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

Teresa Brevini (), Mailis Maes, Gwilym J. Webb, Binu V. John, Claudia D. Fuchs, Gustav Buescher, Lu Wang, Chelsea Griffiths, Marnie L. Brown, William E. Scott, Pehuén Pereyra-Gerber, William T. H. Gelson, Stephanie Brown, Scott Dillon, Daniele Muraro, Jo Sharp, Megan Neary, Helen Box, Lee Tatham, James Stewart, Paul Curley, Henry Pertinez, Sally Forrest, Petra Mlcochova, Sagar S. Varankar, Mahnaz Darvish-Damavandi, Victoria L. Mulcahy, Rhoda E. Kuc, Thomas L. Williams, James A. Heslop, Davide Rossetti, Olivia C. Tysoe, Vasileios Galanakis, Marta Vila-Gonzalez, Thomas W. M. Crozier, Johannes Bargehr, Sanjay Sinha, Sara S. Upponi, Corrina Fear, Lisa Swift, Kourosh Saeb-Parsy, Susan E. Davies, Axel Wester, Hannes Hagström, Espen Melum, Darran Clements, Peter Humphreys, Jo Herriott, Edyta Kijak, Helen Cox, Chloe Bramwell, Anthony Valentijn, Christopher J. R. Illingworth, Bassam Dahman, Dustin R. Bastaich, Raphaella D. Ferreira, Thomas Marjot, Eleanor Barnes, Andrew M. Moon, Alfred S. Barritt, Ravindra K. Gupta, Stephen Baker, Anthony P. Davenport, Gareth Corbett, Vassilis G. Gorgoulis, Simon J. A. Buczacki, Joo-Hyeon Lee, Nicholas J. Matheson, Michael Trauner, Andrew J. Fisher, Paul Gibbs, Andrew J. Butler, Christopher J. E. Watson, George F. Mells, Gordon Dougan, Andrew Owen, Ansgar W. Lohse, Ludovic Vallier () and Fotios Sampaziotis ()
Additional contact information
Teresa Brevini: Wellcome–MRC Cambridge Stem Cell Institute
Mailis Maes: University of Cambridge
Gwilym J. Webb: Cambridge University Hospitals NHS Foundation Trust
Binu V. John: University of Miami and Miami VA Health System
Claudia D. Fuchs: Medical University of Vienna
Gustav Buescher: University Medical Centre Hamburg-Eppendorf
Lu Wang: Newcastle University
Chelsea Griffiths: Newcastle University
Marnie L. Brown: Newcastle University
William E. Scott: Newcastle University
Pehuén Pereyra-Gerber: University of Cambridge
William T. H. Gelson: Cambridge University Hospitals NHS Foundation Trust
Stephanie Brown: Wellcome–MRC Cambridge Stem Cell Institute
Scott Dillon: Wellcome–MRC Cambridge Stem Cell Institute
Daniele Muraro: Wellcome Sanger Institute
Jo Sharp: University of Liverpool
Megan Neary: University of Liverpool
Helen Box: University of Liverpool
Lee Tatham: University of Liverpool
James Stewart: University of Liverpool
Paul Curley: University of Liverpool
Henry Pertinez: University of Liverpool
Sally Forrest: University of Cambridge
Petra Mlcochova: University of Cambridge
Sagar S. Varankar: Wellcome–MRC Cambridge Stem Cell Institute
Mahnaz Darvish-Damavandi: Wellcome–MRC Cambridge Stem Cell Institute
Victoria L. Mulcahy: University of Cambridge
Rhoda E. Kuc: University of Cambridge, Addenbrooke’s Hospital
Thomas L. Williams: University of Cambridge, Addenbrooke’s Hospital
James A. Heslop: Wellcome–MRC Cambridge Stem Cell Institute
Davide Rossetti: Wellcome–MRC Cambridge Stem Cell Institute
Olivia C. Tysoe: Wellcome–MRC Cambridge Stem Cell Institute
Vasileios Galanakis: Wellcome–MRC Cambridge Stem Cell Institute
Marta Vila-Gonzalez: Wellcome–MRC Cambridge Stem Cell Institute
Thomas W. M. Crozier: University of Cambridge
Johannes Bargehr: Wellcome–MRC Cambridge Stem Cell Institute
Sanjay Sinha: Wellcome–MRC Cambridge Stem Cell Institute
Sara S. Upponi: Cambridge University Hospitals NHS Foundation Trust
Corrina Fear: University of Cambridge and NIHR Cambridge Biomedical Research Centre
Lisa Swift: University of Cambridge and NIHR Cambridge Biomedical Research Centre
Kourosh Saeb-Parsy: University of Cambridge and NIHR Cambridge Biomedical Research Centre
Susan E. Davies: Cambridge University Hospitals NHS Foundation Trust
Axel Wester: Karolinska Institutet
Hannes Hagström: Karolinska Institutet
Espen Melum: Oslo University Hospital, Rikshospitalet
Darran Clements: Wellcome–MRC Cambridge Stem Cell Institute
Peter Humphreys: Wellcome–MRC Cambridge Stem Cell Institute
Jo Herriott: University of Liverpool
Edyta Kijak: University of Liverpool
Helen Cox: University of Liverpool
Chloe Bramwell: University of Liverpool
Anthony Valentijn: University of Liverpool
Christopher J. R. Illingworth: MRC–University of Glasgow Centre for Virus Research
Bassam Dahman: Virginia Commonwealth University
Dustin R. Bastaich: Virginia Commonwealth University
Raphaella D. Ferreira: University of Miami and Miami VA Health System
Thomas Marjot: University of Oxford
Eleanor Barnes: University of Oxford
Andrew M. Moon: University of North Carolina
Alfred S. Barritt: University of North Carolina
Ravindra K. Gupta: University of Cambridge
Stephen Baker: University of Cambridge
Anthony P. Davenport: University of Cambridge, Addenbrooke’s Hospital
Gareth Corbett: Cambridge University Hospitals NHS Foundation Trust
Vassilis G. Gorgoulis: National and Kapodistrian University of Athens
Simon J. A. Buczacki: Wellcome–MRC Cambridge Stem Cell Institute
Joo-Hyeon Lee: Wellcome–MRC Cambridge Stem Cell Institute
Nicholas J. Matheson: University of Cambridge
Michael Trauner: Medical University of Vienna
Andrew J. Fisher: Newcastle University
Paul Gibbs: University of Cambridge and NIHR Cambridge Biomedical Research Centre
Andrew J. Butler: University of Cambridge and NIHR Cambridge Biomedical Research Centre
Christopher J. E. Watson: University of Cambridge and NIHR Cambridge Biomedical Research Centre
George F. Mells: Cambridge University Hospitals NHS Foundation Trust
Gordon Dougan: University of Cambridge
Andrew Owen: University of Liverpool
Ansgar W. Lohse: University Medical Centre Hamburg-Eppendorf
Ludovic Vallier: Wellcome–MRC Cambridge Stem Cell Institute
Fotios Sampaziotis: Wellcome–MRC Cambridge Stem Cell Institute

Nature, 2023, vol. 615, issue 7950, 134-142

Abstract: Abstract Preventing SARS-CoV-2 infection by modulating viral host receptors, such as angiotensin-converting enzyme 2 (ACE2)1, could represent a new chemoprophylactic approach for COVID-19 that complements vaccination2,3. However, the mechanisms that control the expression of ACE2 remain unclear. Here we show that the farnesoid X receptor (FXR) is a direct regulator of ACE2 transcription in several tissues affected by COVID-19, including the gastrointestinal and respiratory systems. We then use the over-the-counter compound z-guggulsterone 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 show that the UDCA-mediated downregulation of ACE2 reduces susceptibility to SARS-CoV-2 infection in vitro, in vivo and in human lungs and livers perfused ex situ. Furthermore, we reveal that UDCA reduces the expression of ACE2 in the nasal epithelium in humans. Finally, we identify a correlation between UDCA treatment and positive clinical outcomes after SARS-CoV-2 infection using retrospective registry data, and confirm these findings in an independent validation cohort of recipients of liver transplants. In conclusion, we show that FXR has a role in controlling ACE2 expression and provide evidence that modulation of this pathway could be beneficial for reducing SARS-CoV-2 infection, paving the way for future clinical trials.

Date: 2023
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DOI: 10.1038/s41586-022-05594-0

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