Influência do microbioma intestinal no desenvolvimento de doença de Crohn
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Data
2019-07-19
Autores
Andrighetti, Tahila
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Universidade Estadual Paulista (Unesp)
Resumo
A doença de Crohn é um subtipo de doença inflamatória intestinal caracterizada pela inflamação intestinal e disbiose da microbiota. A doença é causada uma manifestação atípica da resposta imune à presença de proteínas microbianas alteradas na interface da mucosa intestinal. Várias análises meta-ômicas têm sido executadas para caracterizar a microbiota intestinal em casos de doença de Crohn. Entretanto, devido à limitações das tecnologias e desvantagens inerentes aos métodos experimentais existentes, os mecanismos mediados pelas proteínas do microbioma alterado de doença de Crohn ainda não foram exploradas. Para analisar essa interação a nível molecular, executamos uma abordagem computacional que combina conjuntos de dados de metaproteômica publicados de um estudo clínico de pares de gêmeos com predições de interação entre proteínas microbianas e humanas. Essa predição baseia-se em características estruturais, inferências de regiões desordenadas, vias de sinalização e redes de interação para determinar as possíveis funções mediadas pelas proteínas microbianas. Como resultado, foi obtida uma rede de interação microbioma-hospedeiro que inicia sua sinalização com proteínas bacterianas que interagem com proteínas humanas de superfície celular. A expansão desse sinal foi modelada em direção ao núcleo da célula, onde observamos potenciais pontos de modulação de genes de autofagia: um dos processos celulares mais modificados em células de doença de Crohn em comparação às saudáveis. Esse modelo revelou diferenças em potencial entre as condições saudáveis e com doença de Crohn, onde podemos observar modulações de diversos processos biológicos relacionados à autofagia e ao desenvolvimento de doença de Crohn, como mitofagia, apoptose, diferenciação e proliferação celular.
Crohn’s disease (CD) is a subtype of inflammatory bowel disease (IBD) characterized by intestinal inflammation and microbiome dysbiosis. The disease is caused by an atypical manifestation of immune response to altered microbial proteins located in the intestinal mucosa. Various meta-omic based analyses have been carried out to profile and characterize the gut microbiota upon onset of CD. However, the molecular mechanisms mediated by the altered CD microbiome wasn’t explored yet due to the technology limitations and disavantages of the experimental methods. In order to analyse this interactio in a molecular level, we performed a computational approach which uses metaproteomic datasets from a twin-pair CD cohort study and prediction of the interaction between human and bacterial proteins. This prediction relies on structural feature based interaction prediction between microbial and host receptor proteins, disordered region inferences, signalling pathways and interaction networks to determine the possible functions mediated by the microbial proteins. As a result, we obtained a host-microbiome interaction network which starts the molecular signal with bacterial proteins interacting with human receptor proteins interactions. The expansion of this signal was modeled in direction to the cellular nucleus, where reaches autophagy genes modulation spots, hence autophagy is one of the key cellular processes to CD development. This model revealed potential differences between CD and healthy conditions and that there are different cellular processes related to autophagy and CD being modulated, as mitophagy, apoptosis, cellular differentiation and cellular proliferation.
Crohn’s disease (CD) is a subtype of inflammatory bowel disease (IBD) characterized by intestinal inflammation and microbiome dysbiosis. The disease is caused by an atypical manifestation of immune response to altered microbial proteins located in the intestinal mucosa. Various meta-omic based analyses have been carried out to profile and characterize the gut microbiota upon onset of CD. However, the molecular mechanisms mediated by the altered CD microbiome wasn’t explored yet due to the technology limitations and disavantages of the experimental methods. In order to analyse this interactio in a molecular level, we performed a computational approach which uses metaproteomic datasets from a twin-pair CD cohort study and prediction of the interaction between human and bacterial proteins. This prediction relies on structural feature based interaction prediction between microbial and host receptor proteins, disordered region inferences, signalling pathways and interaction networks to determine the possible functions mediated by the microbial proteins. As a result, we obtained a host-microbiome interaction network which starts the molecular signal with bacterial proteins interacting with human receptor proteins interactions. The expansion of this signal was modeled in direction to the cellular nucleus, where reaches autophagy genes modulation spots, hence autophagy is one of the key cellular processes to CD development. This model revealed potential differences between CD and healthy conditions and that there are different cellular processes related to autophagy and CD being modulated, as mitophagy, apoptosis, cellular differentiation and cellular proliferation.
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Palavras-chave
autofagia, bioinformática, biologia de sistemas, doença de Crohn, interação microbioma-hospedeiro