Alleviative effects of glutamate against chemotherapeutic agent-induced intestinal mucositis.

Abstract

5-Fluorouracil (5-FU) is one of the most widely used chemotherapeutic agents; however, it often causes intestinal mucositis with severe diarrhea. An efficient treatment strategy to reduce this side effect is lacking. Glutamate (Glu), a nonessential amino acid, is the most important energy source in the small intestine and has been shown to maintain intestinal morphology, barrier function, and antioxidative capacity. However, the effects of Glu on intestinal mucositis induced by chemotherapeutic agents have not been explored. This study aimed to demonstrate the alleviative effects of Glu on 5-FU-induced intestinal mucositis. Mucositis was induced in C57B/6N mice by intraperitoneal injection of 5-FU (50 mg/kg) for 6 days and assessed by histological and physiological analyses. Glu (500 or 1000 mg/kg) was orally administered as a pretreatment twice daily for 7 days before the initial treatment of 5-FU. Cellular proliferation and apoptosis were assessed using Ki-67 immunostaining and terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assay, respectively. Furthermore, fluorescein isothiocyanate-dextran infiltration was assessed to measure intestinal permeability. In vitro experiments using rat intestinal epithelial cells (IEC-6 cells) were performed to clarify the effect of Glu on 5-FU-induced barrier dysfunction. Glu alleviated 5-FU-induced intestinal mucositis by reducing villi shortening, enhancing cell proliferation, and suppressing apoptosis. It also alleviated the 5-FU-induced increased intestinal permeability. In vitro studies revealed significantly increased trans-epithelial electrical resistance (TEER) in Glu-pretreated IEC-6 cells compared to that in 5-FU-treated and control cells. In conclusion, the findings of this study provide evidence for the potential of Glu to protect against 5-FU-induced intestinal mucositis in patients with cancer.