CRC are the highest among all cancers, and the prevalence of CRC has been increasing in various countries including Japan, Korea, China, and Taiwan (2). In Taiwan, CRC has been the most common cancer since 2006. Approximately 20%–25% of patients with CRC are initially diagnosed as having stage IV CRC with distant metastasis . Although the overall survival (OS) of patients with CRC has increased, the treatment of metastatic CRC (mCRC) remains a clinical challenge. For example, patients with mCRC and BRAF mutation exhibited a poor response to systemic treatment and had an unfavorable prognosis. The RAS gene mutation is a crucial factor for CRC tumorigenesis, invasion, and metastasis and can thus serve as a therapeutic agent. For mCRC treatment, doublet or triplet chemotherapy with fluoropyridine, oxaliplatin, or irinotecan is commonly used as a neoadjuvant therapy. Targeted therapy, including the use of an antivascular endothelial growth factor (VEGF) agent (e.g., bevacizumab ramucirumab, and aflibercept) and anti-epidermal growth factor receptor (EGFR) agents (e.g., cetuximab and panitumumab), has been suggested for mCRC treatment in combination with chemotherapy. However, treatment outcomes have been unfavorable. The 3-year OS rate is approximately 50%, and less than 20% of patients survive beyond 5 years from the time of mCRC diagnosis.
State-of-the-art therapies for mCRC have been widely researched to improve treatment outcomes. The human gut microbiota plays a crucial role in human health and CRC treatment. The balance of the gut microbiota is essential for human health, and it affects the immune system, bowel health, and protection against pathogens. The dysregulation of the gut microbiota, or dysbiosis, is harmful and can result in cancer formation. The toxicity of chemotherapeutic agents can alter the balance of the gut microbiota and break down the mucosal barrier of the bowel. This mechanism induces gastrointestinal mucositis, thus affecting the quality of life of patients and leading to lower treatment compliance.
In CRC treatment, the gut microbiota is strongly associated with chemotherapy-related side effects. For example, diarrhea is an adverse event (AE) that is commonly associated with irinotecan use, and SN-38 (the active metabolite of irinotecan) is the primary toxic agent. Some bacteria in the human bowel can secrete β-glucuronidase that converts SN-38G (the inactive metabolite) to SN-38, which may cause diarrhea. Silymarin, a bioflavonoid complex, can inhibit β-glucuronidase activity to alleviate diarrhea. Apart from side effects, the gut microbiota can also affect treatment outcomes. For instance, Fusobacterium nucleatum was demonstrated to promote the resistance of CRC cells to oxaliplatin through the activation of the autophagy pathway.
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