{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,9]],"date-time":"2026-10-09T23:34:05Z","timestamp":1791588845736,"version":"4.3.4"},"reference-count":50,"publisher":"Wiley","issue":"2","license":[{"start":{"date-parts":[[2025,1,13]],"date-time":"2025-01-13T00:00:00Z","timestamp":1736726400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Liver International"],"published-print":{"date-parts":[[2025,2]]},"abstract":"<jats:title>ABSTRACT<\/jats:title><jats:sec><jats:title>Background and Aims<\/jats:title><jats:p>Primary sclerosing cholangitis (PSC) is a chronic cholestatic liver disease characterised by progressive biliary inflammation and fibrosis, leading to liver cirrhosis and cholangiocarcinoma. GPBAR1 (TGR5) is a G protein\u2010coupled receptor for secondary bile acids. In this study, we have examined the therapeutic potential of BAR501, a selective GPBAR1 agonist in a PSC model.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Single\u2010cell analysis of healthy human liver samples and gene expression analysis of PSC liver samples were conducted. In\u00a0vitro studies on a human cholangiocyte cell line (NHC), U937 and human hepatic stellate cells (hSteCs) were performed. Additionally, <jats:italic>Abcb4<\/jats:italic><jats:sup><jats:italic>\u2212\/\u2212<\/jats:italic><\/jats:sup> mice were treated with BAR501 for 12\u201324\u2009weeks.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Single\u2010cell analysis demonstrated that <jats:italic>GPBAR1<\/jats:italic> is expressed by macrophages, NK cells, sinusoidal cells and to a lesser extent by cholangiocytes. Total liver expression of <jats:italic>GPBAR1<\/jats:italic> increases in PSC patients compared to that in healthy controls and positively correlates with markers for monocytes and NK cells and cytokeratin 19. In\u00a0vitro treatment of NHCs with BAR501 reversed the acquisition of a pro\u2010inflammatory phenotype and the downregulation of <jats:italic>GPBAR1<\/jats:italic> expression promoted by LPS in an NF\u2010\u03baB\u2010dependent manner. Treating <jats:italic>Abcb4<\/jats:italic><jats:sup><jats:italic>\u2212\/\u2212<\/jats:italic><\/jats:sup> mice reduced bile duct inflammation and liver fibrosis and prevented the downregulation of GPBAR1 expression. Treating mice with BAR501 also modulated the bile acid pool composition and reduced the dysbiosis\u2010associated gut permeability, and intestinal and systemic inflammation. Ex\u00a0vivo experiments using conditioned media from BAR501\u2010treated cholangiocytes mitigated the activation of macrophages.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>Our study provides evidence for the therapeutic potential of selective GPBAR1 agonists in intestinal inflammation\u2013associated cholestasis, warranting the evaluation of BAR501 in PSC patients.<\/jats:p><\/jats:sec>","DOI":"10.1111\/liv.16235","type":"journal-article","created":{"date-parts":[[2025,1,13]],"date-time":"2025-01-13T13:22:37Z","timestamp":1736774557000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":17,"title":["Liver <scp>GPBAR1<\/scp> Associates With Immune Dysfunction in Primary Sclerosing Cholangitis and Its Activation Attenuates Cholestasis in Abcb4\u2212\/\u2212 Mice"],"prefix":"10.1111","volume":"45","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-7125-8963","authenticated-orcid":false,"given":"Cristina","family":"Di Giorgio","sequence":"first","affiliation":[{"name":"Department of Medicine and Surgery University of Perugia  Perugia Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ginevra","family":"Urbani","sequence":"additional","affiliation":[{"name":"Department of Medicine and Surgery University of Perugia  Perugia Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Silvia","family":"Marchian\u00f2","sequence":"additional","affiliation":[{"name":"Department of Medicine and Surgery University of Perugia  Perugia Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2995-6896","authenticated-orcid":false,"given":"Michele","family":"Biagioli","sequence":"additional","affiliation":[{"name":"Department of Medicine and Surgery University of Perugia  Perugia Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Martina","family":"Bordoni","sequence":"additional","affiliation":[{"name":"BAR PHARMACEUTICALS SRL  Reggio Emilia Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rachele","family":"Bellini","sequence":"additional","affiliation":[{"name":"Department of Medicine and Surgery University of Perugia  Perugia Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carmen","family":"Massa","sequence":"additional","affiliation":[{"name":"Department of Medicine and Surgery University of Perugia  Perugia Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ginevra","family":"Lachi","sequence":"additional","affiliation":[{"name":"Department of Medicine and Surgery University of Perugia  Perugia 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