Gut Dysbiosis and Increased Intestinal Permeability Drive microRNAs, NLRP-3 Inflammasome and Liver Fibrosis in a Nutritional Model of Non-Alcoholic Steatohepatitis in Adult Male Sprague Dawley Rats

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art_LONGO_Gut_Dysbiosis_and_Increased_Intestinal_Permeability_Drive_microRNAs_2020.PDF.pdf (5.07 MB)
Citações na Scopus
24
Tipo de produção
article
Data de publicação
2020
DOI
Scopus
Web of Science
PubMed
Título da Revista
ISSN da Revista
Título do Volume
Editora
DOVE MEDICAL PRESS LTD
Autores
LONGO, Larisse
FERRARI, Jessica Tonin
RAMPELOTTO, Pabulo Henrique
DELLAVIA, Gustavo Hirata
PASQUALOTTO, Amanda
CERSKI, Carlos Thadeu Schmidt
SILVEIRA, Themis Reverbel da
URIBE-CRUZ, Carolina
ALVARES-DA-SILVA, Mario Reis
Citação
CLINICAL AND EXPERIMENTAL GASTROENTEROLOGY, v.13, p.351-368, 2020
Projetos de Pesquisa
Unidades Organizacionais
Fascículo
Resumo
Background/Aim: The interactions between the gut and liver have been described in the progression of non-alcoholic steatohepatitis (NASH). The aim of this study was to develop an experimental nutritional model of NASH simulating metabolic changes occurring in humans. Materials and Methods: Adult male Sprague Dawley rats were randomized into two groups: controls (standard diet) and intervention (high-fat and choline-deficient diet) for 16 weeks, each experimental group with 10 animals. Biochemical analysis, hepatic lipid content, microRNAs, inflammatory, gut permeability markers and gut microbiota were measured. Results: Animals in the intervention group showed significantly higher delta Lee index (p=0.017), abdominal circumference (p<0.001), abdominal adipose tissue (p<0.001) and fresh liver weight (p<0.001), as well as higher serum levels of alanine aminotransferase (p=0.010), glucose (p=0.013), total cholesterol (p=0.033), LDL cholesterol (p=0.011), and triglycerides (p=0.011), and lower HDL cholesterol (p=0.006) compared to the control group. Higher TLR4 (p=0.041), TLR9 (p=0.033), MyD88 (p=0.001), Casp1 (p<0.001), NLPR3 (p=0.019), liver inflammation index interleukin (IL)-1 beta/IL10 (p<0.001), IL6/IL10 (p=0.002) and TNFa/IL10 (p=0.001) were observed in the intervention group, and also lower permeability markers Ocln (p=0.003) and F11r (p=0.041). Gene expression of miR-122 increased (p=0.041) and miR-145 (p=0.010) decreased in the intervention group. Liver steatosis, inflammation and fibrosis, along with collagen fiber deposition increment (p<0.001), were seen in the intervention group. Regarding gut microbiota, Bray-Curtis dissimilarity index and number of operational taxonomic units were significantly different (p<0.001) between the groups. Composition of the gut microbiota showed a significant correlation with histopathological score of NAFLD (r=0.694) and index IL-1 beta/IL-10 (r=0.522). Conclusion: This experimental model mimicking human NASH demonstrated gut and liver interaction, with gut microbiota and intestinal permeability changes occurring in parallel with systemic and liver inflammation, miRNAs regulation and liver tissue damage.
Palavras-chave
fatty liver disease models, fibrosis, gut microbiota, non-alcoholic fatty liver disease, non-alcoholic steatohepatitis
URI
https://observatorio.fm.usp.br/handle/OPI/37747
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Coleções
Artigos e Materiais de Revistas Científicas - FM/MGT
Artigos e Materiais de Revistas Científicas - LIM/07