Basic Study
Copyright ©The Author(s) 2021. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Hepatol. Dec 27, 2021; 13(12): 2052-2070
Published online Dec 27, 2021. doi: 10.4254/wjh.v13.i12.2052
Gut dysbiosis and systemic inflammation promote cardiomyocyte abnormalities in an experimental model of steatohepatitis
Larisse Longo, Pabulo Henrique Rampelotto, Eduardo Filippi-Chiela, Valessa Emanoele Gabriel de Souza, Fernando Salvati, Carlos Thadeu Cerski, Themis Reverbel da Silveira, Cláudia P Oliveira, Carolina Uribe-Cruz, Mário Reis Álvares-da-Silva
Larisse Longo, Pabulo Henrique Rampelotto, Valessa Emanoele Gabriel de Souza, Themis Reverbel da Silveira, Carolina Uribe-Cruz, Mário Reis Álvares-da-Silva, Experimental Laboratory of Hepatology and Gastroenterology, Hospital de Clínicas de Porto Alegre, Porto Alegre 90035-903, Rio Grande do Sul, Brazil
Larisse Longo, Eduardo Filippi-Chiela, Carlos Thadeu Cerski, Carolina Uribe-Cruz, Mário Reis Álvares-da-Silva, Graduate Program in Gastroenterology and Hepatology, Universidade Federal do Rio Grande do Sul, Porto Alegre 90035-003, Rio Grande do Sul, Brazil
Pabulo Henrique Rampelotto, Graduate Program in Genetics and Molecular Biology, Universidade Federal do Rio Grande do Sul, Porto Alegre 90035-903, Rio Grande do Sul, Brazil
Eduardo Filippi-Chiela, Center of Biotechnology, Universidade Federal do Rio Grande do Sul, Porto Alegre 91501-970, Rio Grande do Sul, Brazil
Eduardo Filippi-Chiela, Department of Morphological Sciences, Universidade Federal do Rio Grande do SulPorto Alegre 90050-170, Rio Grande do Sul, Brazil
Eduardo Filippi-Chiela, Experimental Research Center, Hospital de Clínicas de Porto Alegre, Porto Alegre 90035-903, Rio Grande do Sul, Brazil
Fernando Salvati, School of Medicine, Instituto Meridional de Educação-IMED, Passo Fundo 99070-220, Rio Grande do Sul, Brazil
Carlos Thadeu Cerski, Unit of Surgical Pathology, Hospital de Clínicas de Porto Alegre, Porto Alegre 90035-903, Rio Grande do Sul, Brazil
Cláudia P Oliveira, Department of Gastroenterology (LIM07), Faculdade de Medicina da Universidade de São Paulo, São Paulo 01246903, Brazil
Mário Reis Álvares-da-Silva, Division of Gastroenterology, Hospital de Clínicas de Porto Alegre, Porto Alegre 90035-903, Rio Grande do Sul, Brazil
Author contributions: Longo L, Rampelotto PH, Filippi-Chiela E and Álvares-da-Silva MR performed the conceptualization, methodology, formal analysis, investigation, data curation, writing of the original draft, writing-review, and editing; de Souza VEG, Salvati F, and Cerski CT performed the conceptualization, methodology, and formal analysis; da Silveira TR, Oliveira CP and Uribe-Cruz C contributed to the conceptualization, data curation writing the original draft, writing-review and editing.
Institutional review board statement: IRB approval was obtained for this study from the Grupo de Pesquisa em Pós-Graduação – Comissão de Ética em Uso Animal do Hospital de Clínicas de Porto Alegre.
Institutional animal care and use committee statement: All experimental procedures were approved by the Ethics Committee for the Use of Animals (No. 17-0021 and No. 17-0531) in accordance with international guidelines for animal welfare and measures were taken to minimize animal pain and discomfort.
Conflict-of-interest statement: The authors declare that they have no competing interests.
Data sharing statement: If requested and after approval, the authors authorize data sharing.
ARRIVE guidelines statement: The authors have read the ARRIVE guidelines, and the manuscript was prepared and revised according to the ARRIVE guidelines.
Open-Access: This article is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution NonCommercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/Licenses/by-nc/4.0/
Corresponding author: Larisse Longo, PhD, Postdoc, Experimental Laboratory of Hepatology and Gastroenterology, Hospital de Clínicas de Porto Alegre, Rua Ramiro Barcelos, 2350/Sala 12214, 2° Andar, Porto Alegre 90035-903, Rio Grande do Sul, Brazil. larisselongo@hotmail.com
Received: April 1, 2021
Peer-review started: April 1, 2021
First decision: July 16, 2021
Revised: July 20, 2021
Accepted: October 18, 2021
Article in press: October 18, 2021
Published online: December 27, 2021
Abstract
BACKGROUND

Cardiovascular disease is the main cause of death in metabolic-associated fatty liver disease, and gut microbiota dysbiosis is associated with both of them.

AIM

To assess the relationship between gut dysbiosis and cardiovascular risk (CVR) in an experimental model of steatohepatitis.

METHODS

Adult male Sprague-Dawley rats were randomized to a control group (n = 10) fed a standard diet and an intervention group (n = 10) fed a high-fat choline-deficient diet for 16 wk. Biochemical, molecular, hepatic, and cardiac histopathology. Gut microbiota variables were evaluated.

RESULTS

The intervention group had a significantly higher atherogenic coefficient, Castelli’s risk index (CRI)-I and CRI-II, interleukin-1β, tissue inhibitor of metalloproteinase-1 (all P < 0.001), monocyte chemoattractant protein-1 (P = 0.005), and plasminogen activator inhibitor-1 (P = 0.037) than the control group. Gene expression of miR-33a increased (P = 0.001) and miR-126 (P < 0.001) decreased in the intervention group. Steatohepatitis with fibrosis was seen in the intervention group, and heart computerized histological imaging analysis showed a significant decrease in the percentage of cardiomyocytes with a normal morphometric appearance (P = 0.007), reduction in the mean area of cardiomyocytes (P = 0.037), and an increase of atrophic cardiomyocytes (P = 0.007). There were significant correlations between the cardiomyocyte morphometry markers and those of progression and severity of liver disease and CVR. The intervention group had a lower Shannon diversity index and fewer changes in the structural pattern of gut microbiota (both P < 0.001) than controls. Nine microbial families that are involved in lipid metabolism were differentially abundant in intervention group and were significantly correlated with markers of liver injury and CVR.

CONCLUSION

The study found a link between gut dysbiosis and significant cardiomyocyte abnormalities in animals with steatohepatitis.

Keywords: Animal model, Cardiovascular diseases, Gut microbiota, Metabolic-associated fatty liver disease, Predicted lipid metabolism, Risk cardiovascular, Steatohepatitis

Core Tip: Cardiovascular disease is the main cause of death in metabolic-associated fatty liver disease (MAFLD) and gut microbiota dysbiosis is associated with both. Among the risk factors, we report significant correlations between the presence of atherogenic dyslipidemia, systemic inflammation, endothelial dysfunction, liver fibrogenesis, and gut dysbiosis, all of which contributed to the progression of MAFLD and increased cardiovascular risk.