{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,18]],"date-time":"2026-09-18T19:52:45Z","timestamp":1789761165898,"version":"4.0.1"},"reference-count":44,"publisher":"MDPI AG","issue":"15","license":[{"start":{"date-parts":[[2020,8,4]],"date-time":"2020-08-04T00:00:00Z","timestamp":1596499200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>The progression of nonalcoholic steatohepatitis (NASH) is complicated. The multiple parallel-hits theory is advocated, which includes adipocytokines, insulin resistance, endotoxins, and oxidative stress. Pathways involving the gut\u2013liver axis also mediate the progression of NASH. Angiotensin-II receptor blockers (ARB) suppress hepatic fibrosis via the activation of hepatic stellate cells (HSCs). Rifaximin, a nonabsorbable antibacterial agent, is used for the treatment of hepatic encephalopathy and has been recently reported to improve intestinal permeability. We examined the inhibitory effects on and mechanism of hepatic fibrogenesis by combining ARB and rifaximin administration. Fischer 344 rats were fed a choline-deficient\/l-amino acid-defined (CDAA) diet for 8 weeks to generate the NASH model. The therapeutic effect of combining an ARB and rifaximin was evaluated along with hepatic fibrogenesis, the lipopolysaccharide\u2013Toll-like receptor 4 (TLR4) regulatory cascade, and intestinal barrier function. ARBs had a potent inhibitory effect on hepatic fibrogenesis by suppressing HSC activation and hepatic expression of transforming growth factor-\u03b2 and TLR4. Rifaximin reduced intestinal permeability by rescuing zonula occludens-1 (ZO-1) disruption induced by the CDAA diet and reduced portal endotoxin. Rifaximin directly affect to ZO-1 expression on intestinal epithelial cells. The combination of an ARB and rifaximin showed a stronger inhibitory effect compared to that conferred by a single agent. ARBs improve hepatic fibrosis by inhibiting HSCs, whereas rifaximin improves hepatic fibrosis by improving intestinal permeability through improving intestinal tight junction proteins (ZO-1). Therefore, the combination of ARBs and rifaximin may be a promising therapy for NASH fibrosis.<\/jats:p>","DOI":"10.3390\/ijms21155589","type":"journal-article","created":{"date-parts":[[2020,8,5]],"date-time":"2020-08-05T06:02:21Z","timestamp":1596607341000},"page":"5589","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":35,"title":["Effective Combination Therapy of Angiotensin-II Receptor Blocker and Rifaximin for Hepatic Fibrosis in Rat Model of Nonalcoholic Steatohepatitis"],"prefix":"10.3390","volume":"21","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2402-574X","authenticated-orcid":false,"given":"Yukihisa","family":"Fujinaga","sequence":"first","affiliation":[{"name":"Department of Gastroenterology, Nara Medical University, Nara 634-8522, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4361-0592","authenticated-orcid":false,"given":"Hideto","family":"Kawaratani","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology, Nara Medical University, Nara 634-8522, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2922-5679","authenticated-orcid":false,"given":"Daisuke","family":"Kaya","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology, Nara Medical University, Nara 634-8522, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuki","family":"Tsuji","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology, Nara Medical University, Nara 634-8522, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Takahiro","family":"Ozutsumi","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology, Nara Medical University, Nara 634-8522, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Masanori","family":"Furukawa","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology, Nara Medical University, Nara 634-8522, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Koh","family":"Kitagawa","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology, Nara Medical University, Nara 634-8522, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shinya","family":"Sato","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology, Nara Medical University, Nara 634-8522, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Norihisa","family":"Nishimura","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology, Nara Medical University, Nara 634-8522, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yasuhiko","family":"Sawada","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology, Nara Medical University, Nara 634-8522, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hiroaki","family":"Takaya","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology, Nara Medical University, Nara 634-8522, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kosuke","family":"Kaji","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology, Nara Medical University, Nara 634-8522, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Naotaka","family":"Shimozato","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology, Nara Medical University, Nara 634-8522, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kei","family":"Moriya","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology, Nara Medical University, Nara 634-8522, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3158-5318","authenticated-orcid":false,"given":"Tadashi","family":"Namisaki","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology, Nara Medical University, Nara 634-8522, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6675-0475","authenticated-orcid":false,"given":"Takemi","family":"Akahane","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology, Nara Medical University, Nara 634-8522, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6666-5633","authenticated-orcid":false,"given":"Akira","family":"Mitoro","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology, Nara Medical University, Nara 634-8522, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hitoshi","family":"Yoshiji","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology, Nara Medical University, Nara 634-8522, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2020,8,4]]},"reference":[{"key":"ref_1","first-page":"47","article-title":"Obesity and the metabolic syndrome","volume":"29","author":"Vega","year":"2004","journal-title":"Minerva Endocrinol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"4079","DOI":"10.3748\/wjg.v22.i16.4079","article-title":"Nonalcoholic fatty liver disease as a multi-systemic disease","volume":"22","author":"Hakan","year":"2016","journal-title":"World J. Gastroenterol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"842","DOI":"10.1016\/S0016-5085(98)70599-2","article-title":"Steatohepatitis: A tale of two \u201chits\u201d?","volume":"114","author":"Day","year":"1998","journal-title":"Gastroenterology"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1836","DOI":"10.1002\/hep.24001","article-title":"Evolution of inflammation in nonalcoholic fatty liver disease: The multiple parallel hits hypothesis","volume":"52","author":"Tilg","year":"2010","journal-title":"Hepatology"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1693","DOI":"10.3892\/mmr.2014.2995","article-title":"Reduction of endotoxin attenuates liver fibrosis through suppression of hepatic stellate cell activation and remission of intestinal permeability in a rat non-alcoholic steatohepatitis model","volume":"11","author":"Douhara","year":"2015","journal-title":"Mol. Med. Rep."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"76","DOI":"10.1097\/MOL.0b013e3283347ebb","article-title":"Gut microbiota as a regulator of energy homeostasis and ectopic fat deposition: Mechanisms and implications for metabolic disorders","volume":"21","author":"Musso","year":"2010","journal-title":"Curr. Opin. Lipidol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"737","DOI":"10.1159\/000324281","article-title":"Gut-liver axis and sensing microbes","volume":"28","author":"Szabo","year":"2010","journal-title":"Dig. Dis."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"471","DOI":"10.1016\/j.numecd.2012.02.007","article-title":"Gut\u2013liver axis: The impact of gut microbiota on nonalcoholic fatty liver disease","volume":"22","author":"Compare","year":"2012","journal-title":"Nutr. Metab. Cardiovasc. Dis."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"538","DOI":"10.3389\/fimmu.2016.00538","article-title":"Critical roles of Kupffer cells in the pathogenesis of alcoholic liver disease: From basic science to clinical trials","volume":"7","author":"Zeng","year":"2016","journal-title":"Front. Immunol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"440","DOI":"10.1016\/S1665-2681(19)31457-7","article-title":"Gut microbiota and nonalcoholic fatty liver disease","volume":"11","author":"Machado","year":"2012","journal-title":"Ann. Hepatol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"769","DOI":"10.3945\/jn.110.135657","article-title":"Regulation of tight junction permeability by intestinal bacteria and dietary components","volume":"141","author":"Ulluwishewa","year":"2011","journal-title":"J. Nutr."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"284","DOI":"10.1111\/hepr.13281","article-title":"Combining probiotics and an angiotensin-II type 1 receptor blocker has beneficial effects on hepatic fibrogenesis in a rat model of non-alcoholic steatohepatitis","volume":"49","author":"Sawada","year":"2019","journal-title":"Hepatol. Res."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"443","DOI":"10.1111\/jgh.13841","article-title":"Beneficial effects of Rifaximin in post-infectious irritable bowel syndrome mouse model beyond gut microbiota","volume":"33","author":"Jin","year":"2018","journal-title":"J. Gastroenterol. Hepatol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"103","DOI":"10.1038\/s12276-018-0126-x","article-title":"Mechanisms regulating intestinal barrier integrity and its pathological implications","volume":"50","author":"Chelakkot","year":"2018","journal-title":"Exp. Mol. Med."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"667","DOI":"10.1038\/ja.2014.106","article-title":"Rifaximin: Beyond the traditional antibiotic activity","volume":"67","author":"Calanni","year":"2014","journal-title":"J. Antibiot."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"1548","DOI":"10.1111\/jgh.13759","article-title":"Retrospective cross-sectional pilot study of rifaximin dosing for the prevention of recurrent hepatic encephalopathy","volume":"32","author":"Lyon","year":"2017","journal-title":"J. Gastroenterol. Hepatol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1093\/jtm\/tax025","article-title":"A meta-analysis of the use of rifaximin to prevent travellers\u2019 diarrhoea","volume":"24","author":"Ng","year":"2017","journal-title":"J. Travel Med."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"8355","DOI":"10.3748\/wjg.v23.i47.8355","article-title":"Rifaximin ameliorates hepatic encephalopathy and endotoxemia without affecting the gut microbiome diversity","volume":"23","author":"Kaji","year":"2017","journal-title":"World J. Gastroenterol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"745","DOI":"10.1053\/jhep.2001.28231","article-title":"Angiotensin-II type 1 receptor interaction is a major regulator for liver fibrosis development in rats","volume":"34","author":"Yoshiji","year":"2001","journal-title":"Hepatology"},{"key":"ref_20","doi-asserted-by":"crossref","unstructured":"Yoshiji, H., Noguchi, R., Ikenaka, Y., Namisaki, T., Kitade, M., Kaji, K., Shirai, Y., Yoshii, J., Yanase, K., and Yamazaki, M. (2009). Losartan, an angiotensin- II type 1 receptor blocker, attenuates the liver fibrosis development of non-alcoholic steatohepatitis in the rat. BMC Res. Notes, 2.","DOI":"10.1186\/1756-0500-2-70"},{"key":"ref_21","first-page":"81","article-title":"Cocktail therapy with a combination of interferon, ribavirin and angiotensin-II type 1 receptor blocker attenuates murine liver fibrosis development","volume":"28","author":"Yoshiji","year":"2011","journal-title":"Int. J. Mol. Med."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"723","DOI":"10.1111\/jgh.12112","article-title":"Cross talk between Toll like receptor-4 signaling and angiotensin-II in liver fibrosis development in the rat model of non-alcoholic steatohepatitis","volume":"28","author":"Shirai","year":"2013","journal-title":"J. Gastroenterol. Hepatol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"1324","DOI":"10.1038\/nm1663","article-title":"TLR4 enhances TGF-beta signaling and hepatic fibrosis","volume":"13","author":"Seki","year":"2007","journal-title":"Nat. Med."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"124","DOI":"10.1016\/j.hepres.2006.07.003","article-title":"Angiotensin-II and vascular endothelial growth factor interaction plays an important role in rat liver fibrosis development","volume":"36","author":"Yoshiji","year":"2006","journal-title":"Hepatol. Res."},{"key":"ref_25","first-page":"7","article-title":"The clinical aspects of non-alcoholic fatty liver disease","volume":"54","author":"Bjornsson","year":"2008","journal-title":"Minerva Gastroenterol. Dietol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"1655","DOI":"10.1053\/j.gastro.2008.03.003","article-title":"Mechanisms of hepatic fibrogenesis","volume":"134","author":"Friedman","year":"2008","journal-title":"Gastroenterology"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"44","DOI":"10.3389\/fcimb.2019.00044","article-title":"Rifaximin alters intestinal microbiota and prevents progression of ankylosing spondylitis in mice","volume":"9","author":"Yang","year":"2019","journal-title":"Front. Cell Infect. Microbiol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"317","DOI":"10.1016\/j.ejphar.2011.06.058","article-title":"Inhibition of NF-\u03baB by a PXR-dependent pathway mediates counter-regulatory activities of rifaximin on innate immunity in intestinal epithelial cells","volume":"668","author":"Mencarelli","year":"2011","journal-title":"Eur. J. Pharmacol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"296","DOI":"10.1111\/nmo.12315","article-title":"Tight junctions and IBS--the link between epithelial permeability, low-grade inflammation, and symptom generation?","volume":"26","author":"Piche","year":"2014","journal-title":"Neurogastroenterol. Motil."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"631","DOI":"10.1007\/s00018-012-1070-x","article-title":"Regulation of intestinal epithelial permeability by tight junctions","volume":"70","author":"Suzuki","year":"2013","journal-title":"Cell. Mol. Life Sci."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"1877","DOI":"10.1002\/hep.22848","article-title":"Increased intestinal permeability and tight junction alterations in nonalcoholic fatty liver disease","volume":"49","author":"Miele","year":"2009","journal-title":"Hepatology"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"571","DOI":"10.1016\/j.jhep.2007.04.019","article-title":"Toll-like receptor-4 signaling and Kupffer cells play pivotal roles in the pathogenesis of non-alcoholic steatohepatitis","volume":"47","author":"Rivera","year":"2007","journal-title":"J. Hepatol."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"1125","DOI":"10.1016\/j.jhep.2013.01.038","article-title":"Activated intestinal macrophages in patients with cirrhosis release NO and IL-6 that may disrupt intestinal barrier function","volume":"58","author":"Vanheel","year":"2013","journal-title":"J. Hepatol."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"155","DOI":"10.1016\/B978-0-12-405211-6.00006-1","article-title":"Toll-like receptors in liver disease","volume":"59","author":"Petrasek","year":"2013","journal-title":"Adv. Clin. Chem."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"687","DOI":"10.1210\/er.2001-0038","article-title":"The nuclear pregnane X receptor: A key regulator of xenobiotic metabolism","volume":"23","author":"Kliewer","year":"2002","journal-title":"Endocr. Rev."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"4896","DOI":"10.1046\/j.1432-1033.2002.03207.x","article-title":"Identification of residues in the PXR ligand binding domain critical for species specific and constitutive activation","volume":"269","author":"Ostberg","year":"2002","journal-title":"Eur. J. Biochem."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"17882","DOI":"10.1074\/jbc.M601302200","article-title":"Role of NF-kappaB in regulation of PXR-mediated gene expression: A mechanism for the suppression of cytochrome P-450 3A4 by proinflammatory agents","volume":"281","author":"Gu","year":"2006","journal-title":"J. Biol. Chem."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"32","DOI":"10.1124\/jpet.110.170225","article-title":"Therapeutic role of rifaximin in inflammatory bowel disease: Clinical implication of human pregnane x receptor activation","volume":"335","author":"Cheng","year":"2010","journal-title":"J. Pharmacol. Exp. Ther."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"1317","DOI":"10.1111\/hepr.12860","article-title":"Combined treatment with dipeptidyl peptidase-4 inhibitor (sitagliptin) and angiotensin-II type 1 receptor blocker (losartan) suppresses progression in a non-diabetic rat model of steatohepatitis","volume":"47","author":"Okura","year":"2017","journal-title":"Hepatol Res."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"G707","DOI":"10.1152\/ajpgi.00372.2018","article-title":"Rifaximin prevents ethanol-induced liver injury in obese KK-A(y) mice through modulation of small intestinal microbiota signature","volume":"317","author":"Kitagawa","year":"2019","journal-title":"Am. J Physiol. Gastrointest. Liver Physiol."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"6655","DOI":"10.3748\/wjg.14.6655","article-title":"Innate immune reactivity of the liver in rats fed a choline-deficient L-amino-acid-defined diet","volume":"14","author":"Kawaratani","year":"2008","journal-title":"World J. Gastroenterol."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"57","DOI":"10.1016\/j.ejphar.2007.08.031","article-title":"Ursodeoxycholic acid protects concanavalin A-induced mouse liver injury through inhibition of intrahepatic tumor necrosis factor-alpha and macrophage inflammatory protein-2 production","volume":"578","author":"Ishizaki","year":"2008","journal-title":"Eur. J. Pharmacol."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"765","DOI":"10.1111\/hepr.12008","article-title":"Dual blockade of angiotensin-II and aldosterone suppresses the progression of a non-diabetic rat model of steatohepatitis","volume":"43","author":"Noguchi","year":"2013","journal-title":"Hepatol. Res."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"481","DOI":"10.1007\/s00535-013-0783-4","article-title":"Dipeptidyl peptidase-4 inhibitor attenuates hepatic fibrosis via suppression of activated hepatic stellate cell in rats","volume":"49","author":"Kaji","year":"2014","journal-title":"J. Gastroenterol."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/21\/15\/5589\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T09:54:20Z","timestamp":1760176460000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/21\/15\/5589"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,8,4]]},"references-count":44,"journal-issue":{"issue":"15","published-online":{"date-parts":[[2020,8]]}},"alternative-id":["ijms21155589"],"URL":"https:\/\/doi.org\/10.3390\/ijms21155589","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2020,8,4]]}}}