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©The Author(s) 2024. Published by Baishideng Publishing Group Inc. All rights reserved.
Rifaximin on epigenetics and autophagy in animal model of hepatocellular carcinoma secondary to metabolic-dysfunction associated steatotic liver disease
Matheus Truccolo Michalczuk, Larisse Longo, Melina Belén Keingeski, Bruno de Souza Basso, Gabriel Tayguara Silveira Guerreiro, Jessica T Ferrari, José Eduardo Vargas, Cláudia P Oliveira, Carolina Uribe-Cruz, Carlos Thadeu Schmidt Cerski, Eduardo Filippi-Chiela, Mário Reis Álvares-da-Silva
Matheus Truccolo Michalczuk, Mário Reis Álvares-da-Silva, Division of Gastroenterology, Hospital de Clínicas de Porto Alegre, Porto Alegre 90035-903, Rio Grande do Sul, Brazil
Matheus Truccolo Michalczuk, Larisse Longo, Melina Belén Keingeski, Gabriel Tayguara Silveira Guerreiro, Jessica T Ferrari, Carolina Uribe-Cruz, Carlos Thadeu Schmidt Cerski, Eduardo Filippi-Chiela, 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
Larisse Longo, Melina Belén Keingeski, Bruno de Souza Basso, Gabriel Tayguara Silveira Guerreiro, 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
José Eduardo Vargas, Laboratory of Inflammatory and Neoplastic Cells, Universidade Federal do Paraná, Paraná 81530900, Brazil
Cláudia P Oliveira, Department of Gastroenterology (LIM07), Faculdade de Medicina da Universidade de São Paulo, São Paulo 01246903, Brazil
Carolina Uribe-Cruz, Facultad de Ciencias de la Salud, Universidad Católica de las Misiones, Posadas, Misiones 3300, Argentina
Carlos Thadeu Schmidt Cerski, Unit of Surgical Pathology, Hospital de Clinicas de Porto Alegre, Porto Alegre 90035-903, Rio Grande do Sul, Brazil
Eduardo Filippi-Chiela, Center of Biotechnology, Universidade Federal do Rio Grande do Sul, Porto Alegre 90035-003, Rio Grande do Sul, Brazil
Eduardo Filippi-Chiela, Department of Morphological Sciences, Universidade Federal do Rio Grande do Sul, Porto Alegre 90.050-170, Rio Grande do Sul, Brazil
Mário Reis Álvares-da-Silva, Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq), Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq) Researcher, Brasília 71.605-001, Brazil
Co-first authors: Matheus Truccolo Michalczuk and Larisse Longo.
Author contributions: Michalczuk MT and Longo L performed the conceptualization, methodology, formal analysis, investigation, data curation, writing of the original draft, writing-review, and editing; Keingeski MB, Guerreiro GTS, Ferrari JT, Filippi-Chiela E, Uribe-Cruz C and Cerski CTS performed the methodology and formal analysis, writing review and editing; Basso BS performed the methodology; Vargas JE performed the analysis; Oliveira CP performed the methodology and writing review; Álvares-da-Silva MR performed the conceptualization, methodology, formal analysis, investigation, data curation, writing of the original draft, writing-review, editing and research fundraising.
Supported by the following Brazilian funding agencies: Financiamento e Incentivo à Pesquisa from Hospital de Clínicas de Porto Alegre (FIPE/HCPA), No. 2021-0105 (to Álvares-da-Silva MR); Coordination for the Improvement of Higher Education Personnel, CAPES/PNPD; and this study was financed in part by the Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq) (to Álvares-da-Silva MR).
Institutional review board statement: Institutional review board approval was obtained for this study from the Grupo de Pesquisa em Pós-Graduação – Comissão de Ética em Uso Animal do Hospital de Clinicas de Porto Alegre.
Institutional animal care and use committee statement: All experimental procedures were approved by the Ethics Committee for the Use of Animals protocol No. 2021-0105, in accordance with international guidelines for animal welfare and measures were taken to minimize animal pain and discomfort.
Conflict-of-interest statement: All the authors report no relevant conflicts of interest for this article.
Data sharing statement: Technical appendix, statistical code, and dataset available from the corresponding author at marioreis@live.com.
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:
https://creativecommons.org/Licenses/by-nc/4.0/ Corresponding author: Mário Reis Álvares-da-Silva, MD, PhD, Professor, Division of Gastroenterology, Hospital de Clínicas de Porto Alegre, Rua Ramiro Barcelos, n° 2350/ sala 2033, 2° andar Santa Cecília, Porto Alegre 90035-903, Rio Grande do Sul, Brazil. mrsilva@hcpa.edu.br
Received: November 3, 2023
Peer-review started: November 3, 2023
First decision: December 1, 2023
Revised: December 11, 2023
Accepted: January 2, 2024
Article in press: January 2, 2024
Published online: January 27, 2024
ARTICLE HIGHLIGHTS
Research background
Metabolic-dysfunction associated steatotic liver disease (MASLD) incidence is increasing worldwide. Hepatocellular carcinoma (HCC) is a complex and heterogeneous neoplasm, and there’s evidence showing MASLD-related HCC has some unique features, including gut microbiota (GM). However, current treatment does not take this heterogeneity into account, dealing with viral and non-viral HCC in the same way. This study is intended to characterize autophagy and epigenetics in experimental MASLD-HCC and its response to rifaximin (RIF), a minimally-absorbed broad-spectrum oral antibiotic, that may interfere in GM-derived inflammation.
Research motivation
Epigenetic changes, autophagy and GM are involved in hepatocarcinogenesis, but there is no definite evidence of a positive effect of its modulation in human steatohepatitis. RIF may influence in these complex mechanisms. Understanding GM influence on epigenetics and autophagy can help not only as a diagnostic tool but also as a target for new therapies.
Research objectives
The main objective was to investigate rifaximin (RIF) effects on epigenetic and autophagy markers in experimental HCC secondary to MASLD. Future research in humans with MASLD can open a new therapeutic pathway to decrease HCC burden in this setting.
Research methods
We conducted an innovative RIF experiment in a MASLD-HCC model with 24 adult Sprague-Dawley rats, randomly assigned in three groups (n = 8, each) and treated from 5-16 wk. We compared the results of control animals to RIF group and MASLD (animals in the last two groups received a high-fat choline deficient diet plus diethylnitrosamine in drinking water. Gene expression of epigenetic and autophagy markers was obtained at the end of experiment.
Research results
All animals in RIF and MASLD groups developed steatohepatitis, fibrosis, and cirrhosis. All MASLD animals also presented HCC, but in RIF group three rats did not develop tumor. Some microRNAs, metalloproteinases and aggressivity markers were higher in rats that developed HCC comparing with those that not developed, and the opposite occurred with the autophagy markers.
Research conclusions
The results suggest that autophagy and epigenetics could exert influence on MASLD-HCC via GM interference with RIF and support clinical studies in the area.
Research perspectives
RIF may have effect on autophagy and epigenetic markers as shown in this study. These initial results in animals shall be confirmed in other preclinical and clinical studies before recommending its use in high-risk patients with MASLD cirrhosis.
