Glutamate alliviate the intestinal damage caused by chemotherapeutic agents
Authors: Jonan Shizuka , Haneda Mai , Hamouda Nahla , Amagase Kikuko 
Published: May 2023

Background & Aim: 5-fluorouracil (5-FU), a type of anticancer drug, induces enteritis with diarrhea in high frequency and significantly reduces the quality of life of patients. Though inhibition of cell growth, induction of apoptosis, and changes in the intestinal microflora have been reported in the pathogenesis of 5-FU-induced enteritis, efficient treatment and prevention have not yet been established. In recently years, the usefulness of amino acids for various gastrointestinal disorders has been reported. Glutamate is the most abundant nonessential amino acid in the diet and is involved in the regulation and maintenance of function of gastrointestinal tract. The purpose of this study is to examine the protective effect of glutamate against 5-FU-induced small intestinal inflammation and to propose new targets for prevention and treatment. Materials & Methods: Intestinal mucositis was induced in male C57BL/6 mice by repeated administration of 5-FU (50 mg/kg, i.p.) for 6 days. glutamate was administered twice daily for 7 days prior to the start of 5-FU administration, and body weight and fecal status were measured daily during 5-FU administration. Twenty-four hours after the last dose of 5-FU, ileal tissue was removed for histological and immunohistological evaluation. The epithelial barrier function was also examined by using 4kDa FITC-labeled dextran (FD-4). Rat intestinal cell line (IEC-6) was also used to measure the epithelial barrier function. To analyze the factors that were involved in mucositis by 5-FU, Western blotting were performed. Results: Continuous administration of 5-FU was observed to cause weight loss and exacerbation of diarrhea. Administration of 5-FU shortened the villi, decreased the number of proliferative cells, induced apoptotic cells around the crypts, and reduced intestinal barrier function. Glutamate showed a protective effect against 5-FU-induced diarrhea, shortening of small intestinal villi, inhibition of proliferating cells and induction of apoptosis. The translocation of FD-4 into the blood was significantly increased by 5-FU, while glutamate had no significant effect. However, it clearly reduced FD-4 infiltration into ileal tissue. The effect of glutamate was associated with epithelial barrier function and the pretreatment of glutamate significantly recovered the decrease of epithelial electrical resistance by 5-FU. Moreover, glutamate inhibited the decrease of the expression of excitatory amino acid transporter 3 (EAAT3) by 5-FU. Conclusion: We conclude that glutamate prevents 5-FU-induced intestinal mucositis. It is suggested that glutamate improves epithelial damages caused by 5-FU through enhancing glutamate uptake and improves intestinal morphology and functions. Thus, glutamate may be helpful for preventing and treating intestinal mucositis during cancer chemotherapy.

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This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.