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However, the functional implications for intestinal microbiota and inflammasome-mediated innate immune response in CLD remain elusive. Here we investigated the functional role of gut\u2013liver crosstalk for CLD in the murine Mdr2 knockout\n                      <jats:italic>\n                        (Mdr2\n                        <jats:sup>\u2212\/\u2212<\/jats:sup>\n                        )\n                      <\/jats:italic>\n                      model resembling human primary sclerosing cholangitis (PSC).\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Design<\/jats:title>\n                    <jats:p>\n                      Male\n                      <jats:italic>Mdr2<\/jats:italic>\n                      <jats:sup>\u2212\/\u2212<\/jats:sup>\n                      ,\n                      <jats:italic>\n                        Mdr2\n                        <jats:sup>\u2212\/\u2212<\/jats:sup>\n                      <\/jats:italic>\n                      crossed with hepatocyte-specific deletion of caspase-8 (\n                      <jats:italic>\n                        Mdr2\n                        <jats:sup>\u2212\/\u2212<\/jats:sup>\n                      <\/jats:italic>\n                      \/Casp8\n                      <jats:sup>\u2206hepa<\/jats:sup>\n                      ) and wild-type (WT) control mice were housed for 8 or 52\u2009weeks, respectively, to characterise the impact of Mdr2 deletion on liver and gut including bile acid and microbiota profiling. To block caspase activation, a pan-caspase inhibitor (IDN-7314) was administered. Finally, the functional role of\n                      <jats:italic>\n                        Mdr2\n                        <jats:sup>\u2212\/\u2212<\/jats:sup>\n                      <\/jats:italic>\n                      -associated intestinal dysbiosis was studied by microbiota transfer experiments.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      <jats:italic>\n                        Mdr2\n                        <jats:sup>\u2212\/\u2212<\/jats:sup>\n                      <\/jats:italic>\n                      mice displayed an unfavourable intestinal microbiota signature and pronounced NLRP3 inflammasome activation within the gut\u2013liver axis. Intestinal dysbiosis in\n                      <jats:italic>\n                        Mdr2\n                        <jats:sup>\u2212\/\u2212<\/jats:sup>\n                      <\/jats:italic>\n                      mice prompted intestinal barrier dysfunction and increased bacterial translocation amplifying the hepatic NLRP3-mediated innate immune response. Transfer of\n                      <jats:italic>\n                        Mdr2\n                        <jats:sup>\u2212\/\u2212<\/jats:sup>\n                      <\/jats:italic>\n                      microbiota into healthy WT control mice induced significant liver injury in recipient mice, highlighting the causal role of intestinal dysbiosis for disease progression. Strikingly, IDN-7314 dampened inflammasome activation, ameliorated liver injury, reversed serum bile acid profile and cholestasis-associated microbiota signature.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>MDR2-associated cholestasis triggers intestinal dysbiosis. In turn, translocation of endotoxin into the portal vein and subsequent NLRP3 inflammasome activation contribute to higher liver injury. This process does not essentially depend on caspase-8 in hepatocytes, but can be blocked by IDN-7314.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1136\/gutjnl-2018-316670","type":"journal-article","created":{"date-parts":[[2019,3,14]],"date-time":"2019-03-14T17:15:25Z","timestamp":1552583725000},"page":"1477-1492","update-policy":"https:\/\/doi.org\/10.1136\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":171,"title":["Intestinal dysbiosis augments liver disease progression via NLRP3 in a murine model of primary sclerosing cholangitis"],"prefix":"10.1136","volume":"68","author":[{"given":"Lijun","family":"Liao","sequence":"first","affiliation":[{"name":"Department of Medicine III, University Hospital RWTH Aachen, Aachen, Germany"},{"name":"Department of Anesthesiology and Pain Management, Tongji University, Shanghai, Shanghai, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0047-3794","authenticated-orcid":false,"given":"Kai Markus","family":"Schneider","sequence":"additional","affiliation":[{"name":"Department of Medicine III, University Hospital RWTH Aachen, Aachen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eric J C","family":"Galvez","sequence":"additional","affiliation":[{"name":"Department of Microbial Immune Regulation, Helmholtz Centre for Infection Research, Braunschweig, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mick","family":"Frissen","sequence":"additional","affiliation":[{"name":"Department of Medicine III, University Hospital RWTH Aachen, Aachen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7347-3085","authenticated-orcid":false,"given":"Hanns-Ulrich","family":"Marschall","sequence":"additional","affiliation":[{"name":"Wallenberg Laboratory, Department of Molecular and Clinical Medicine, Institute of Medicine, Sahlgrenska Academy, Gothenburg, Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Huan","family":"Su","sequence":"additional","affiliation":[{"name":"Department of Medicine III, University Hospital RWTH Aachen, Aachen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maximilian","family":"Hatting","sequence":"additional","affiliation":[{"name":"Department of Medicine III, University Hospital RWTH Aachen, Aachen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Annika","family":"Wahlstr\u00f6m","sequence":"additional","affiliation":[{"name":"Department of Molecular and Clinical Medicine, 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Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Henning W","family":"Zimmermann","sequence":"additional","affiliation":[{"name":"Department of Medicine III, University Hospital RWTH Aachen, Aachen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8888-1030","authenticated-orcid":false,"given":"Thomas","family":"Longerich","sequence":"additional","affiliation":[{"name":"Institute of Pathology, UniversitatsKlinikum Heidelberg, Heidelberg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Till","family":"Strowig","sequence":"additional","affiliation":[{"name":"Department of Microbial Immune Regulation, Helmholtz Centre for Infection Research, Braunschweig, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christian","family":"Liedtke","sequence":"additional","affiliation":[{"name":"Department of Medicine III, University Hospital RWTH Aachen, Aachen, 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