Papel da microbiota intestinal no desenvolvimento e gravidade de mucosite induzida por irinotecano em modelo murino
Autor(a) principal: | |
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Data de Publicação: | 2014 |
Tipo de documento: | Dissertação |
Idioma: | por |
Título da fonte: | Repositório Institucional da UFMG |
Texto Completo: | http://hdl.handle.net/1843/BUBD-AC7EE8 |
Resumo: | 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. |
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Papel da microbiota intestinal no desenvolvimento e gravidade de mucosite induzida por irinotecano em modelo murinoIrinotecano-glucuronidaseMicrobiota intestinalInflamação intestinalMucositeMicrobiologiaMicrobioma GastrointestinalGlucuronidaseMucositeMucositis 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.A mucosite é um dos efeitos colaterais mais debilitantes da quimioterapia e/ ou radioterapia, e alguns estudos relatam que uma microbiota intestinal alterada poderia ter influência no seu desenvolvimento. Com relação à mucosite induzida pelo quimioterápico 5 cloridrato de irinotecano, CPT-11, tem sido proposto que as bactérias produtoras da enzima -glucuronidase poderiam estar envolvidas na amplificação dos efeitos deletérios da mucosite, por transformar novamente o metabólito inativo, SN-38G, na forma ativa, SN-38, após sua secreção intestinal. Entretanto, o real papel da microbiota, em especial das bactérias produtoras de -glucuronidase, nunca foi demonstrado. O objetivo do nosso 10 estudo foi avaliar o papel da microbiota intestinal e a participação das bactérias produtoras de -glucuronidase no desenvolvimento de mucosite induzida por CPT-11,em modelo murino. Camundongos convencionais (CV), isentos de germes (IG) e monoassociados com Escherichia coli produtora de -glucuronidase (MN-TG1) ou E. coli, cujo gene codificador para -glucuronidase foi deletado(MN-L91) receberam por via intra-peritoneal o 15 irinotecano nos dias 0, 1 e 2 , e foram sacrificados no dia 5 para análises. Após a indução de mucosite,os animais CV apresentaram aumento significativo da atividade de MPO e EPO e níveis mais elevados de IL-1 e TNF,quando comparados aos animais IG. Os camundongos CV também apresentaram maiores lesões no epitélio intestinal, coerente com a sua permeabilidade intestinal aumentada. Além disso, os animais CV 20 apresentaramaumento da produção de sIgA intestinal e de IgG e IgA no soro, ao passo que a IgG intestinal foi menor para o grupo CV do que para o grupo IG, ambos com mucosite induzida. A IL-10 foi maior no tecido intestinal de animais IG, o que auxilia na compreensão da hiporresponsividade deste último grupo de animais. A concentração de SN-38 no fluido intestinal foi menor no grupo CV do que no grupo IG, o que justifica, em 25 parte, o maior dano intestinal visualizado no grupo CV. A convencionalização de animais IG reverteu o fenótipo encontrado, evidenciando o papel importante da microbiota intestinal para o desenvolvimento da mucosite. A ativação do sistema imunológico, com a injeção de LPS por via intraperitoneal, demonstrou que o conjunto de sinais e sintomas verificados durante a mucosite induzida por CPT-11 é devido à presença da microbiota e 30 não ao estado de sistema imunológico ativado nesses animais. Além disso, os animais do grupo MN-TG1 mostraram um aumento da permeabilidade intestinal, quando comparados com os animais MN-L91 , demonstrando, assim, o efeito da enzima -glucuronidase para a conversão dos metabóltios. Os nossos dados revelaram que a microbiota intestinal, especialmente as bactérias produtoras de -glucuronidase, tem um papel no desenvolvimento de mucosite induzida por CPT-11 em modelo murino, e este conhecimento pode ser útil em casos clínicos, uma vez que a microbiota pode ser modulada via dieta, antibióticos ou o uso de pró-, pré- e simbióticos.Universidade Federal de Minas GeraisUFMGFlaviano dos Santos MartinsAngelica Thomaz VieiraSilvia Helena Sousa Pietra Pedroso2019-08-09T13:45:58Z2019-08-09T13:45:58Z2014-02-21info:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/masterThesisapplication/pdfhttp://hdl.handle.net/1843/BUBD-AC7EE8info:eu-repo/semantics/openAccessporreponame:Repositório Institucional da UFMGinstname:Universidade Federal de Minas Gerais (UFMG)instacron:UFMG2019-11-14T09:39:46Zoai:repositorio.ufmg.br:1843/BUBD-AC7EE8Repositório InstitucionalPUBhttps://repositorio.ufmg.br/oairepositorio@ufmg.bropendoar:2019-11-14T09:39:46Repositório Institucional da UFMG - Universidade Federal de Minas Gerais (UFMG)false |
dc.title.none.fl_str_mv |
Papel da microbiota intestinal no desenvolvimento e gravidade de mucosite induzida por irinotecano em modelo murino |
title |
Papel da microbiota intestinal no desenvolvimento e gravidade de mucosite induzida por irinotecano em modelo murino |
spellingShingle |
Papel da microbiota intestinal no desenvolvimento e gravidade de mucosite induzida por irinotecano em modelo murino Silvia Helena Sousa Pietra Pedroso Irinotecano -glucuronidase Microbiota intestinal Inflamação intestinal Mucosite Microbiologia Microbioma Gastrointestinal Glucuronidase Mucosite |
title_short |
Papel da microbiota intestinal no desenvolvimento e gravidade de mucosite induzida por irinotecano em modelo murino |
title_full |
Papel da microbiota intestinal no desenvolvimento e gravidade de mucosite induzida por irinotecano em modelo murino |
title_fullStr |
Papel da microbiota intestinal no desenvolvimento e gravidade de mucosite induzida por irinotecano em modelo murino |
title_full_unstemmed |
Papel da microbiota intestinal no desenvolvimento e gravidade de mucosite induzida por irinotecano em modelo murino |
title_sort |
Papel da microbiota intestinal no desenvolvimento e gravidade de mucosite induzida por irinotecano em modelo murino |
author |
Silvia Helena Sousa Pietra Pedroso |
author_facet |
Silvia Helena Sousa Pietra Pedroso |
author_role |
author |
dc.contributor.none.fl_str_mv |
Flaviano dos Santos Martins Angelica Thomaz Vieira |
dc.contributor.author.fl_str_mv |
Silvia Helena Sousa Pietra Pedroso |
dc.subject.por.fl_str_mv |
Irinotecano -glucuronidase Microbiota intestinal Inflamação intestinal Mucosite Microbiologia Microbioma Gastrointestinal Glucuronidase Mucosite |
topic |
Irinotecano -glucuronidase Microbiota intestinal Inflamação intestinal Mucosite Microbiologia Microbioma Gastrointestinal Glucuronidase Mucosite |
description |
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. |
publishDate |
2014 |
dc.date.none.fl_str_mv |
2014-02-21 2019-08-09T13:45:58Z 2019-08-09T13:45:58Z |
dc.type.status.fl_str_mv |
info:eu-repo/semantics/publishedVersion |
dc.type.driver.fl_str_mv |
info:eu-repo/semantics/masterThesis |
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masterThesis |
status_str |
publishedVersion |
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http://hdl.handle.net/1843/BUBD-AC7EE8 |
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http://hdl.handle.net/1843/BUBD-AC7EE8 |
dc.language.iso.fl_str_mv |
por |
language |
por |
dc.rights.driver.fl_str_mv |
info:eu-repo/semantics/openAccess |
eu_rights_str_mv |
openAccess |
dc.format.none.fl_str_mv |
application/pdf |
dc.publisher.none.fl_str_mv |
Universidade Federal de Minas Gerais UFMG |
publisher.none.fl_str_mv |
Universidade Federal de Minas Gerais UFMG |
dc.source.none.fl_str_mv |
reponame:Repositório Institucional da UFMG instname:Universidade Federal de Minas Gerais (UFMG) instacron:UFMG |
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Universidade Federal de Minas Gerais (UFMG) |
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UFMG |
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UFMG |
reponame_str |
Repositório Institucional da UFMG |
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Repositório Institucional da UFMG |
repository.name.fl_str_mv |
Repositório Institucional da UFMG - Universidade Federal de Minas Gerais (UFMG) |
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repositorio@ufmg.br |
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1816829819513470976 |