The Effects of a Modified Mediterranean Diet on Gut Microbiota and Chemotherapy Side Effects in Patients With Metastatic Colorectal Cancer Undergoing First-Line Chemotherapy With or Without Either Antiepidermal Growth Factor Receptor or Antivascular Endothelial Growth Factor Agent: Protocol for a Randomized Pilot Study in Italy

Background: The gut microbiota is attracting increasing interest as a factor possibly impacting colorectal cancer risk, therapy toxicity, and, as a consequence, patient’s quality of life. It has been observed that microbial imbalance in the gut and in cancer tissue is facilitated by a Western type of diet, rich in meat, sugars, and refined grains, while a Mediterranean diet, rich in low saturated fat and fibers, promotes gut eubiosis, and results in reduced risk of developing colorectal cancer. Specifically, a high fiber content diet has been associated with a reduced incidence of therapy related adverse events in patients with malignant melanoma. Objective: This study aimed to analyze and compare the gut microbiota of patients with metastatic colorectal cancer undergoing first-line chemotherapy with or without a biological agent (antiepidermal growth factor receptor or antivascular endothelial growth factor), and receiving either a free standard Western diet, or a modified Mediterranean diet, and the impact of microbiota on chemotherapy toxicity. Methods: This is a pilot nondrug, interventional prospective, randomized, controlled, single-center (Italian), open-label trial. Patients (n=40) living in Italy, and with a local style of life, will be randomized 1:1 to either a modified Mediterranean diet or a free Western-type diet. Blood and fecal samples will be collected at baseline and control visits, for metagenomic and metabolomic analysis. The primary endpoint is the Firmicutes:Bacteroidetes ratio after completion of the third cycle of first-line chemotherapy (time T1). Secondary endpoints are (1) the percentage of patients experiencing gastrointestinal side effects at T1, (2) the percentage of patients experiencing grade 3/4 gastrointestinal side effects at T1, and (3) changes in the Firmicutes:Bacteroidetes ratio, overall microbiome composition, and metabolome at T1, and after the sixth chemotherapy cycle (T2) versus baseline. Results: This pilot trial received ethics approval on July 24, 2024. By July 2025, a total of 17 participants have been recruited. The study will conclude with the visit at T2 for the last enrolled patient. Results are expected to be published in October 2028. Conclusions: This study has the potential to provide critical insights into the role of diet in modifying the gut microbiota, diminishing chemotherapy-related side effects, and possibly enhancing the therapeutic efficacy in metastatic colorectal cancer by improving tolerability. In addition, data may pave the way for future research in immunotherapy, potentially influencing both clinical practice and public health strategies. Trial Registration: Clinicaltrial.gov NCT06794931; https://clinicaltrials.gov/search?term=NCT06794931 International Registered Report Identifier (IRRID): DERR1-10.2196/72950