2. Academic Validation
  3. FXR inhibition may protect from SARS-CoV-2 infection by reducing ACE2

FXR inhibition may protect from SARS-CoV-2 infection by reducing ACE2

  • Nature. 2022 Dec 5. doi: 10.1038/s41586-022-05594-0.
Teresa Brevini 1,  Mailis Maes 2,  Gwilym J Webb 3,  Binu V John 4,  Claudia D Fuchs 5,  Gustav Buescher 6,  Lu Wang 7,  Chelsea Griffiths 7,  Marnie L Brown 7,  William E Scott 3rd 7,  Pehuén Pereyra-Gerber 2,  William T H Gelson 3 8,  Stephanie Brown 9,  Scott Dillon 9,  Daniele Muraro 10,  Jo Sharp 11,  Megan Neary 11,  Helen Box 11,  Lee Tatham 11,  James Stewart 12,  Paul Curley 11,  Henry Pertinez 11,  Sally Forrest 2,  Petra Mlcochova 2 4,  Sagar S Varankar 9,  Mahnaz Darvish-Damavandi 9 13,  Victoria L Mulcahy 14,  Rhoda E Kuc 15,  Thomas L Williams 15,  James A Heslop 9,  Davide Rossetti 9,  Olivia C Tysoe 9 16,  Vasileios Galanakis 9,  Marta Vila-Gonzalez 9,  Thomas W M Crozier 2,  Johannes Bargehr 9 8 17,  Sanjay Sinha 9 17,  Sara S Upponi 18,  Corrina Fear 16,  Lisa Swift 16,  Kourosh Saeb-Parsy 16 19,  Susan E Davies 20,  Axel Wester 21,  Hannes Hagström 21,  Espen Melum 22 23 24 25 26,  Darran Clements 9,  Peter Humphreys 9,  Jo Herriott 11,  Edyta Kijak 11,  Helen Cox 11,  Chloe Bramwell 11,  Anthony Valentijn 11,  Christopher J R Illingworth 27 28,  UK-PBC research consortium,  Bassam Dahman 29,  Dustin R Bastaich 29,  Raphaella D Ferreira 4,  Thomas Marjot 30,  Eleanor Barnes 30,  Andrew M Moon 31,  Alfred S Barritt 4th 31,  Ravindra K Gupta 2 8,  Stephen Baker 2,  Anthony P Davenport 15,  Gareth Corbett 32,  Vassilis G Gorgoulis 33 34 35,  Simon J A Buczacki 9 13,  Joo-Hyeon Lee 9 36,  Nicholas J Matheson 2 8 31 37,  Michael Trauner 5,  Andrew J Fisher 7,  Paul Gibbs 16 19,  Andrew J Butler 16 19,  Christopher J E Watson 16 19 38,  George F Mells 3 14,  Gordon Dougan 2,  Andrew Owen 11,  Ansgar W Lohse 6,  Ludovic Vallier 39 40 41 42,  Fotios Sampaziotis 43 44 45
Affiliations

Affiliations

  • 1 Wellcome - MRC Cambridge Stem Cell Institute, Cambridge, UK. tb647@cam.ac.uk.
  • 2 Cambridge Institute of Therapeutic Immunology & Infectious Disease (CITIID), Department of Medicine, University of Cambridge, Cambridge, UK.
  • 3 Cambridge Liver Unit, Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK.
  • 4 Division of Gastroenterology and Hepatology, University of Miami and Miami VA Health System, Miami, FL, USA.
  • 5 Hans Popper Laboratory of Molecular Hepatology, Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria.
  • 6 Department of Medicine, University Medical Centre Hamburg-Eppendorf, Hamburg, Germany.
  • 7 Transplant and Regenerative Medicine Laboratory, Translational and Clinical Research Institute, Faculty of Medical Sciences, Newcastle University, Newcastle Upon Tyne, UK.
  • 8 Department of Medicine, University of Cambridge, Cambridge, UK.
  • 9 Wellcome - MRC Cambridge Stem Cell Institute, Cambridge, UK.
  • 10 Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, Cambridge, UK.
  • 11 Centre of Excellence in Long-acting Therapeutics (CELT), Department of Pharmacology and Therapeutics, Institute of Systems, Molecular and Integrative Biology, University of Liverpool, Liverpool, UK.
  • 12 Department of Infection Biology and Microbiomes, Institute of Infection, Veterinary and Ecological Sciences, University of Liverpool, Liverpool, UK.
  • 13 Nuffield Department of Surgical Sciences, Old Road Campus Research Building, Oxford, UK.
  • 14 Academic Department of Medical Genetics, University of Cambridge, Cambridge, UK.
  • 15 Experimental Medicine and Immunotherapeutics, University of Cambridge, Addenbrooke's Hospital, Cambridge, UK.
  • 16 Department of Surgery, University of Cambridge and NIHR Cambridge Biomedical Research centre, Cambridge, UK.
  • 17 Division of Cardiovascular Medicine, University of Cambridge, Cambridge, UK.
  • 18 Department of Radiology, Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK.
  • 19 Roy Calne Transplant Unit, Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK.
  • 20 Department of Histopathology, Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK.
  • 21 Department of Medicine, Huddinge, Karolinska Institutet, Stockholm, Sweden.
  • 22 Norwegian PSC Research Center, Department of Transplantation Medicine, Division of Surgery, Inflammatory Diseases and Transplantation, Oslo University Hospital, Rikshospitalet, Oslo, Norway.
  • 23 Research Institute of Internal Medicine, Division of Surgery, Inflammatory Diseases and Transplantation, Oslo University Hospital, Rikshospitalet, Oslo, Norway.
  • 24 Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway.
  • 25 Section of Gastroenterology, Department of Transplantation Medicine, Division of Surgery, Inflammatory Diseases and Transplantation, Oslo University Hospital, Rikshospitalet, Oslo, Norway.
  • 26 Hybrid Technology Hub Centre of Excellence, Institute of Basic Medical Sciences, Faculty of Medicine, University of Oslo, Oslo, Norway.
  • 27 MRC-University of Glasgow Centre for Virus Research, Glasgow, UK.
  • 28 Department of Applied Mathematics and Theoretical Physics, University of Cambridge, Cambridge, UK.
  • 29 Department of Health Behavior and Policy, Virginia Commonwealth University, Richmond, VA, USA.
  • 30 Oxford Liver Unit, Translational Gastroenterology Unit, Oxford University Hospitals NHS Foundation Trust, University of Oxford, Oxford, UK.
  • 31 Division of Gastroenterology and Hepatology, University of North Carolina, Chapel Hill, NC, USA.
  • 32 Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK.
  • 33 Dept. of Histology and Embryology, School of Medicine, National and Kapodistrian University of Athens, Athens, Greece.
  • 34 Ninewells Hospital and Medical School, University of Dundee, Dundee, UK.
  • 35 Biomedical Research Foundation, Academy of Athens, Athens, Greece.
  • 36 Department of Physiology, Development and Neuroscience, University of Cambridge, Cambridge, UK.
  • 37 NHS Blood and Transplant, Cambridge, UK.
  • 38 National Institute of Health Research (NIHR) Cambridge Biomedical Research Centre, and the NIHR Blood and Transplant Research Unit (BTRU) at the University of Cambridge in collaboration with Newcastle University and in partnership with NHS Blood and Transplant (NHSBT), Cambridge, UK.
  • 39 Wellcome - MRC Cambridge Stem Cell Institute, Cambridge, UK. lv255@cam.ac.uk.
  • 40 Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, Cambridge, UK. lv255@cam.ac.uk.
  • 41 Berlin Institute of Health (BIH), BIH Centre for Regenerative Therapies (BCRT), Charité - Universitätsmedizin Berlin, Berlin, Germany. lv255@cam.ac.uk.
  • 42 Max Planck Institute for Molecular Genetics, Berlin, Germany. lv255@cam.ac.uk.
  • 43 Wellcome - MRC Cambridge Stem Cell Institute, Cambridge, UK. fs347@cam.ac.uk.
  • 44 Cambridge Liver Unit, Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK. fs347@cam.ac.uk.
  • 45 Department of Medicine, University of Cambridge, Cambridge, UK. fs347@cam.ac.uk.
PMID: 36470304 DOI: 10.1038/s41586-022-05594-0
Abstract

Prevention of SARS-CoV-2 Infection through the modulation of viral host receptors, such as ACE21, could represent a new chemoprophylactic approach for COVID-19 complementing vaccination2,3. However, the mechanisms controlling ACE2 expression remain elusive. Here, we identify the farnesoid X receptor (FXR) as a direct regulator of ACE2 transcription in multiple COVID19-affected tissues, including the gastrointestinal and respiratory systems. We then use the over-the-counter compound z-guggulsterone (ZGG) and the off-patent drug ursodeoxycholic acid (UDCA) to reduce FXR signalling and downregulate ACE2 in human lung, cholangiocyte and intestinal organoids and in the corresponding tissues in mice and hamsters. We demonstrate that UDCA-mediated ACE2 downregulation reduces susceptibility to SARS-CoV-2 Infection in vitro, in vivo and in human lungs and livers perfused ex situ. Furthermore, we illustrate that UDCA reduces ACE2 expression in the nasal epithelium in humans. Finally, we identify a correlation between UDCA treatment and positive clinical outcomes following SARS-CoV-2 Infection using retrospective registry data, and confirm these findings in an independent validation cohort of liver transplant recipients. In conclusion, we identify a novel function of FXR in controlling ACE2 expression and provide evidence that modulation of this pathway could be beneficial for reducing SARS-CoV-2 Infection, paving the road for future clinical trials.

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