You are here

Article Text

Article menu
Download PDFPDF
Gut microbiota
Original research
Alterations of the bile microbiome in primary sclerosing cholangitis
  1. Timur Liwinski1,
  2. Roman Zenouzi1,
  3. Clara John2,
  4. Hanno Ehlken3,
  5. Malte C Rühlemann4,
  6. Corinna Bang5,
  7. Stefan Groth3,
  8. Wolfgang Lieb6,
  9. Marcus Kantowski3,
  10. Nils Andersen7,
  11. Guido Schachschal3,
  12. Tom H Karlsen8,9,
  13. Johannes R Hov9,10,
  14. Thomas Rösch7,
  15. Ansgar W Lohse7,
  16. Joerg Heeren2,
  17. Andre Franke5,
  18. Christoph Schramm1,11
  1. 1 1st Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
  2. 2 Biochemistry and Molecular Cell Biology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
  3. 3 Department of Interdisciplinary Endoscopy, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
  4. 4 Christian-Albrechts-Universität zu Kiel, Institute of Clinical Molecular Biology, Kiel, Germany
  5. 5 Institute for Clinical Molecular Biology, Christian Albrechts University of Kiel, Kiel, Germany
  6. 6 Institute of Epidemiology and Biobank PopGen, Christian-Albrechts-University of Kiel, Kiel, Germany
  7. 7 University Medical Center Hamburg-Eppendorf, Hamburg, Germany
  8. 8 Department of Transplantation Medicine, Oslo University Hospital, Oslo, Norway
  9. 9 Institute of Clinical Medicine, University of Oslo, Oslo, Norway
  10. 10 Norwegian PSC Research Center, Department of Transplantation Medicine, Oslo University Hospital, Oslo, Norway
  11. 11 Martin Zeitz Center for Rare Diseases, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
  1. Correspondence to Professor Christoph Schramm, Department of Medicine and Martin Zeitz Center for Rare Diseases, University Medical Center Hamburg-Eppendorf, Hamburg 20246, Germany; c.schramm{at}uke.de

Abstract

Background Patients with primary sclerosing cholangitis (PSC) display an altered colonic microbiome compared with healthy controls. However, little is known on the bile duct microbiome and its interplay with bile acid metabolism in PSC.

Methods Patients with PSC (n=43) and controls without sclerosing cholangitis (n=22) requiring endoscopic retrograde cholangiography were included prospectively. Leading indications in controls were sporadic choledocholithiasis and papillary adenoma. A total of 260 biospecimens were collected from the oral cavity, duodenal fluid and mucosa and ductal bile. Microbiomes of the upper alimentary tract and ductal bile were profiled by sequencing the 16S-rRNA-encoding gene (V1–V2). Bile fluid bile acid composition was measured by high-performance liquid chromatography mass spectrometry and validated in an external cohort (n=20).

Results The bile fluid harboured a diverse microbiome that was distinct from the oral cavity, the duodenal fluid and duodenal mucosa communities. The upper alimentary tract microbiome differed between PSC patients and controls. However, the strongest differences between PSC patients and controls were observed in the ductal bile fluid, including reduced biodiversity (Shannon entropy, p=0.0127) and increase of pathogen Enterococcus faecalis (FDR=4.18×10−5) in PSC. Enterococcus abundance in ductal bile was strongly correlated with concentration of the noxious secondary bile acid taurolithocholic acid (r=0.60, p=0.0021).

Conclusion PSC is characterised by an altered microbiome of the upper alimentary tract and bile ducts. Biliary dysbiosis is linked with increased concentrations of the proinflammatory and potentially cancerogenic agent taurolithocholic acid.

  • primary sclerosing cholangitis
  • enteric bacterial microflora
  • bile acid metabolism
  • anti-bacterial mucosal immunity
  • biliary endoscopy

https://doi.org/10.1136/gutjnl-2019-318416

Statistics from Altmetric.com

    Request Permissions

    If you wish to reuse any or all of this article please use the link below which will take you to the Copyright Clearance Center’s RightsLink service. You will be able to get a quick price and instant permission to reuse the content in many different ways.

    View Full Text

    Footnotes

    • TL and RZ contributed equally.

    • Contributors TL performed all statistical analyses, prepared the graphics, interpreted the data and wrote the manuscript. RZ contributed to the acquisition and interpretation of the data and contributed to critical revision of intellectual content. CJ performed the bile acid assay and contributed to critical revision of intellectual content. HE contributed to acquisition of the data and contributed to critical revision of intellectual content. MCR gave bioinformatic and statistical advice and contributed to critical revision of intellectual content. CB was responsible for next-generation sequencing and contributed to critical revision of intellectual content. HE, SG, GS, MK, TR, NA, AWL and CS performed endoscopic retrograde cholangiography and acquisition of bile samples. THK and JRH contributed external validation data and contributed to critical revision of intellectual content. WL, JH and AWL contributed to critical revision of intellectual content. AF and CS planned and supervised the study, contributed to critical revision of intellectual content and critically revised the manuscript.

    • Funding This work was supported by the Deutsche Forschungsgemeinschaft (DFG) ‘Clinical Research Group 306’ (KFO306) ─ Primary Sclerosing Cholangitis. Furthermore, the study was supported by the Deutsche Forschungsgemeinschaft (DFG) Cluster of Excellence ‘Inflammation at Interfaces’ (http://www.inflammation-at-interfaces.de, no: EXC306 and EXC306/2), the Collaborative Research Center 1182 ‘Origin and Function of Metaorganisms’ (www.metaorganism-research.com, no: SFB1182) and the German Ministry of Education and Research (BMBF) programme: Med sysINFLAME (http://www.gesundheitsforschung-bmbf.de/de/5111.php, no: 01ZX1306A). CS receives support from the Helmut and Hannelore Greve-Foundation.

    • Competing interests None declared.

    • Ethics approval The protocol was reviewed by the appropriate ethics committee (PV4114).

    • Provenance and peer review Not commissioned; externally peer reviewed.

    • Patient consent for publication Not required.