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Caio Tavares Fagundeshttp://lattes.cnpq.br/6415571987991013Flaviano dos Santos MartinsLiliane Martins dos SantosCaroline Marcantonio FerreiraSávio Henrique de Cicco Sandeshttp://lattes.cnpq.br/9311261664327117Rafaela Ribeiro Álvares Batista2023-06-27T17:07:50Z2023-06-27T17:07:50Z2023-05-03http://hdl.handle.net/1843/55420A 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 de triptofano (TRP) na atenuação de doenças inflamatórias intestinais (IBD), via ativação do receptor de hidrocarbonetos aromáticos (AHR). Nosso objetivo foi avaliar o papel dos metabólitos de TRP e da ativação de AHR na resposta à mucosite intestinal. Após o tratamento com 5-FU, houve alteração da concentração de quinurenina (KYN), sintetizada a partir do TRP pela enzima Indoleamina 2,3-dioxigenase 1 (IDO1), e dos metabólitos microbianos de TRP, concomitante à alteração da atividade de AHR. Os animais deficientes em AHR (Ahr-/-) apresentaram maior susceptibilidade à mucosite intestinal, aumento da lesão tecidual e da permeabilidade intestinal, simultânea à maior translocação bacteriana de cocos Gram-positivo, em relação aos animais selvagens (WT). O tratamento com um metabólito microbiano de TRP, potencial ligante de AHR, protegeu da letalidade induzida pelo 5-FU, porém, não inibiu o aumento de permeabilidade intestinal ou translocação bacteriana. A expressão de um gene-alvo da ativação de AHR, enzima do citocromo P450 da família 1, subfamília A polipeptídeo 1 (Cyp1a1), é reduzida no intestino de animais deficientes em IDO1 (Ido1-/-). Animais Ido1-/- também apresentaram maior susceptibilidade à mucosite intetsinal, acompanhada de uma expressiva permeabilidade intestinal, menor expressão de genes de barreira em relação aos animais WT, alteração do metabolismo microbiano de TRP e da composição da microbiota intestinal em relação aos animais WT submetidos à mucosite, incluindo gêneros de bactérias que contribuem para a função de barreira intestinal. Após sugerir um papel protetor dos metabólitos de TRP e de AHR na mucosite, foi avaliado o papel de Supressores da sinalização de citocinas 2 (SOCS2), que é uma proteína induzida por AHR e associada ao controle de doenças inflamatórias. Houve redução na expressão de Socs2 no intestino de animais WT simultaneamente ao comprometimento da integridade do epitélio intestinal e da função de barreira, além de uma menor expressão desse gene nos animais Ido1-/-. Os animais deficientes em SOCS2 (Socs2-/-) apresentaram maior susceptibilidade à mucosite, que foi associada à maior lesão tecidual e permeabilidade intestinal, menor expressão de genes de barreira e maior translocação bacteriana. Em conjunto, o metabolismo de TRP e a ativação de AHR desempenham um papel indispensável na proteção da mucosite intestinal induzida por 5-FU, por controlar a lesão tecidual, a função de barreira e a translocação bacteriana.Intestinal mucositis is a frequent adverse effect in patients undergoing chemotherapy, such as with 5-Fluorouracil (5-FU), which may result in discontinuation of treatment. Previous studies suggest the importance of tryptophan metabolites (TRP) in the attenuation of inflammatory bowel diseases (IBD), via activation of the aromatic hydrocarbon receptor (AHR). Our aim was to evaluate the role of TRP metabolites and AHR activation in the response to intestinal mucositis. After treatment with 5-FU, there was a change in the concentration of kynurenine (KYN), synthesized from TRP by the enzyme indoleamine 2,3-dioxygenase 1 (IDO1), and in the microbial metabolites of TRP, concomitant with the change in AHR activity. Animals deficient in AHR (Ahr-/-) showed greater susceptibility to mucositis, increased tissue damage and intestinal permeability, simultaneously with greater bacterial translocation of Gram-positive cocci, compared to wild animals (WT). Treatment with a microbial TRP metabolite, potential AHR ligand, protected against 5-FU-induced lethality, however, did not inhibit the increase in intestinal permeability or bacterial translocation. Expression of an AHR activation target gene, cytochrome P450 enzyme family 1, subfamily A, polypeptide 1 (Cyp1a1), is reduced in the gut of IDO1-deficient animals (Ido1-/-). Ido1-/- animals also showed greater susceptibility to mucositis, accompanied by an expressive intestinal permeability, lower expression of barrier genes in relation to WT animals, alteration of the microbial metabolism of TRP and microbiota composition in relation to WT animals submitted to mucositis, including genera of bacteria that contribute to intestinal barrier function. After suggesting a protective role for TRP and AHR metabolites in mucositis, the role of Cytokine Signaling Suppressors 2 (SOCS2), which is a protein induced by AHR and associated with the control of inflammatory diseases, was evaluated. There was a reduction in the expression of Socs2 in the intestine of WT animals, simultaneously with the impairment of the integrity of the intestinal epithelium and the barrier function, in addition to a lower expression of this gene in the Ido1-/- animals. Animals deficient in SOCS2 (Socs2-/-) showed greater susceptibility to mucositis, which was associated with greater tissue damage and intestinal permeability, lower expression of barrier genes and greater bacterial translocation. Together, TRP metabolism and AHR activation play an indispensable role in protecting against 5-FU-induced intestinal mucositis by controlling tissue damage, barrier function, and bacterial translocation.CAPES - Coordenação de Aperfeiçoamento de Pessoal de Nível SuperiorporUniversidade Federal de Minas GeraisPrograma de Pós-Graduação em MicrobiologiaUFMGBrasilICB - DEPARTAMENTO DE MICROBIOLOGIAhttp://creativecommons.org/licenses/by-nc-nd/3.0/pt/info:eu-repo/semantics/openAccessMicrobiologiaMucositeFluoruracilaTriptofanoHidrocarbonetos aromáticosMicrobioma gastrointestinalMicrobiologiaMucositeFluoruracilaTriptofanoHidrocarbonetos AromáticosMicrobioma GastrointestinalImpactos do metabolismo do triptofano na mucosite intestinal induzida por quimioterapiainfo:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/doctoralThesisreponame:Repositório Institucional da UFMGinstname:Universidade Federal de Minas Gerais (UFMG)instacron:UFMGORIGINALTESE - repositório.pdfTESE - repositório.pdfapplication/pdf5422292https://repositorio.ufmg.br/bitstream/1843/55420/1/TESE%20-%20reposit%c3%b3rio.pdf7a130c0b74419f108718748a46989d7dMD51CC-LICENSElicense_rdflicense_rdfapplication/rdf+xml; charset=utf-8811https://repositorio.ufmg.br/bitstream/1843/55420/2/license_rdfcfd6801dba008cb6adbd9838b81582abMD52LICENSElicense.txtlicense.txttext/plain; charset=utf-82118https://repositorio.ufmg.br/bitstream/1843/55420/3/license.txtcda590c95a0b51b4d15f60c9642ca272MD531843/554202023-06-27 14:07:51.415oai:repositorio.ufmg.br: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ório InstitucionalPUBhttps://repositorio.ufmg.br/oaiopendoar:2023-06-27T17:07:51Repositório Institucional da UFMG - Universidade Federal de Minas Gerais (UFMG)false
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