A high fat diet exacerbates 5FU-induced intestinal mucositis and impairs the immune response in tumor-bearing mice 2331585

Abstract

Abstract Introduction 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. Funding Source F31AT012589 (BMB), F31CA278490 (TDC), F99CA294251 (TDC), K99CA27689 (BNV), U01CA272977 (EAM) Topic Categories Immune Response Regulation: Cellular Mechanisms (IRC)