Intestinal homeostasis and host defense as promoted by commensal bacteria and the colonic mucus layer
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Data
2018-10-29
Autores
Celiberto, Larissa Sbaglia [UNESP]
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Universidade Estadual Paulista (Unesp)
Resumo
O trato gastrointestinal abriga a maior população de microrganismos no corpo humano, onde eles desempenham um papel importante na promoção da saúde do hospedeiro. A alteração na composição da microbiota pode levar à disbiose intestinal, que consequentemente desencadeia ou agrava doenças intestinais e extra-intestinais. Microrganismos benéficos também conhecidos como probióticos são constantemente investigados como uma terapia complementar nas doenças relacionadas à disbiose. No entanto, sua eficácia no tratamento de condições severas, como por exemplos as doenças inflamatórias intestinais (DII), é bastante variável e apresenta resultados controversos. Para abordar a importância de uma abordagem probiótica personalizada para tratar a inflamação intestinal, primeiro examinamos o efeito de bactérias personalizadas usando um modelo de colite induzida por produtos químicos. Os animais que receberam comensais isolados de suas próprias fezes foram mais protegidos contra a inflamação, pois mostraram sinais reduzidos de colite, menor dano histológico e menores níveis de marcadores inflamatórios, quando comparados aos ratos que receberam uma cepa probiótica comercial. Em seguida, o papel da mucina intestinal Muc2 e da enzima Core-1 que glicosilam foram explorados usando o modelo de colite infecciosa Citrobacter rodentium. A camada de muco intestinal é a primeira linha de defesa no intestino e é composta em grande parte pela mucina Muc2. Uma vez que quase todas as bactérias entéricas devem atravessar a camada de muco para infectar o hospedeiro, as interações bacterianas muco-entéricas são fundamentais para um melhor conhecimento sobre doenças infecciosas, bem como sobre condições inflamatórias ligadas à disbiose (por exemplo, DII). Especificamente, comparamos a suscetibilidade de C. rodentium ao infectar camundongos WT, Muc2 - / -, core 3 (C3GnT) - / -, core -1 (C1galt1) - / - e C1galt1 f / f. Embora os animais C3GnT - / - tenham apresentado um fenótipo muito semelhante aos animais WT com modesta inflamação, a ausência completa da mucina Muc2, ou apenas dos O-glicanos derivados do core 1 resultou em danos histológicos significativamente maiores, com alteração do epitélio intestinal e aumento dos danos patológicos. Curiosamente, a suplementação de tributirina protegeu os camundongos contra a infecção, resultando em menor dano histológico e menor colonização por C. rodentium em comparação aos grupos controles. Estes estudos destacam uma nova terapia personalizada que pode ser relevante para as doenças afetadas pela disbiose, bem como o papel chave da mucina Muc2 e sua glicosilação core 1 na defesa do hospedeiro contra infecções entéricas.
The intestinal tract harbours the largest population of microbes in the human body where they play an important role in promoting the health of their host. If the composition of these microbes is altered, this may lead to dysbiosis that triggers or exacerbates intestinal and extra-intestinal diseases. Probiotics have been investigated as a complementary therapy in dysbiosis-related diseases. However, their effectiveness in treating severe conditions such as Inflammatory Bowel Disease (IBD) is quite variable and have shown controversial results. To address the importance of a personalized probiotic approach to treat intestinal inflammation, we first examined the effect of personalized bacteria using a model of chemical induced colitis. The animals that received commensals isolated from their own feces were more protected against inflammation as they showed reduced signs of colitis, less histological damage and lower levels of inflammatory markers as compared to mice given a commercial probiotic strain. Next, the role of the intestinal mucin Muc2 and the Core-1 enzyme that glycosylates it were explored using the Citrobacter rodentium model of infectious colitis. The intestinal mucus layer is the first line of defense in the intestine and is largely composed of the secreted mucin Muc2. Since almost all enteric bacteria must cross the overlying mucus layer to infect the host, the mucus-enteric bacterial interactions provide fundamental knowledge about infectious diseases as well as inflammatory conditions linked to dysbiosis (e.g. IBD). Specifically, we compared C. rodentium susceptibility by infecting WT, Muc2 -/-, core 3 (C3GnT) -/-, core -1 (C1galt1) -/-, and C1galt1 f/f mice. While C3GnT -/- mice showed a very similar phenotype to WT mice with only mild inflammation, complete absence of Muc2 or just core 1 derived O-glycans resulted in significantly higher histological damage, barrier disruption, and increased pathogen burdens. Interestingly, the supplementation of tributyrin protected mice against infection resulting in less histological damage and lower C. rodentium colonization as compared to control groups. These studies highlight a novel personalized therapy that may be considered relevant to diseases affected by dysbiosis as well as the key role of Muc2 and its core 1 glycosylation in host defense against enteric infections.
The intestinal tract harbours the largest population of microbes in the human body where they play an important role in promoting the health of their host. If the composition of these microbes is altered, this may lead to dysbiosis that triggers or exacerbates intestinal and extra-intestinal diseases. Probiotics have been investigated as a complementary therapy in dysbiosis-related diseases. However, their effectiveness in treating severe conditions such as Inflammatory Bowel Disease (IBD) is quite variable and have shown controversial results. To address the importance of a personalized probiotic approach to treat intestinal inflammation, we first examined the effect of personalized bacteria using a model of chemical induced colitis. The animals that received commensals isolated from their own feces were more protected against inflammation as they showed reduced signs of colitis, less histological damage and lower levels of inflammatory markers as compared to mice given a commercial probiotic strain. Next, the role of the intestinal mucin Muc2 and the Core-1 enzyme that glycosylates it were explored using the Citrobacter rodentium model of infectious colitis. The intestinal mucus layer is the first line of defense in the intestine and is largely composed of the secreted mucin Muc2. Since almost all enteric bacteria must cross the overlying mucus layer to infect the host, the mucus-enteric bacterial interactions provide fundamental knowledge about infectious diseases as well as inflammatory conditions linked to dysbiosis (e.g. IBD). Specifically, we compared C. rodentium susceptibility by infecting WT, Muc2 -/-, core 3 (C3GnT) -/-, core -1 (C1galt1) -/-, and C1galt1 f/f mice. While C3GnT -/- mice showed a very similar phenotype to WT mice with only mild inflammation, complete absence of Muc2 or just core 1 derived O-glycans resulted in significantly higher histological damage, barrier disruption, and increased pathogen burdens. Interestingly, the supplementation of tributyrin protected mice against infection resulting in less histological damage and lower C. rodentium colonization as compared to control groups. These studies highlight a novel personalized therapy that may be considered relevant to diseases affected by dysbiosis as well as the key role of Muc2 and its core 1 glycosylation in host defense against enteric infections.
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Palavras-chave
DII, colite, microbiota, banco de microbiota, probióticos personalizados, mucosa intestinal, IBD, colitis, microbiota biobank, personalized probiotic, mucus layer