Papel da microbiota no desenvolvimento da mucosite intestinal induzida pelo quimioterápico 5-fluorouracil (5-FU)

Abstract

Antineoplasic-induced mucositis in gatrointestinal tract is an important and costly dose-limiting side effect of chemotherapy and radiotherapy and may result in disruption and/or delay of treatment. The microbiota present in the gastrointestinal tract is involved in several inflammatory bowel diseases, however its role in mucositis development is not known. The aim of this study was to investigate the role of the microbiota in the development and severity of 5-fluorouracil (5-FU) chemotherapy-induced mucositis. Conventional mice (CV) treated with 5-FU showed intestinal inflammation and tissue damage. In order to assess the role of the microbiota in mucositis we use germ-free mice (GF) and mice treated with an antibiotics cocktail for microbial depletion (AB). Absence of microbiota in both models was associated with reduced inflammation and gut tissue preservation after 5-FU treatment. 5-FU-induced tissue damage in CV mice was associated with increased content of enterobacteria and E. coli in the feces. Prevention of enterobacteria increase in CV mice by ciprofloxacin treatment prevented 5-FU-induced tissue damage. Colonization with whole microbiota or E. coli monocolonization of GF mice were effective in reversing the protective phenotype of these animals after 5-FU treatment promoting inflammation and tissue damage. GF animals showed increased basal corticosterone concentration and monocolonization with E. coli reduced the concentration of this hormone after mucositis induction. Our data demonstrate that microbiota absence protects the mice from 5-FU-induced damage. Increase of enterobacteria and E. coli in CV mice exacerbate 5-FU-induced tissue damage. E. coli increase can inhibit the corticosterone increase and exacerbate chemotherapy effects.