The gut microbiota contributes to a mouse model of spontaneous bile duct inflammation

JOURNAL OF HEPATOLOGY

卷:66

Article

Schrumpf, Elisabeth^1,2,3,4  Kummen, Martin^1,2,3,4  Valestrand, Laura^1,2,3,4,5  Greiner, Thomas U.^6,7  Holm, Kristian^1,2,3,4  Arulampalam, Velmurugesan^8,9  Reims, Henrik M.¹⁰  Baines, John^11,12  Backhed, Fredrik^6,7  Karlsen, Tom H.^1,2,3,4,5  Blumberg, Richard S.¹³  Hov, Johannes R.^1,2,3,4,5  Melum, Espen^1,2,3,4,5 

[1] Natl Hosp Norway, Oslo Univ Hosp, Div Surg Inflammatory Med & Transplantat, Norwegian PSC Res Ctr, Postboks 4950 Nydalen, N-0424 Oslo, Norway

[2] Univ Oslo, KG Jebsen Inflammat Res Ctr, Oslo, Norway

[3] Univ Oslo, Inst Clin Med, Oslo, Norway

[4] Natl Hosp Norway, Oslo Univ Hosp, Div Surg Inflammatory Med & Transplantat, Internal Med Res Inst, Oslo, Norway

[5] Natl Hosp Norway, Oslo Univ Hosp, Div Surg Inflammatory Med & Transplantat Surg & T, Sect Gastroenterol,Div Surg, Oslo, Norway

[6] Univ Gothenburg, Inst Med, Dept Mol & Clin Med, Wallenberg Lab, Gothenburg, Sweden

[7] Univ Gothenburg, Inst Med, Dept Mol & Clin Med, Sahlgrenska Ctr Cardiovasc & Metab Res, Gothenburg, Sweden

[8] Karolinska Inst, Dept Comparat Med, CFGR, Stockholm, Sweden

[9] Karolinska Inst, Dept Microbiol Tumor & Cell Biol MTC, Stockholm, Sweden

[10] Natl Hosp Norway, Oslo Univ Hosp, Dept Pathol, Oslo, Norway

[11] Max Planck Inst Evolutionary Biol, Plon, Germany

[12] Christian Albrechts Univ Kiel, Inst Expt Med, Kiel, Germany

[13] Harvard Med Sch, Brigham & Womens Hosp, Dept Med, Div Gastroenterol Hepatol & Endoscopy, Boston, MA USA

关键词: Germ free;    Microbiota;    NOD.c3c4;    PBC;    PSC;    Mice;    inbred NOD;    Inflammation;    Mucous membrane;    Gastrointestinal microbiome;    Liver;    Antibacterial agents;   

DOI  :  10.1016/j.jhep.2016.09.020

来源: Elsevier

【 摘 要 】

Background & Aims: 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. Methods: 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. Results: 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. Conclusions: 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 micro biota contributes to disease in this murine model of biliary inflammation. Lay summary: 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. (C) 2016 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.

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