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Please use this identifier to cite or link to this item: http://hdl.handle.net/10564/4093

Title: Dual therapy with zinc acetate and rifaximin prevents from ethanolinduced liver fibrosis by maintaining intestinal barrier integrity
Other Titles: 酢酸亜鉛とリファキシミンの併用療法による腸管バリアー機能維持によるエタノール誘発性肝線維化予防効果
Authors: Fujimoto, Yuki
Kaji, Kosuke
Nishimura, Norihisa
Enomoto, Masahide
Murata, Koji
Takeda, Soichi
Takaya, Hiroaki
Kawaratani, Hideto
Moriya, Kei
Namisaki, Tadashi
Akahane, Takemi
Yoshiji, Hitoshi
Keywords: Liver fibrosis
Intestinal permeability
Alcoholic liver disease
Lipopolysaccharide
Toll-like receptor
Tight junction protein
Issue Date: 28-Dec-2021
Publisher: Baishideng Publishing Group
Citation: World journal of gastroenterology Vol.27 No.48 p.8323-8342 (2021 Dec)
Abstract: BACKGROUND Hepatic overload of gut-derived lipopolysaccharide dictates the progression of alcoholic liver disease (ALD) by inducing oxidative stress and activating Kupffer cells and hepatic stellate cells through toll-like receptor 4 signaling. Therefore, targeting the maintenance of intestinal barrier integrity has attracted attention for the treatment of ALD. Zinc acetate and rifaximin, which is a nonabsorbable antibiotic, had been clinically used for patients with cirrhosis, particularly those with hepatic encephalopathy, and had been known to improve intestinal barrier dysfunction. However, only few studies focused on their efficacies in preventing the ALD-related fibrosis development. AIM To investigate the effects of a combined zinc acetate with rifaximin on liver fibrosis in a mouse ALD model. METHODS To induce ALD-related liver fibrosis, female C57BL/6J mice were fed a 2.5% (v/v) ethanol-containing Lieber-DeCarli liquid diet and received intraperitoneal carbon tetrachloride (CCl4) injection twice weekly (1 mL/kg) for 8 wk. Zinc acetate (100 mg/L) and/or rifaximin (100 mg/L) were orally administered during experimental period. Hepatic steatosis, inflammation and fibrosis as well as intestinal barrier function were evaluated by histological and molecular analyses. Moreover, the direct effects of both agents on Caco-2 barrier function were assessed by in vitro assays.RESULTSIn the ethanol plus CCl4-treated mice, combination of zinc acetate and rifaximin attenuated oxidative lipid peroxidation with downregulation of Nox2 and Nox4. This combination significantly inhibited the Kupffer cells expansion and the proinflammatory response with blunted hepatic exposure of lipopolysaccharide and the toll-like receptor 4/nuclear factor kB pathway. Consequently, liver fibrosis and hepatic stellate cells activation were efficiently suppressed with downregulation of Mmp-2, -9, -13, and Timp1. Both agents improved the atrophic changes and permeability in the ileum, with restoration of tight junction proteins (TJPs) by decreasing the expressions of tumor necrosis factor α and myosin light chain kinase. In the in vitro assay, both agents directly reinforced ethanol or lipopolysaccharide-stimulated paracellular permeability and upregulated TJPs in Caco-2 cells. CONCLUSION Dual therapy with zinc acetate and rifaximin may serve as a strategy to prevent ALD-related fibrosis by maintaining intestinal barrier integrity.
Description: 博士(医学)・甲第862号・令和5年3月15日
©The Author(s) 2021. Published by Baishideng Publishing Group Inc. All rights reserved. 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.
URI: http://hdl.handle.net/10564/4093
ISSN: 10079327
DOI: https://doi.org/10.3748/wjg.v27.i48.8323
Academic Degrees and number: 24601甲第862号
Degree-granting date: 2023-03-15
Degree name: 博士(医学)
Degree-granting institutions: 奈良県立医科大学
Appears in Collections:2022年度

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