{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,20]],"date-time":"2026-09-20T17:36:08Z","timestamp":1789925768323,"version":"4.0.1"},"reference-count":139,"publisher":"MDPI AG","issue":"10","license":[{"start":{"date-parts":[[2018,10,1]],"date-time":"2018-10-01T00:00:00Z","timestamp":1538352000000},"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>Cholangiocytes, the epithelial cells lining the bile ducts, represent the unique target of a group of progressive diseases known as cholangiopathies whose pathogenesis remain largely unknown. In normal conditions, cholangiocytes are quiescent and participate to the final bile volume and composition. Following exogenous or endogenous stimuli, cholangiocytes undergo extensive modifications of their phenotype. Reactive cholangiocytes actively proliferate and release a set of proinflammatory molecules, which act in autocrine\/paracrine manner mediating the cross-talk with other liver cell types and innate and adaptive immune cells. Cholangiocytes themselves activate innate immune responses against gut-derived microorganisms or bacterial products that reach the liver via enterohepatic circulation. Gut microbiota has been implicated in the development and progression of the two most common cholangiopathies, i.e., primary sclerosing cholangitis (PSC) and primary biliary cholangitis (PBC), which have distinctive microbiota composition compared to healthy individuals. The impairment of intestinal barrier functions or gut dysbiosis expose cholangiocytes to an increasing amount of microorganisms and may exacerbate inflammatory responses thus leading to fibrotic remodeling of the organ. The present review focuses on the complex interactions between the activation of innate immune responses in reactive cholangiocytes, dysbiosis, and gut permeability to bacterial products in the pathogenesis of PSC and PBC.<\/jats:p>","DOI":"10.3390\/ijms19103003","type":"journal-article","created":{"date-parts":[[2018,10,2]],"date-time":"2018-10-02T08:23:50Z","timestamp":1538468630000},"page":"3003","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":41,"title":["Inflammation and the Gut-Liver Axis in the Pathophysiology of Cholangiopathies"],"prefix":"10.3390","volume":"19","author":[{"given":"Debora Maria","family":"Giordano","sequence":"first","affiliation":[{"name":"Clinic of Gastroenterology and Hepatology, Universit\u00e0 Politecnica delle Marche, Via Tronto 10, 60126 Ancona, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Claudio","family":"Pinto","sequence":"additional","affiliation":[{"name":"Clinic of Gastroenterology and Hepatology, Universit\u00e0 Politecnica delle Marche, Via Tronto 10, 60126 Ancona, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Luca","family":"Maroni","sequence":"additional","affiliation":[{"name":"Clinic of Gastroenterology and Hepatology, Universit\u00e0 Politecnica delle Marche, Via Tronto 10, 60126 Ancona, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Antonio","family":"Benedetti","sequence":"additional","affiliation":[{"name":"Clinic of Gastroenterology and Hepatology, Universit\u00e0 Politecnica delle Marche, Via Tronto 10, 60126 Ancona, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marco","family":"Marzioni","sequence":"additional","affiliation":[{"name":"Clinic of Gastroenterology and Hepatology, Universit\u00e0 Politecnica delle Marche, Via Tronto 10, 60126 Ancona, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2018,10,1]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1220","DOI":"10.1016\/j.bbadis.2017.06.024","article-title":"Pathobiology of biliary epithelia","volume":"1864","author":"Cheung","year":"2018","journal-title":"Biochim. Biophys. Acta"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"687","DOI":"10.5009\/gnl16033","article-title":"Biology of cholangiocytes: From bench to bedside","volume":"10","author":"Yoo","year":"2016","journal-title":"Gut Liver"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"368","DOI":"10.1016\/j.jcmgh.2015.05.005","article-title":"Functional and Structural Features of Cholangiocytes in Health and Disease","volume":"1","author":"Maroni","year":"2015","journal-title":"Cell Mol. Gastroenterol. Hepatol."},{"key":"ref_4","first-page":"27","article-title":"Recent advances on the mechanisms regulating cholangiocyte proliferation and the significance of the neuroendocrine regulation of cholangiocyte pathophysiology","volume":"1","author":"Franchitto","year":"2013","journal-title":"Ann. Transl. Med."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"738","DOI":"10.1053\/jhep.2001.21900","article-title":"Heterogeneity and plasticity of hepatocyte lineage cells","volume":"33","author":"Sell","year":"2001","journal-title":"Hepatology"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"e109","DOI":"10.1038\/ctg.2015.33","article-title":"Current Concepts in Primary Biliary Cirrhosis and Primary Sclerosing Cholangitis","volume":"6","author":"Sclair","year":"2015","journal-title":"Clin. Transl. Gastroenterol."},{"key":"ref_7","first-page":"266","article-title":"Primary Biliary Cirrhosis and Primary Sclerosing Cholangitis: A Review Featuring a Women\u2019s Health Perspective","volume":"24","author":"Vaziri","year":"2014","journal-title":"J. Clin. Transl. Hepatol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"1520","DOI":"10.1111\/liv.13880","article-title":"Novel and emerging therapies for cholestatic liver diseases","volume":"38","author":"Goldstein","year":"2018","journal-title":"Liver Int."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"242","DOI":"10.1016\/j.smim.2009.06.005","article-title":"Toll-like receptors (TLRs) and Nod-like receptors (NLRs) in inflammatory disorders","volume":"21","author":"Fukata","year":"2009","journal-title":"Semin. Immunol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"1633","DOI":"10.1016\/S0016-5085(96)70027-6","article-title":"Regrowth of the rat biliary tree after 70% partial hepatectomy is coupled to increased secretin-induced ductal secretion","volume":"111","author":"Lesage","year":"1996","journal-title":"Gastroenterology"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"791","DOI":"10.1016\/j.mayocp.2015.03.017","article-title":"The cholangiopathies","volume":"90","author":"Lazaridis","year":"2015","journal-title":"Mayo. Clin. Proc."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"251","DOI":"10.1007\/s00428-011-1048-3","article-title":"Ductal plates in hepatic ductular reactions. Hypothesis and implications. I. Types of ductular reaction reconsidered","volume":"458","author":"Desmet","year":"2011","journal-title":"Virchows. Archiv."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"186","DOI":"10.1111\/j.1469-7580.2011.01462.x","article-title":"Biliary tree stem\/progenitor cells in glands of extrahepatic and intraheptic bile ducts: An anatomical in situ study yielding evidence of maturational lineages","volume":"220","author":"Carpino","year":"2012","journal-title":"J. Anat."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"1681","DOI":"10.1053\/gast.2000.20184","article-title":"Estrogens stimulate proliferation of intrahepatic biliary epithelium in rats","volume":"119","author":"Alvaro","year":"2000","journal-title":"Gastroenterology"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"415","DOI":"10.1053\/j.gastro.2006.07.023","article-title":"Proliferating Cholangiocytes: A Neuroendocrine Compartment in the Diseased Liver","volume":"132","author":"Alvaro","year":"2007","journal-title":"Gastroenterology"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"575","DOI":"10.1016\/j.jhep.2012.10.011","article-title":"The dynamic biliary epithelia: Molecules, pathways, and disease","volume":"58","author":"Tabibian","year":"2013","journal-title":"J. Hepatol."},{"key":"ref_17","first-page":"G922","article-title":"Upregulation of secretin receptor gene expression in rat cholangiocytes after bile duct ligation","volume":"266","author":"Alpini","year":"1994","journal-title":"Am. J. Physiol."},{"key":"ref_18","first-page":"G527","article-title":"Secretin stimulates bile ductular secretory activity through the cAMP system","volume":"263","author":"Lenzen","year":"1992","journal-title":"Am. J. Physiol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"15523","DOI":"10.1016\/S0021-9258(19)49566-5","article-title":"Secretin stimulates exocytosis in isolated bile duct epithelial cells by a cyclic AMP-mediated mechanism","volume":"267","author":"Kato","year":"1992","journal-title":"J. Biol. Chem."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"1592","DOI":"10.1053\/j.gastro.2007.08.020","article-title":"Cyclic AMP Regulates Bicarbonate Secretion in Cholangiocytes Through Release of ATP Into Bile","volume":"133","author":"Minagawa","year":"2007","journal-title":"Gastroenterology"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"528","DOI":"10.1016\/j.jhep.2004.06.009","article-title":"CAMP stimulates the secretory and proliferative capacity of the rat intrahepatic biliary epithelium through changes in the PKA\/Src\/MEK\/ERK1\/2 pathway","volume":"41","author":"Francis","year":"2004","journal-title":"J. Hepatol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"G11","DOI":"10.1152\/ajpgi.00025.2009","article-title":"Follicle-stimulating hormone increases cholangiocyte proliferation by an autocrine mechanism via cAMP-dependent phosphorylation of ERK1\/2 and Elk-1","volume":"297","author":"Mancinelli","year":"2009","journal-title":"Am. J. Physiol. Gastrointest. Liver Physiol."},{"key":"ref_23","first-page":"G1064","article-title":"Large but not small intrahepatic bile ducts are involved in secretin- regulated ductal bile secretion","volume":"272","author":"Alpini","year":"1997","journal-title":"Am. J. Physiol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"282","DOI":"10.1038\/labinvest.2011.158","article-title":"Histamine stimulates the proliferation of small and large cholangiocytes by activation of both IP3\/Ca2+and cAMP-dependent signaling mechanisms","volume":"92","author":"Francis","year":"2012","journal-title":"Lab Investig"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"2205","DOI":"10.1101\/gad.1102703","article-title":"Transcriptional regulation by calcium, calcineurin, and NFAT","volume":"17","author":"Hogan","year":"2003","journal-title":"Genes Dev."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"2637","DOI":"10.1007\/s00018-008-8086-2","article-title":"Ca2+\/Calmodulin-dependent Protein Kinases","volume":"65","author":"Swulius","year":"2013","journal-title":"Cell Mol. Life Sci."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"C499","DOI":"10.1152\/ajpcell.00369.2007","article-title":"Small mouse cholangiocytes proliferate in response to H1 histamine receptor stimulation by activation of the IP3\/CaMK I\/CREB pathway","volume":"295","author":"Francis","year":"2008","journal-title":"AJP Cell Physiol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"628","DOI":"10.1002\/hep.24041","article-title":"Activation of alpha(1)-adrenergic receptors stimulate the growth of small mouse cholangiocytes via calcium-dependent activation of nuclear factor of activated T cells 2 and specificity protein 1","volume":"53","author":"Alpini","year":"2011","journal-title":"Hepatology"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"3184","DOI":"10.1007\/s10620-012-2255-8","article-title":"Calcineurin\/NFATc1 pathway contributes to cell proliferation in hepatocellular carcinoma","volume":"57","author":"Wang","year":"2012","journal-title":"Dig. Dis. Sci."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"1175","DOI":"10.1016\/S0016-5085(03)01201-0","article-title":"Loss of inositol 1,4,5-trisphosphate receptors from bile duct epithelia is a common event in cholestasis","volume":"125","author":"Shibao","year":"2003","journal-title":"Gastroenterology"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"903","DOI":"10.1053\/j.gastro.2004.06.047","article-title":"Calcium-dependent regulation of secretion in biliary epithelial cells: The role of apamin-sensitive SK channels","volume":"127","author":"Feranchak","year":"2004","journal-title":"Gastroenterology"},{"key":"ref_32","first-page":"118","article-title":"Prolonged administration of secretin to normal rats increases biliary proliferation and secretin-induced ductal secretory activity","volume":"3","author":"Guerrier","year":"2014","journal-title":"Hepatobiliary Surg. Nutr."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"739","DOI":"10.3109\/00365527109179946","article-title":"Immunofluorescent localization of secretin and enteroglucagon in human intestinal mucosa","volume":"6","author":"Polak","year":"1971","journal-title":"Scand. J. Gastroenterol."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"1795","DOI":"10.1053\/j.gastro.2014.02.030","article-title":"Secretin stimulates biliary cell proliferation by regulating expression of microRNA 125b and MicroRNA let7a in mice","volume":"146","author":"Glaser","year":"2014","journal-title":"Gastroenterology"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"204","DOI":"10.1002\/hep.23657","article-title":"Knockout of secretin receptor reduces large cholangiocyte hyperplasia in mice with extrahepatic cholestasis induced by bile duct ligation","volume":"52","author":"Glaser","year":"2010","journal-title":"Hepatology"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"1061","DOI":"10.1016\/j.ajpath.2014.12.004","article-title":"Gonadotropin-releasing hormone stimulates biliary proliferation by paracrine\/autocrine mechanisms","volume":"185","author":"Ray","year":"2015","journal-title":"Am. J. Pathol."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"1005","DOI":"10.2108\/zsj.21.1005","article-title":"GnRH as a cell proliferation regulator: mechanism of action and evolutionary implications","volume":"21","author":"Enomoto","year":"2004","journal-title":"Zoolog. Sci."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"251","DOI":"10.2144\/000114167","article-title":"Lessons learned from vivo-morpholinos: How to avoid vivo-morpholino toxicity","volume":"56","author":"Ferguson","year":"2014","journal-title":"Biotechniques"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"65","DOI":"10.1016\/0165-5728(92)90156-F","article-title":"Immunoregulatory effects of neuropeptides. Stimulation of interleukin-2 production by substance P","volume":"37","author":"Rameshwar","year":"1992","journal-title":"J. Neuroimmunol."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"177","DOI":"10.1016\/S1665-2681(19)31658-8","article-title":"Serum concentrations of substance P in cholestasis","volume":"9","author":"Trivedi","year":"2010","journal-title":"Ann. Hepatol."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"G759","DOI":"10.1152\/ajpgi.00018.2014","article-title":"Overexpression of membrane metalloendopeptidase inhibits substance P stimulation of cholangiocarcinoma growth","volume":"306","author":"Meng","year":"2014","journal-title":"Am. J. Physiol. Gastrointest Liver Physiol."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"528","DOI":"10.1002\/hep.29138","article-title":"Substance P increases liver fibrosis by differential changes in senescence of cholangiocytes and hepatic stellate cells","volume":"66","author":"Wan","year":"2017","journal-title":"Hepatology"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"G297","DOI":"10.1152\/ajpgi.00418.2010","article-title":"Knockout of the neurokinin-1 receptor reduces cholangiocyte proliferation in bile duct-ligated mice","volume":"301","author":"Glaser","year":"2011","journal-title":"Am. J. Physiol. Gastrointest. Liver Physiol."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"1406","DOI":"10.1038\/labinvest.2014.129","article-title":"Inhibition of mast cell-derived histamine secretion by cromolyn sodium treatment decreases biliary hyperplasia in cholestatic rodents","volume":"94","author":"Kennedy","year":"2014","journal-title":"Lab Investig."},{"key":"ref_45","first-page":"2245","article-title":"Increased portal tract infiltration of mast cells and eosinophils in primary biliary cirrhosis","volume":"92","author":"Nakamura","year":"1997","journal-title":"Am. J. Gastroenterol"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"2336","DOI":"10.1023\/A:1020107915919","article-title":"Gastrointestinal melatonin: Localization, function, and clinical relevance","volume":"47","author":"Bubenik","year":"2002","journal-title":"Dig. Dis. Sci."},{"key":"ref_47","first-page":"313","article-title":"Melatonin ameliorates liver fibrosis induced by bile-duct ligation in rats","volume":"53","author":"Tahan","year":"2010","journal-title":"Can J. Surg."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"819","DOI":"10.1016\/j.ajpath.2016.12.015","article-title":"The Neuropeptide Galanin Is Up-Regulated during Cholestasis and Contributes to Cholangiocyte Proliferation","volume":"187","author":"McMillin","year":"2017","journal-title":"Am. J. Pathol."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"1270","DOI":"10.1053\/j.gastro.2005.12.034","article-title":"Vascular Endothelial Growth Factor Stimulates Rat Cholangiocyte Proliferation Via an Autocrine Mechanism","volume":"130","author":"Gaudio","year":"2006","journal-title":"Gastroenterology"},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"663","DOI":"10.1016\/j.jhep.2010.04.022","article-title":"Pancreatic Duodenal Homeobox-1 de novo expression drives cholangiocyte neuroendocrine-like transdifferentiation","volume":"53","author":"Marzioni","year":"2010","journal-title":"J Hepatol."},{"key":"ref_51","unstructured":"Charles, H.L. (2013). MicroRNAs in Liver Diseases. MicroRNAs in Medicine, John Wiley & Sons, Inc.. [1st ed.]."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"279","DOI":"10.1038\/nrgastro.2016.154","article-title":"Genetics of primary sclerosing cholangitis and pathophysiological implications","volume":"14","author":"Jiang","year":"2017","journal-title":"Nat. Rev. Gastroenterol. Hepatol."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"19030","DOI":"10.1073\/pnas.1106408108","article-title":"Colonic mucosa-associated microbiota is influenced by an interaction of Crohn disease and FUT2 (Secretor) genotype","volume":"108","author":"Rausch","year":"2011","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"227","DOI":"10.1055\/s-2002-34501","article-title":"Functional heterogeneity of cholangiocytes","volume":"22","author":"Marzioni","year":"2002","journal-title":"Semin. Liver Dis."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"555","DOI":"10.1002\/hep.510310302","article-title":"Functional Heterogeneity of the Intrahepatic Biliary Epithelium","volume":"31","author":"Kanno","year":"2016","journal-title":"Hepatology"},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"707","DOI":"10.1146\/annurev-immunol-031210-101405","article-title":"The Inflammasome NLRs in Immunity, Inflammation, and Associated Diseases","volume":"29","author":"Davis","year":"2011","journal-title":"Annu. Rev. Immunol."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"335","DOI":"10.1146\/annurev.immunol.21.120601.141126","article-title":"Toll-like receptors","volume":"21","author":"Takeda","year":"2003","journal-title":"Annu. Rev. Immunol."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"467","DOI":"10.1111\/j.1478-3231.2006.01254.x","article-title":"Human intrahepatic biliary epithelial cells function in innate immunity by producing IL-6 and IL-8 via the TLR4-NF-\u03baB and -MAPK signaling pathways","volume":"26","author":"Yokoyama","year":"2006","journal-title":"Liver Int."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"497","DOI":"10.1038\/icb.2008.37","article-title":"The immunobiology of cholangiocytes","volume":"86","author":"Chen","year":"2008","journal-title":"Immunol. Cell Biol."},{"key":"ref_60","first-page":"88","article-title":"Toll-like receptor signaling","volume":"4","author":"Akira","year":"2004","journal-title":"Nature"},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"210","DOI":"10.1038\/nri2725","article-title":"NLRP3 inflammasome activation: The convergence of multiple signaling pathways on ROS production?","volume":"10","author":"Tschopp","year":"2010","journal-title":"Nat. Rev. Immunol."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"821","DOI":"10.1016\/j.cell.2010.01.040","article-title":"The Inflammasomes","volume":"140","author":"Schroder","year":"2010","journal-title":"Cell"},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"31","DOI":"10.1038\/nri1997","article-title":"Inflammasome adaptors and sensors: Intracellular regulators of infection and inflammation","volume":"7","author":"Mariathasan","year":"2007","journal-title":"Nat. Rev. Immunol."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"366","DOI":"10.1016\/j.ajpath.2016.10.010","article-title":"Nlrp3 Activation Induces Il-18 Synthesis and Affects the Epithelial Barrier Function in Reactive Cholangiocytes","volume":"187","author":"Maroni","year":"2017","journal-title":"Am. J. Pathol."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"276","DOI":"10.2741\/A923","article-title":"The role of cholangiocytes in the development of chronic inflammatory liver disease","volume":"7","author":"Adams","year":"2002","journal-title":"Front. Biosci."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"245","DOI":"10.1111\/j.1478-3231.2010.02367.x","article-title":"Significance of periductal Langerhans cells and biliary epithelial cell-derived macrophage inflammatory protein-3\u03b1 in the pathogenesis of primary biliary cirrhosis","volume":"31","author":"Harada","year":"2011","journal-title":"Liver Int."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"521","DOI":"10.1016\/S0092-8674(00)80438-9","article-title":"Identification and molecular characterization of fractalkine receptor CX3CR1, which mediates both leukocyte migration and adhesion","volume":"91","author":"Imai","year":"1997","journal-title":"Cell"},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"1627","DOI":"10.1016\/S0002-9440(10)65034-1","article-title":"The development and compensation of biliary cirrhosis in interleukin-6-deficient mice","volume":"156","author":"Ezure","year":"2000","journal-title":"Am. J. Pathol."},{"key":"ref_69","first-page":"205","article-title":"A review of the physiological and immunological functions of biliary epithelial cells: Targets for primary biliary cirrhosis, primary sclerosing cholangitis and drug-induced ductopenias","volume":"11","author":"Wu","year":"2004","journal-title":"Clin. Dev. Immunol."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"1245","DOI":"10.1136\/gut.34.9.1245","article-title":"Intercellular adhesion molecule-1 and MHC antigens on human intrahepatic bile duct cells: effect of pro-inflammatory cytokines","volume":"34","author":"Ayres","year":"1993","journal-title":"Gut"},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"550","DOI":"10.1016\/S0168-8278(98)80149-9","article-title":"Expression and cytokine regulation of immune recognition elements by normal human biliary epithelial and established liver cell lines in vitro","volume":"29","author":"Cruickshank","year":"1998","journal-title":"J. Hepatol."},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"533","DOI":"10.1002\/hep.22637","article-title":"Fibrogenesis in pediatric cholestatic liver disease: Role of taurocholate and hepatocyte-derived monocyte chemotaxis protein-1 in hepatic stellate cell recruitment","volume":"49","author":"Ramm","year":"2009","journal-title":"Hepatology"},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"660","DOI":"10.1136\/jclinpath-2011-200040","article-title":"Monocyte chemoattractant protein-1 derived from biliary innate immunity contributes to hepatic fibrogenesis","volume":"64","author":"Harada","year":"2011","journal-title":"J. Clin. Pathol."},{"key":"ref_74","first-page":"423","article-title":"Increased expression of monocyte chemotactic protein-1 during active hepatic fibrogenesis: correlation with monocyte infiltration","volume":"152","author":"Marra","year":"1998","journal-title":"Am. J. Pathol."},{"key":"ref_75","first-page":"1221","article-title":"Transforming growth factors beta 1 and beta 2 are differentially expressed in fibrotic liver disease","volume":"139","author":"Milani","year":"1991","journal-title":"Am. J. Pathol."},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"1246","DOI":"10.1002\/hep.21792","article-title":"Transforming growth factor-beta and substrate stiffness regulate portal fibroblast activation in culture","volume":"46","author":"Li","year":"2007","journal-title":"Hepatology"},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"682","DOI":"10.1016\/j.gastro.2005.05.050","article-title":"Cholangiocyte endothelin 1 and transforming growth factor \u03b21 production in rat experimental hepatopulmonary syndrome","volume":"129","author":"Luo","year":"2005","journal-title":"Gastroenterology"},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"13","DOI":"10.4137\/JCD.S2785","article-title":"Mechanisms of Biliary Damage","volume":"3","author":"Yang","year":"2010","journal-title":"J. Cell Death"},{"key":"ref_79","first-page":"942","article-title":"Taurocholic acid feeding prevents tumor necrosis factor-alpha-induced damage of cholangiocytes by a PI3K-mediated pathway","volume":"232","author":"Ueno","year":"2007","journal-title":"Exp. Biol. Med. (Maywood)"},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1172\/jci.insight.88747","article-title":"Preferential TNF \u03b1 signaling via TNFR2 regulates epithelial injury and duct obstruction in experimental biliary atresia","volume":"2","author":"Shivakumar","year":"2017","journal-title":"JCI Insight."},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"518","DOI":"10.1002\/hep.23019","article-title":"Repair-related activation of hedgehog signaling promotes cholangiocyte chemokine production","volume":"50","author":"Omenetti","year":"2009","journal-title":"Hepatology"},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"1275","DOI":"10.1136\/gut.2008.148619","article-title":"The hedgehog pathway regulates remodelling responses to biliary obstruction in rats","volume":"57","author":"Omenetti","year":"2008","journal-title":"Gut"},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"1091","DOI":"10.1002\/hep.21660","article-title":"Bile ductules and stromal cells express hedgehog ligands and\/or hedgehog target genes in primary biliary cirrhosis","volume":"45","author":"Jung","year":"2007","journal-title":"Hepatology"},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"98","DOI":"10.1016\/j.jhep.2007.07.032","article-title":"Sonic hedgehog is an autocrine viability factor for myofibroblastic hepatic stellate cells","volume":"48","author":"Yang","year":"2008","journal-title":"J. Hepatol."},{"key":"ref_85","first-page":"3331","article-title":"Hedgehog signaling regulates epithelial-mesenchymal transition during biliary fibrosis in rodents and humans","volume":"118","author":"Omenetti","year":"2008","journal-title":"J. Clin. Investig."},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"499","DOI":"10.1038\/labinvest.3700537","article-title":"Hedgehog-mediated mesenchymal-epithelial interactions modulate hepatic response to bile duct ligation","volume":"87","author":"Omenetti","year":"2007","journal-title":"Lab Investig."},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"2263","DOI":"10.1002\/hep.26993","article-title":"Cholangiocyte senescence by way of N-Ras activation is a characteristic of primary sclerosing cholangitis","volume":"59","author":"Tabibian","year":"2014","journal-title":"Hepatology"},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"261","DOI":"10.1053\/j.gastro.2004.04.009","article-title":"Regurgitation of bile acids from leaky bile ducts causes sclerosing cholangitis in Mdr2 (Abcb4) knockout mice","volume":"127","author":"Fickert","year":"2004","journal-title":"Gastroenterology"},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"30352","DOI":"10.1074\/jbc.M111.269464","article-title":"Cholangiocyte N-Ras protein mediates lipopolysaccharide-induced interleukin 6 secretion and proliferation","volume":"286","author":"Splinter","year":"2011","journal-title":"J. Biol. Chem."},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"825","DOI":"10.1016\/j.jhep.2016.05.030","article-title":"Senescence in chronic liver disease: Is the future in aging?","volume":"65","author":"Aravinthan","year":"2016","journal-title":"J. Hepatol."},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"11238","DOI":"10.1038\/s41598-018-29609-x","article-title":"The role of the secretin\/secretin receptor axis in inflammatory cholangiocyte communication via extracellular vesicles","volume":"8","author":"Sato","year":"2018","journal-title":"Sci. Rep."},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"689","DOI":"10.1007\/BF01296423","article-title":"Defense system in the biliary tract against bacterial infection","volume":"37","author":"Sung","year":"1992","journal-title":"Dig. Dis. Sci."},{"key":"ref_93","doi-asserted-by":"crossref","first-page":"373878","DOI":"10.1155\/2010\/373878","article-title":"Biliary innate immunity: Function and modulation","volume":"2010","author":"Harada","year":"2010","journal-title":"Mediat. Inflamm."},{"key":"ref_94","first-page":"925","article-title":"Peptide antibiotic human beta-defensin-1 and -2 contribute to antimicrobial defense of the intrahepatic biliary tree","volume":"40","author":"Harada","year":"2004","journal-title":"Hepatology"},{"key":"ref_95","doi-asserted-by":"crossref","first-page":"480","DOI":"10.1111\/liv.13009","article-title":"The enteric microbiome in hepatobiliary health and disease","volume":"36","author":"Tabibian","year":"2016","journal-title":"Liver Int."},{"key":"ref_96","doi-asserted-by":"crossref","first-page":"532","DOI":"10.1177\/2050640616663453","article-title":"Elevated trimethylamine-N-oxide (TMAO) is associated with poor prognosis in primary sclerosing cholangitis patients with normal liver function","volume":"5","author":"Kummen","year":"2017","journal-title":"United Eur. Gastroenterol. J."},{"key":"ref_97","doi-asserted-by":"crossref","first-page":"275","DOI":"10.1016\/j.jcmgh.2015.04.003","article-title":"The Gut Microbiota and Liver Disease","volume":"1","author":"Llorente","year":"2015","journal-title":"Cell. Mol. Gastroenterol. Hepatol."},{"key":"ref_98","doi-asserted-by":"crossref","first-page":"2035","DOI":"10.1136\/gutjnl-2016-312729","article-title":"Gut microbiome and liver diseases","volume":"65","author":"Tilg","year":"2016","journal-title":"Gut"},{"key":"ref_99","doi-asserted-by":"crossref","first-page":"935","DOI":"10.1111\/j.1478-3231.2006.01325.x","article-title":"Endotoxin tolerance in human intrahepatic biliary epithelial cells is induced by upregulation of IRAK-M","volume":"26","author":"Harada","year":"2006","journal-title":"Liver Int."},{"key":"ref_100","doi-asserted-by":"crossref","first-page":"1092","DOI":"10.1016\/j.cgh.2011.08.027","article-title":"Inflammatory bowel disease is associated with poor outcomes of patients with primary sclerosing cholangitis","volume":"9","author":"Ngu","year":"2011","journal-title":"Clin. Gastroenterol. Hepatol."},{"key":"ref_101","doi-asserted-by":"crossref","first-page":"389537","DOI":"10.1155\/2013\/389537","article-title":"Role of the microbiota and antibiotics in primary sclerosing cholangitis","volume":"2013","author":"Tabibian","year":"2013","journal-title":"Biomed. Res. Int."},{"key":"ref_102","doi-asserted-by":"crossref","first-page":"69","DOI":"10.1097\/00042737-200601000-00012","article-title":"The role of dominant stenoses in bacterial infections of bile ducts in primary sclerosing cholangitis","volume":"18","author":"Pohl","year":"2006","journal-title":"Eur. J. Gastroenterol. Hepatol."},{"key":"ref_103","doi-asserted-by":"crossref","first-page":"149","DOI":"10.1016\/j.jhep.2009.01.023","article-title":"Influence of dominant bile duct stenoses and biliary infections on outcome in primary sclerosing cholangitis","volume":"51","author":"Rudolph","year":"2009","journal-title":"J. Hepatol."},{"key":"ref_104","doi-asserted-by":"crossref","first-page":"9","DOI":"10.1016\/S0168-8278(00)80153-1","article-title":"Amplification and sequence analysis of partial bacterial 16S ribosomal RNA gene in gallbladder bile from patients with primary biliary cirrhosis","volume":"33","author":"Hiramatsu","year":"2000","journal-title":"J. Hepatol."},{"key":"ref_105","doi-asserted-by":"crossref","first-page":"330","DOI":"10.1002\/lt.21679","article-title":"A re-evaluation of the risk factors for the recurrence of primary sclerosing cholangitis in liver allografts","volume":"15","author":"Alabraba","year":"2009","journal-title":"Liver Transpl."},{"key":"ref_106","doi-asserted-by":"crossref","first-page":"1943","DOI":"10.1016\/S0140-6736(02)11861-7","article-title":"Risk factors for recurrence of primary sclerosing cholangitis of liver allograft","volume":"360","author":"Vera","year":"2002","journal-title":"Lancet"},{"key":"ref_107","doi-asserted-by":"crossref","first-page":"604","DOI":"10.1111\/apt.12232","article-title":"Randomised clinical trial: vancomycin or metronidazole in patients with primary sclerosing cholangitis\u2014A pilot study","volume":"37","author":"Tabibian","year":"2013","journal-title":"Aliment. Pharmacol. Ther."},{"key":"ref_108","doi-asserted-by":"crossref","first-page":"129","DOI":"10.1080\/08916930600623841","article-title":"Lipoteichoic acid may affect the pathogenesis of bile duct damage in primary biliary cirrhosis","volume":"39","author":"Haruta","year":"2006","journal-title":"Autoimmunity"},{"key":"ref_109","doi-asserted-by":"crossref","first-page":"577","DOI":"10.1038\/labinvest.2010.40","article-title":"Long-term bacterial exposure can trigger nonsuppurative destructive cholangitis associated with multifocal epithelial inflammation","volume":"90","author":"Haruta","year":"2010","journal-title":"Lab Investig."},{"key":"ref_110","doi-asserted-by":"crossref","first-page":"1102","DOI":"10.1053\/j.gastro.2009.11.046","article-title":"Genome-Wide Association Analysis in Primary Sclerosing Cholangitis","volume":"138","author":"Karlsen","year":"2010","journal-title":"Gastroenterology"},{"key":"ref_111","doi-asserted-by":"crossref","first-page":"17","DOI":"10.1038\/ng.728","article-title":"Genome-wide association analysis in primary sclerosing cholangitis identifies two non-HLA susceptibility loci","volume":"43","author":"Melum","year":"2011","journal-title":"Nat. Genet."},{"key":"ref_112","doi-asserted-by":"crossref","first-page":"670","DOI":"10.1038\/ng.2616","article-title":"Dense genotyping of immune-related disease regions identifies nine new risk loci for primary sclerosing cholangitis","volume":"45","author":"Liu","year":"2013","journal-title":"Nat. Genet."},{"key":"ref_113","doi-asserted-by":"crossref","first-page":"182","DOI":"10.1007\/s12016-014-8423-1","article-title":"Fucosyltransferase 2: A Genetic Risk Factor for Primary Sclerosing Cholangitis and Crohn\u2019s Disease\u2014A Comprehensive Review","volume":"48","author":"Maroni","year":"2015","journal-title":"Clin. Rev. Allergy Immunol."},{"key":"ref_114","doi-asserted-by":"crossref","first-page":"2372","DOI":"10.1016\/j.cgh.2015.07.014","article-title":"Inflammation but Not Biliary Obstruction Is Associated with Carbohydrate Antigen 19-9 Levels in Patients With Primary Sclerosing Cholangitis","volume":"13","author":"Wannhoff","year":"2015","journal-title":"Clin. Gastroenterol. Hepatol"},{"key":"ref_115","doi-asserted-by":"crossref","first-page":"542","DOI":"10.1002\/hep.29029","article-title":"Knockout of the primary sclerosing cholangitis-risk gene Fut2 causes liver disease in mice","volume":"66","author":"Maroni","year":"2017","journal-title":"Hepatology"},{"key":"ref_116","doi-asserted-by":"crossref","first-page":"185","DOI":"10.1002\/hep.27927","article-title":"Absence of the intestinal microbiota exacerbates hepatobiliary disease in a murine model of primary sclerosing cholangitis","volume":"63","author":"Tabibian","year":"2016","journal-title":"Hepatology"},{"key":"ref_117","doi-asserted-by":"crossref","first-page":"382","DOI":"10.1016\/j.jhep.2016.09.020","article-title":"The gut microbiota contributes to a mouse model of spontaneous bile duct inflammation","volume":"66","author":"Schrumpf","year":"2017","journal-title":"J. Hepatol."},{"key":"ref_118","doi-asserted-by":"crossref","first-page":"1313","DOI":"10.1172\/JCI115996","article-title":"Degradation of endogenous bacterial cell wall polymers by the muralytic enzyme mutanolysin prevents hepatobiliary injury in genetically susceptible rats with experimental intestinal bacterial overgrowth","volume":"90","author":"Lichtman","year":"1992","journal-title":"J. Clin. Investig."},{"key":"ref_119","doi-asserted-by":"crossref","first-page":"515","DOI":"10.1016\/S1076-6332(05)80410-6","article-title":"A microcholangiographic study of liver disease models in rats","volume":"2","author":"Lichtman","year":"1995","journal-title":"Acad. Radiol."},{"key":"ref_120","doi-asserted-by":"crossref","first-page":"631","DOI":"10.1007\/BF02365447","article-title":"Small duct cholangitis induced by N-formyl l-methionine l-leucine l-tyrosine in rats","volume":"29","author":"Yamada","year":"1994","journal-title":"J. Gastroenterol."},{"key":"ref_121","doi-asserted-by":"crossref","first-page":"15.25.1","DOI":"10.1002\/0471142735.im1525s104","article-title":"Dextran sulfate sodium (DSS)-induced colitis in mice","volume":"104","author":"Chassaing","year":"2014","journal-title":"Curr. Protoc. Immunol."},{"key":"ref_122","doi-asserted-by":"crossref","first-page":"6016","DOI":"10.3748\/wjg.v23.i33.6016","article-title":"Dextran sodium sulfate colitis murine model: An indispensable tool for advancing our understanding of inflammatory bowel diseases pathogenesis","volume":"23","author":"Eichele","year":"2017","journal-title":"World J. Gastroenterol."},{"key":"ref_123","doi-asserted-by":"crossref","first-page":"437","DOI":"10.1124\/dmd.32.4.437","article-title":"Endotoxin-mediated disturbance of hepatic cytochrome P450 function and development of endotoxin tolerance in the rat model of dextran sulfate sodium-induced experimental colitis","volume":"32","author":"Masubuchi","year":"2004","journal-title":"Drug Metab. Dispos."},{"key":"ref_124","doi-asserted-by":"crossref","first-page":"1498","DOI":"10.1053\/j.gastro.2011.06.052","article-title":"Loss of CFTR affects biliary epithelium innate immunity and causes TLR4NF-\u03baB-mediated inflammatory response in mice","volume":"141","author":"Fiorotto","year":"2011","journal-title":"Gastroenterology"},{"key":"ref_125","first-page":"626","article-title":"The relationship between the gut microbiota and liver disease","volume":"11","author":"Bajaj","year":"2015","journal-title":"Gastroenterol. Hepatol."},{"key":"ref_126","doi-asserted-by":"crossref","first-page":"1823","DOI":"10.1042\/BCJ20160510","article-title":"Introduction to the human gut microbiota","volume":"474","author":"Thursby","year":"2017","journal-title":"Biochem. J."},{"key":"ref_127","doi-asserted-by":"crossref","first-page":"1681","DOI":"10.1136\/gutjnl-2015-311004","article-title":"Primary sclerosing cholangitis is characterised by intestinal dysbiosis independent from IBD","volume":"65","author":"Sabino","year":"2016","journal-title":"Gut"},{"key":"ref_128","doi-asserted-by":"crossref","first-page":"59","DOI":"10.1038\/nature13568","article-title":"Alterations of the human gut microbiome in liver cirrhosis","volume":"513","author":"Qin","year":"2014","journal-title":"Nature"},{"key":"ref_129","doi-asserted-by":"crossref","first-page":"562","DOI":"10.1002\/hep.24423","article-title":"Characterization of fecal microbial communities in patients with liver cirrhosis","volume":"54","author":"Chen","year":"2011","journal-title":"Hepatology"},{"key":"ref_130","doi-asserted-by":"crossref","first-page":"382","DOI":"10.1016\/j.chom.2014.02.005","article-title":"The treatment-naive microbiome in new-onset Crohn\u2019s disease","volume":"15","author":"Gevers","year":"2014","journal-title":"Cell Host Microbe"},{"key":"ref_131","doi-asserted-by":"crossref","first-page":"959","DOI":"10.1053\/j.gastro.2011.05.035","article-title":"Enterococcus faecalis metalloprotease compromises epithelial barrier and contributes to intestinal inflammation","volume":"141","author":"Steck","year":"2011","journal-title":"Gastroenterology"},{"key":"ref_132","doi-asserted-by":"crossref","first-page":"611","DOI":"10.1136\/gutjnl-2015-310500","article-title":"The gut microbial profile in patients with primary sclerosing cholangitis is distinct from patients with ulcerative colitis without biliary disease and healthy controls","volume":"66","author":"Kummen","year":"2017","journal-title":"Gut"},{"key":"ref_133","doi-asserted-by":"crossref","first-page":"1344","DOI":"10.1136\/gutjnl-2016-312533","article-title":"Characterisation of the fecal microbiota in Japanese patients with paediatric-onset primary sclerosing cholangitis","volume":"66","author":"Iwasawa","year":"2017","journal-title":"Gut"},{"key":"ref_134","doi-asserted-by":"crossref","unstructured":"Li, B., Selmi, C., Tang, R., Gershwin, M.E., and Ma, X. (2018). The microbiome and autoimmunity: a paradigm from the gut\u2013liver axis. Cell Mol. Immunol.","DOI":"10.1038\/cmi.2018.7"},{"key":"ref_135","doi-asserted-by":"crossref","first-page":"2272","DOI":"10.1111\/1462-2920.13401","article-title":"Alterations and correlations of the gut microbiome, metabolism and immunity in patients with primary biliary cirrhosis","volume":"18","author":"Lv","year":"2016","journal-title":"Environ. Microbiol."},{"key":"ref_136","doi-asserted-by":"crossref","first-page":"534","DOI":"10.1136\/gutjnl-2016-313332","article-title":"Gut microbial profile is altered in primary biliary cholangitis and partially restored after UDCA therapy","volume":"67","author":"Tang","year":"2018","journal-title":"Gut"},{"key":"ref_137","doi-asserted-by":"crossref","first-page":"342","DOI":"10.1093\/ecco-jcc\/jju023","article-title":"The mucosa-associated microbiota of PSC patients is characterized by low diversity and low abundance of uncultured Clostridiales II","volume":"9","author":"Rossen","year":"2015","journal-title":"J. Crohns Colitis"},{"key":"ref_138","doi-asserted-by":"crossref","first-page":"4344","DOI":"10.1038\/ncomms5344","article-title":"Tipping elements in the human intestinal ecosystem","volume":"5","author":"Lahti","year":"2014","journal-title":"Nat. Commun."},{"key":"ref_139","doi-asserted-by":"crossref","first-page":"790","DOI":"10.1111\/apt.13552","article-title":"The features of mucosa-associated microbiota in primary sclerosing cholangitis","volume":"43","author":"Torres","year":"2016","journal-title":"Aliment. Pharmacol. Ther."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/19\/10\/3003\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T15:23:33Z","timestamp":1760196213000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/19\/10\/3003"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2018,10,1]]},"references-count":139,"journal-issue":{"issue":"10","published-online":{"date-parts":[[2018,10]]}},"alternative-id":["ijms19103003"],"URL":"https:\/\/doi.org\/10.3390\/ijms19103003","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2018,10,1]]}}}