title: The gut microbiota contributes to a mouse model of spontaneous bile duct inflammation.
abstract: A strong association between human inflammatory biliary diseases and gut inflammation has led to the hypothesis that gut microbes and lymphocytes activated in the intestine play a role in biliary inflammation. The NOD.c3c4 mouse model develops spontaneous biliary inflammation in extra- and intrahepatic bile ducts. We aimed to clarify the role of the gut microbiota in the biliary disease of NOD.c3c4 mice.
  
  
  
  We sampled cecal content and mucosa from conventionally raised (CONV-R) NOD.c3c4 and NOD control mice, extracted DNA and performed 16S rRNA sequencing. NOD.c3c4 mice were rederived into a germ free (GF) facility and compared with CONV-R NOD.c3c4 mice. NOD.c3c4 mice were also co-housed with NOD mice and received antibiotics from weaning.
  
  
  
  The gut microbial profiles of mice with and without biliary disease were different both before and after rederivation (unweighted UniFrac-distance). GF NOD.c3c4 mice had less distended extra-hepatic bile ducts than CONV-R NOD.c3c4 mice, while antibiotic treated mice showed reduction of biliary infarcts. GF animals also showed a reduction in liver weight compared with CONV-R NOD.c3c4 mice, and this was also observed in antibiotic treated NOD.c3c4 mice. Co-housing of NOD and NOD.c3c4 mice indicated that the biliary phenotype was neither transmissible nor treatable by co-housing with healthy mice.
  
  
  
  NOD.c3c4 and NOD control mice show marked differences in the gut microbiota. GF NOD.c3c4 mice develop a milder biliary affection compared with conventionally raised NOD.c3c4 mice. Our findings suggest that the intestinal microbiota contributes to disease in this murine model of biliary inflammation.
  
  
  
  Mice with liver disease have a gut microflora (microbiota) that differs substantially from normal mice. In a normal environment, these mice spontaneously develop disease in their bile ducts. However, when these mice, are raised in an environment devoid of bacteria, the disease in the bile ducts diminishes. Overall this clearly indicates that the bacteria in the gut (the gut microbiota) influences the liver disease in these mice.
authors.affiliation: Norwegian PSC Research Center, Division of Surgery, Inflammatory Medicine and Transplantation, Oslo University Hospital, Rikshospitalet, Oslo, Norway; K.G. Jebsen Inflammation Research Centre and Institute of Clinical Medicine, University of Oslo, Oslo, Norway; Research Institute of Internal Medicine, Division of Surgery, Inflammatory Medicine and Transplantation, Oslo University Hospital, Rikshospitalet, Oslo, Norway.
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Schrumpf
authors.affiliation: Norwegian PSC Research Center, Division of Surgery, Inflammatory Medicine and Transplantation, Oslo University Hospital, Rikshospitalet, Oslo, Norway; K.G. Jebsen Inflammation Research Centre and Institute of Clinical Medicine, University of Oslo, Oslo, Norway; Research Institute of Internal Medicine, Division of Surgery, Inflammatory Medicine and Transplantation, Oslo University Hospital, Rikshospitalet, Oslo, Norway.
authors.forename: Martin
authors.initials: M
authors.lastname: Kummen
authors.affiliation: Norwegian PSC Research Center, Division of Surgery, Inflammatory Medicine and Transplantation, Oslo University Hospital, Rikshospitalet, Oslo, Norway; K.G. Jebsen Inflammation Research Centre and Institute of Clinical Medicine, University of Oslo, Oslo, Norway; Research Institute of Internal Medicine, Division of Surgery, Inflammatory Medicine and Transplantation, Oslo University Hospital, Rikshospitalet, Oslo, Norway; Section of Gastroenterology, Division of Surgery, Inflammatory Medicine and Transplantation, Surgery, and Transplantation, Oslo University Hospital, Rikshospitalet, Oslo, Norway.
authors.forename: Laura
authors.initials: L
authors.lastname: Valestrand
authors.affiliation: The Wallenberg Laboratory and Sahlgrenska Center for Cardiovascular and Metabolic Research, Department of Molecular and Clinical Medicine, Institute of Medicine, University of Gothenburg, Gothenburg, Sweden.
authors.forename: Thomas U
authors.initials: TU
authors.lastname: Greiner
authors.affiliation: Norwegian PSC Research Center, Division of Surgery, Inflammatory Medicine and Transplantation, Oslo University Hospital, Rikshospitalet, Oslo, Norway; K.G. Jebsen Inflammation Research Centre and Institute of Clinical Medicine, University of Oslo, Oslo, Norway; Research Institute of Internal Medicine, Division of Surgery, Inflammatory Medicine and Transplantation, Oslo University Hospital, Rikshospitalet, Oslo, Norway.
authors.forename: Kristian
authors.initials: K
authors.lastname: Holm
authors.affiliation: Core Facility for Germfree Research (CFGR), Department of Comparative Medicine and Department of Microbiology, Tumor and Cell Biology (MTC), Karolinska Institutet, Stockholm, Sweden.
authors.forename: Velmurugesan
authors.initials: V
authors.lastname: Arulampalam
authors.affiliation: Department of Pathology, Oslo University Hospital, Rikshospitalet, Oslo, Norway.
authors.forename: Henrik M
authors.initials: HM
authors.lastname: Reims
authors.affiliation: Max Planck Institute for Evolutionary Biology, Plön, Germany; Institute for Experimental Medicine, Christian-Albrechts-University of Kiel, Kiel, Germany.
authors.forename: John
authors.initials: J
authors.lastname: Baines
authors.affiliation: The Wallenberg Laboratory and Sahlgrenska Center for Cardiovascular and Metabolic Research, Department of Molecular and Clinical Medicine, Institute of Medicine, University of Gothenburg, Gothenburg, Sweden.
authors.forename: Fredrik
authors.initials: F
authors.lastname: Bäckhed
authors.affiliation: Norwegian PSC Research Center, Division of Surgery, Inflammatory Medicine and Transplantation, Oslo University Hospital, Rikshospitalet, Oslo, Norway; K.G. Jebsen Inflammation Research Centre and Institute of Clinical Medicine, University of Oslo, Oslo, Norway; Research Institute of Internal Medicine, Division of Surgery, Inflammatory Medicine and Transplantation, Oslo University Hospital, Rikshospitalet, Oslo, Norway; Section of Gastroenterology, Division of Surgery, Inflammatory Medicine and Transplantation, Surgery, and Transplantation, Oslo University Hospital, Rikshospitalet, Oslo, Norway.
authors.forename: Tom H
authors.initials: TH
authors.lastname: Karlsen
authors.affiliation: Division of Gastroenterology, Hepatology and Endoscopy, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
authors.forename: Richard S
authors.initials: RS
authors.lastname: Blumberg
authors.affiliation: Norwegian PSC Research Center, Division of Surgery, Inflammatory Medicine and Transplantation, Oslo University Hospital, Rikshospitalet, Oslo, Norway; K.G. Jebsen Inflammation Research Centre and Institute of Clinical Medicine, University of Oslo, Oslo, Norway; Research Institute of Internal Medicine, Division of Surgery, Inflammatory Medicine and Transplantation, Oslo University Hospital, Rikshospitalet, Oslo, Norway; Section of Gastroenterology, Division of Surgery, Inflammatory Medicine and Transplantation, Surgery, and Transplantation, Oslo University Hospital, Rikshospitalet, Oslo, Norway.
authors.forename: Johannes R
authors.initials: JR
authors.lastname: Hov
authors.affiliation: Norwegian PSC Research Center, Division of Surgery, Inflammatory Medicine and Transplantation, Oslo University Hospital, Rikshospitalet, Oslo, Norway; K.G. Jebsen Inflammation Research Centre and Institute of Clinical Medicine, University of Oslo, Oslo, Norway; Research Institute of Internal Medicine, Division of Surgery, Inflammatory Medicine and Transplantation, Oslo University Hospital, Rikshospitalet, Oslo, Norway; Section of Gastroenterology, Division of Surgery, Inflammatory Medicine and Transplantation, Surgery, and Transplantation, Oslo University Hospital, Rikshospitalet, Oslo, Norway. Electronic address: espen.melum@medisin.uio.no.
authors.forename: Espen
authors.initials: E
authors.lastname: Melum
mesh_terms: D000818:Animals; D001652:Bile Ducts / Q000276:immunology; D002761:Cholangitis / Q000276:immunology*; D004195:Disease Models, Animal; D000069196:Gastrointestinal Microbiome / Q000502:physiology*; D007422:Intestines / Q000276:immunology / Q000382:microbiology; D008213:Lymphocyte Activation / Q000502:physiology*; D051379:Mice
keywords: Anti-bacterial agents; Gastrointestinal microbiome; Germ free; Inflammation; Liver; Mice; Microbiota; Mucous membrane; NOD.c3c4; PBC; PSC; inbred NOD