Papel da microbiota intestinal no desenvolvimento e gravidade de mucosite induzida por irinotecano em modelo murino

Abstract

Mucositis is one of the most debilitating side effects of chemo and radiotherapy and some studies have reported that an altered intestinal microbiota could have influence on its development. Regarding the induced by irinotecan hydrochloride, CPT-11, it has been 5 proposed that -glucuronidase-producing bacteria could be involved in exacerbation of mucositis by transforming back the SN-38G inactive metabolite to active SN-38 form after its intestinal secretion. The aim of our study was to evaluate the role of the intestinal microbiota and -glucuronidase-producing bacteria in the development of irinotecan-induced mucositis in a murine model. Conventional (CV), germ-free (GF), and 10 monoassociated mice with Escherichia coli producing -glucuronidase (MN-TG1) or E. coli strain deleted for the gene encoding -glucuronidase (MN-L91) received CPT-11 i.p. by days 0, 1 and 2, and were sacrificed on day 5 for analysis. After mucositis induction, CV mice showed a significant increase in MPO and EPO activity and higher levels of IL-1and TNF when compared to GF mice. CV animals also showed more lesions of 15 intestinal epithelium, coherent with their higher intestinal permeability. Additionally, CV animals showed increased production of intestinal sIgA and serum IgA and IgG, whereas the intestinal IgG was lower in CV than for IG animals, both with mucositis. The SN-38 level was lower in CV than in GF animals, which helps to understand, at least in parts, the increased intestinal damage seen in the CV. IL-10 level was higher in the intestinal tissue 20 of GF animals, which helps to understand the hyporesponsiveness of these last animals. Conventionalization of animals reversed the phenotype found for the GF group to the CV one, evidencing the effect of the microbiota. Activation of the immune system with LPS injection demonstrated that the mucositis phenotype is due to the presence of the microbiota, and not to the activated immune system status. In addition, MN-TG1 mice 25 showed an increased permeability when compared to MN-L91 animals, evidencing the effect of the -glucuronidase to convert SN-38G into SN-38. Our data proved that intestinal microbiota, especially -glucuronidase-producing bacteria, has a role in the development of irinotecan-induced mucositis in a murine model, and this knowledge may be helpful in clinical cases, since the microbiota may be modulated via diet, antibiotics or 30 the use of pro-, pre- and symbiotics.