Relação entre programação fetal induzida por restrição alimentar materna e doença inflamatória intestinal
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Data
2024-02-29
Autores
Soares, Antonio Weskley [UNIFESP]
Orientadores
Landgraf, Richardt Gama [UNIFESP]
Tipo
Dissertação de mestrado
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ISSN da Revista
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Introdução: A doença inflamatória intestinal (DII) é uma condição crônica e inflamatória que acomete o intestino, sendo classificada em retocolite ulcerativa (RCU) e doença de Crohn (DC). A restrição alimentar durante a gravidez, além de prejudicar o crescimento fetal, expõe o feto a altas concentrações de glicocorticoides maternos, e esse ambiente intrauterino pode programar o desenvolvimento de doenças na vida adulta. Objetivo: Avaliar a relação entre o baixo peso ao nascer induzido por restrição
alimentar materna e o desenvolvimento de doença inflamatória intestinal em modelo de inflamação intestinal induzida por DSS. Métodos: Ratos e ratas da linhagem Wistar, com idades compreendidas entre 12 e 16 semanas, foram acasalados. Após a confirmação da presença de espermatozoides no esfregaço vaginal, as fêmeas foram distribuídas em dois grupos distintos: o primeiro grupo recebeu alimentação e acesso irrestrito à água (dieta e água ad libitum), enquanto o segundo grupo foi
submetido a uma restrição alimentar de 50%, mantendo acesso irrestrito à água. Após desmame da prole e ao completar 12 semanas os animais foram divididos em 4 grupos: 02 grupos controle; Peso Normal ao Nascer-PNN, Baixo Peso ao Nascer-BPN e 02 grupos que passaram por indução da doença; PNN+DSS e BPN+DSS. A colite aguda experimental foi induzida em ratos Wistar machos pela administração de DSS a 3% na água potável por seis dias. Foram monitorados o peso corporal, o consumo de água e ração e a presença de sangue nas fezes. No 7o dia, os animais foram eutanasiados e o cólon removido para análise histopatológica e expressão de proteínas e citocinas inflamatórias. Resultados: Embora não tenha havido diferença estatística no percentual de perda de peso, consumo de ração, água e água+DSS
entre os grupos, observamos que o Índice de Atividade Clínica da Doença foi maior para o grupo PNN+DSS em relação aos demais e se correlacionou significativamente com alterações patológicas na fase aguda da doença. Isto pode ser confirmado com o aumento da expressão de COX-2 observado no mesmo grupo. Observamos que a IL-1β teve uma expressão significativamente maior no grupo PNN+DSS em relação ao seu controle, enquanto os grupos BPN não mostraram diferenças significativas.
Em relação a IL-10, os animais BPN controle apresentaram uma expressão mais alta do que os animais dos grupos PNN e BPN+DSS. A IL-5 mostrou um aumento significativo no grupo PNN+DSS em comparação com o grupo PNN controle. A MIP2 teve aumento na expressão nos grupos PNN+DSS e BPN+DSS em comparação com os grupos controle. A expressão do fator de TNF-α aumentou em ambos os grupos PNN+DSS e BPN+DSS, evidenciando respostas inflamatórias em doenças inflamatórias intestinais no modelo de programação fetal por Restrição Alimentar Materna. Conclusão: Nossas descobertas revelam que a programação fetal por restrição alimentar influencia a resposta à inflamação intestinal, com diferenças notáveis entre os grupos de prole BPN e PNN. O aumento da IL-10 nos animais BPN sugere uma possível redução na resposta inflamatória, enquanto a complexidade
dessas interações destaca a necessidade de mais investigações para compreender plenamente os mecanismos subjacentes e suas implicações nas doenças inflamatórias intestinais.
Introduction: Inflammatory bowel disease (IBD) is a chronic inflammatory condition affecting the intestine, classified into ulcerative colitis (UC) and Crohn's disease (CD). Maternal dietary restriction, aside from impairing fetal growth, exposes the fetus to high concentrations of maternal glucocorticoids, potentially programming the development of diseases in adulthood. Objective: To assess the relationship between low birth weight induced by maternal dietary restriction and the development of inflammatory bowel disease in a model of DSS-induced intestinal inflammation. Methods: 12-16-week-old male and female Wistar rats were mated. After confirming the presence of sperm in vaginal smears, the females were divided into two distinct groups: the first group received unrestricted access to food and water (ad libitum diet and water), while the second group was subjected to a 50% dietary restriction, maintaining unrestricted access to water. After weaning the offspring and reaching 12 weeks of age, the animals were divided into 4 groups: 02 control groups; Normal Birth Weight (NBW), Low Birth Weight (LBW), and 02 groups subjected to disease induction; NBW+DSS and LBW+DSS. Experimental acute colitis was induced in male Wistar rats by administering 3% DSS in drinking water for six days. Body weight, water and food consumption, and the presence of blood in the feces were monitored. On the 7th day, the animals were euthanized, and the colon was removed for histopathological analysis and the expression of inflammatory proteins and cytokines. Results: Although there were no statistically significant differences in the percentage of weight loss, food consumption, water intake, and water+DSS among the groups, we observed a higher Clinical Disease Activity Index in the NBW+DSS group compared to the others, significantly correlated with pathological changes in the acute phase of the disease. This can be confirmed by the increased expression of COX-2 observed in the same group. We observed that IL-1β had significantly higher expression in the NBW+DSS group compared to its control, while the LBW groups showed no significant differences. Regarding IL-10, the control LBW animals had higher expression than the NBW and LBW+DSS groups. IL-5 showed a significant increase in the NBW+DSS group compared to the NBW control group. MIP2 showed increased expression in the NBW+DSS and LBW+DSS groups compared to the control groups. The expression of TNF-α increased in both NBW+DSS and LBW+DSS groups, highlighting inflammatory responses in inflammatory bowel diseases in the fetal programming by maternal dietary restriction model. Conclusion: Our findings reveal that fetal programming by maternal dietary restriction influences the response to intestinal inflammation, with notable differences between NBW and LBW offspring. The increase in IL-10 in LBW animals suggests a possible reduction in the inflammatory response, while the complexity of these interactions emphasizes the need for further research to fully understand the underlying mechanisms and their implications in inflammatory bowel diseases.
Introduction: Inflammatory bowel disease (IBD) is a chronic inflammatory condition affecting the intestine, classified into ulcerative colitis (UC) and Crohn's disease (CD). Maternal dietary restriction, aside from impairing fetal growth, exposes the fetus to high concentrations of maternal glucocorticoids, potentially programming the development of diseases in adulthood. Objective: To assess the relationship between low birth weight induced by maternal dietary restriction and the development of inflammatory bowel disease in a model of DSS-induced intestinal inflammation. Methods: 12-16-week-old male and female Wistar rats were mated. After confirming the presence of sperm in vaginal smears, the females were divided into two distinct groups: the first group received unrestricted access to food and water (ad libitum diet and water), while the second group was subjected to a 50% dietary restriction, maintaining unrestricted access to water. After weaning the offspring and reaching 12 weeks of age, the animals were divided into 4 groups: 02 control groups; Normal Birth Weight (NBW), Low Birth Weight (LBW), and 02 groups subjected to disease induction; NBW+DSS and LBW+DSS. Experimental acute colitis was induced in male Wistar rats by administering 3% DSS in drinking water for six days. Body weight, water and food consumption, and the presence of blood in the feces were monitored. On the 7th day, the animals were euthanized, and the colon was removed for histopathological analysis and the expression of inflammatory proteins and cytokines. Results: Although there were no statistically significant differences in the percentage of weight loss, food consumption, water intake, and water+DSS among the groups, we observed a higher Clinical Disease Activity Index in the NBW+DSS group compared to the others, significantly correlated with pathological changes in the acute phase of the disease. This can be confirmed by the increased expression of COX-2 observed in the same group. We observed that IL-1β had significantly higher expression in the NBW+DSS group compared to its control, while the LBW groups showed no significant differences. Regarding IL-10, the control LBW animals had higher expression than the NBW and LBW+DSS groups. IL-5 showed a significant increase in the NBW+DSS group compared to the NBW control group. MIP2 showed increased expression in the NBW+DSS and LBW+DSS groups compared to the control groups. The expression of TNF-α increased in both NBW+DSS and LBW+DSS groups, highlighting inflammatory responses in inflammatory bowel diseases in the fetal programming by maternal dietary restriction model. Conclusion: Our findings reveal that fetal programming by maternal dietary restriction influences the response to intestinal inflammation, with notable differences between NBW and LBW offspring. The increase in IL-10 in LBW animals suggests a possible reduction in the inflammatory response, while the complexity of these interactions emphasizes the need for further research to fully understand the underlying mechanisms and their implications in inflammatory bowel diseases.
Descrição
Citação
SOARES, Antonio Weskley. Relação entre programação fetal induzida por restrição alimentar materna e doença inflamatória intestinal e seus efeitos na modulação da microbiota intestinal. 2023. 86 f. Dissertação (Mestrado em Medicina Translacional) - Escola Paulista de Medicina, Universidade Federal de São Paulo, São Paulo, 2023.