| spelling |
Caio Tavares Fagundeshttp://lattes.cnpq.br/6415571987991013Fabiana Simão MachadoBarbara Maximino Rezendehttp://lattes.cnpq.br/9311261664327117Rafaela Ribeiro Álvares Batista2023-04-27T16:54:13Z2023-04-27T16:54:13Z2019-02-28http://hdl.handle.net/1843/52591A mucosite intestinal é um efeito adverso frequente nos pacientes submetidos à quimioterapia, como com o 5-Fluorouracil (5-FU), que pode resultar na interrupção do tratamento. Estudos prévios sugerem a importância dos metabólitos microbianos derivados do aminoácido triptofano (TRP) na atenuação de doenças inflamatórias intestinais (IBD), via ativação do receptor de hidrocarbonetos aromáticos (AHR). No entanto, ainda não há estudos que correlacionem AHR com a proteção contra mucosite intestinal induzida por quimioterápico. Então, nosso objetivo foi avaliar o papel dos metabólitos de TRP e do AHR na resposta à mucosite intestinal induzida por 5-FU. Animais deficientes em AHR (AHR-/-) ou tratados com antagonista desse receptor (α-naftoflavona - α-NF) apresentaram maior susceptibilidade à quimioterapia. A ativação de AHR não mostrou ser dependente do metabolismo do hospedeiro proveniente do TRP, uma vez que animais deficientes em IDO1 (IDO1-/-), enzima que converte TRP em quinurenina (KYN), não apresentaram doença agravada após a quimioterapia. No entanto, o tratamento com ampicilina agravou a doença e promoveu uma disbiose, de maneira semelhante ao documentado nos animais AHR-/- submetidos à quimioterapia. Essas alterações clínicas observadas foram revertidas após a administração de Indol-3-aldeído (Iald), que é um agonista de AHR sintetizado por algumas bactérias ácido-láticas a partir do TRP. Contudo, Iald não interferiu na disbiose observada nos animais tratados com ampicilina. Além disso, não se estabeleceu se Iald influencia na resposta inflamatória, assim como AHR não parece interferir no controle da inflamação intestinal presente nos animais selvagens após administração de 5-FU. Dessa forma, mais análises são requeridas para demonstrar o mecanismo de ativação de AHR por metabólitos microbianos de TRP e suas atividades na regulação da resposta a quimioterápicos. Em conclusão, os resultados do presente trabalho sugerem que bactérias ácido-láticas sensíveis à ampicilina protegem dos efeitos adversos causados pelo quimioterápico, por meio da produção de metabólitos de TRP ligantes de AHR.Intestinal mucositis is a common adverse effect in patients undergoing chemotherapy, such as with 5-Fluorouracil (5-FU), which may result in discontinuation of treatment. Previous studies have suggested the importance of the microbial metabolites derived from the amino acid tryptophan (TRP) in the attenuation of inflammatory bowel diseases (IBD), through activation of the aryl hydrocarbon receptor (AHR). However, studies correlating AHR with protection against chemotherapy-induced intestinal mucositis are scant. Therefore, our objective was to evaluate the role of TRP metabolites and AHR during 5-FU-induced intestinal mucositis. AHR-deficient mice (AHR-/-) or mice treated with this receptor antagonist (α-naphthoflavone - α-NF) were more susceptible to chemotherapy. Activation of AHR was not dependent on host metabolism from TRP, once IDO1- deficient mice (IDO1-/-), enzyme that convert tryptophan (Trp) to kynurenine (KYN), mice were not more susceptible to chemotherapy. However, treatment with ampicillin aggravated the disease and promoted dysbiosis, similarly to what was seen in AHR-/- animals undergoing chemotherapy. These clinical changes were reversed following administration of Indole-3-aldehyde (Iald), which is an AHR agonist synthesized by some lactic-acid bacteria from TRP. However, Iald did not interfere in the dysbiosis observed in the animals treated with ampicillin. In addition, it was not established whether Iald influences the inflammatory response. Hence, AHR does not appear to interfere with the control of the inflammation present in the gut after administration of 5-FU. Thus, further analyzes are required to demonstrate the mechanism of activation of AHR by microbial metabolites of TRP and its activities during the response to chemotherapeutics. In conclusion the findings of the present study suggest that ampicillin-sensitive lactic-acid bacteria protect against the adverse effects caused by chemotherapy by producing AHR-activating TRP metabolites.porUniversidade Federal de Minas GeraisPrograma de Pós-Graduação em MicrobiologiaUFMGBrasilICB - DEPARTAMENTO DE MICROBIOLOGIAhttp://creativecommons.org/licenses/by-nd/3.0/pt/info:eu-repo/semantics/openAccessMicrobiologiaHidrocarbonetos aromáticosTriptofanoDisbioseMucositeFluoruracilaReceptor de Hidrocarbonetos Aromáticos (AHR)Metabolismo de triptofanoDisbioseMucosite intestinal5-fluoruracilPapel do receptor de hidrocarbonetos aromáticos (AHR) e do metabolismo de triptofano no controle da disbiose e da lesão tecidual associada à mucosite intestinal induzida por 5-fluorouracilinfo:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/masterThesisreponame:Repositório Institucional da UFMGinstname:Universidade Federal de Minas Gerais (UFMG)instacron:UFMGORIGINALDissertação_repositório academico_pdfa - Copiar.pdfDissertação_repositório academico_pdfa - Copiar.pdfapplication/pdf3657751https://repositorio.ufmg.br/bitstream/1843/52591/1/Disserta%c3%a7%c3%a3o_reposit%c3%b3rio%20academico_pdfa%20-%20Copiar.pdf2ef54e825cc78d03781aaa9f7bcb6049MD51CC-LICENSElicense_rdflicense_rdfapplication/rdf+xml; charset=utf-8805https://repositorio.ufmg.br/bitstream/1843/52591/2/license_rdf00e5e6a57d5512d202d12cb48704dfd6MD52LICENSElicense.txtlicense.txttext/plain; charset=utf-82118https://repositorio.ufmg.br/bitstream/1843/52591/3/license.txtcda590c95a0b51b4d15f60c9642ca272MD531843/525912023-04-27 13:54:13.66oai:repositorio.ufmg.br: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ório InstitucionalPUBhttps://repositorio.ufmg.br/oaiopendoar:2023-04-27T16:54:13Repositório Institucional da UFMG - Universidade Federal de Minas Gerais (UFMG)false
|