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

Detalhes bibliográficos
Autor(a) principal: Silvia Helena Sousa Pietra Pedroso
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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spelling 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
format masterThesis
status_str publishedVersion
dc.identifier.uri.fl_str_mv http://hdl.handle.net/1843/BUBD-AC7EE8
url http://hdl.handle.net/1843/BUBD-AC7EE8
dc.language.iso.fl_str_mv por
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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
instname_str Universidade Federal de Minas Gerais (UFMG)
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institution UFMG
reponame_str Repositório Institucional da UFMG
collection Repositório Institucional da UFMG
repository.name.fl_str_mv Repositório Institucional da UFMG - Universidade Federal de Minas Gerais (UFMG)
repository.mail.fl_str_mv repositorio@ufmg.br
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