(244) A high fat diet exacerbates 5FU-induced intestinal mucositis and impairs the immune response in tumor-bearing mice.

Introduction/Rationale: Obesity and cancer are among the largest public health burdens worldwide and research continues to demonstrate strong associations between them. Being overweight or obese increases the risk for all-cause and cancer-specific mortality and increases the risk for developing 13 different types of cancers. Chemotherapy-induced mucositis (CIM) affects as many as 90% of cancer patients undergoing treatment. One such drug used to target gastrointestinal cancers is 5-Fluorouracil (5FU), which causes GI distress, reduces quality of life, treatment tolerance, and survival. Diet has been shown to be a modifiable risk factor in diseases and cancers. A high fat diet (HFD) causes many health concerns, including detrimental effects on intestinal epithelium. The purpose of this study was to investigate whether a HFD exacerbates 5FU-induced mucositis in tumor-bearing mice.

Methods: C57BL/6 mice were given either a sham (Control) or 1 injection of MC38 (2x10^4) adenocarcinoma cells in the right hind flank, which caused cancerous growth at the injection site only. Mice were then given 3 cycles of chemotherapy (1 cycle: 5 injections of 5FU (35 mg/kg/d); 5d recovery), inducing intestinal mucositis, or PBS injections (Vehicle). Mice were euthanized, and samples were collected for downstream analysis.

Results: A HFD significantly (p < 0.05) exacerbated 5FU-induced symptomology (diarrhea, rectal bleeding, weight loss) and intestinal apoptosis (Bax), impaired intestinal inflammatory (IL-6, TNF α) and mucin (Muc2) gene expression, but did not exacerbate 5FU-induced villi or goblet cell loss. A HFD significantly increased the relative percent of immune cells in the colonic lamina propria, but significantly impaired myeloid-derived cells (neutrophiles, all/recruited macrophages, dendritic cells) compared to a lean diet.

Conclusion: We believe a HFD caused an inappropriately muted response following chemotherapy administration that likely contributed to worsened mucositis symptomology and disrupted intestinal gene expression.