Administration of riboflavin producing lactic acid bacteria attenuates 5-fluorouracil-induced intestinal mucositis in mice

G. SAVOY DE GIORI; R. LEVIT; J.G. LEBLANC; A. DE MORENO DE LEBLANC

San Miguel de Tucuman

Simposio; SIBAL 2016 - V Simposio Internacional de Bacterias Lácticas; 2016

CERELA

Intestinal mucositis is a frequent side effect of chemotherapy or radiotherapy for cancer and is characterized by inflammation and/or gastrointestinal tract ulcers, leading to gut mucosal dysfunction. 5-Fluorouracil (5-FU), the most frequently prescribed anticancer drug, exerts cytotoxic effects in cancer cells inhibiting the synthesis of deoxyribonucleic acid and stimulating apoptosis trough the promotion of oxidative stress; however, this drug also acts on normal proliferating cells, such as cells of mucous membrane lining of the gastrointestinal tract leading to destruction of the intestinal mucosa, especially in the small intestine. In previous studies, riboflavin producing Lactobacillus plantarum CRL2130 was studied as a therapeutic approach for inflammatory bowel disease and it was demonstrated that it could attenuate TNBS-induced colitis in mice, suggesting its potential use in mucositis. The aim of this study was to evaluate the effect of riboflavin producing strain on 5-FU-induced intestinal mucositis in an experimental mouse model. Twenty-five mice were injected with saline or 5-FU (50mg/Kg animal weight) intraperitoneally daily during six days. Mice were orally given saline solution (control and 5-FU group), Lactobacillus plantarum CRL 2130 (a riboflavin overproducing strain), Lactobacillus plantarum CRL 725 (a non-riboflavin producing strain from which CRL 2130 was derived), or commercial riboflavin twice per day. One day after the last 5-FU administration, mice were euthanized and the jejunum were removed for the analysis of morphology and histopathology. Blood samples were collected for determination of serum cytokine concentrations by cytometric bead array. Animal  weight and diarrhea occurrence were also recorded. 5-FU induced a significant decreased in body weight, caused the onset of diarrhea and animals that received this drug developed severe mucosal damage reflected by high inflammation score and low villus high/crypt depth ratio in the small intetsine. Furthermore, 5-FU significantly decrease IL-10/IL-17; IL-10/INF-γ; IL-10/TNF-α ratio in serum compared with healthy animals. Administration of the CRL 2130 significantly reversed all of the changes. The use of the commercial vitamin at the same concentration produced by CRL 2130 showed similar beneficial effects. CRL 725 not show significant differences compared to the 5-FU-treated animals. In conclusion, our results show that oral administration of riboflavin producing strain CRL 2130 can prevent 5-FU-induced intestinal mucositis in a mouse model. This beneficial effect might be associated with the antioxidant potential of riboflavin produced by CRL 2130 against oxidative stress caused by the chemotherapy drug or to its anti-inflammatory effect.