FXR inhibition may protect from SARS-CoV-2 infection by reducing ACE2
Creators: name: Fear, Corrina
name: Cox, Helen
name: Wang, Lu
name: Trauner, Michael
name: Buescher, Gustav
name: Muraro, Daniele
name: Gorgoulis, Vassilis G.
name: Butler, Andrew J.
name: Clements, Darran
name: Dillon, Scott
name: Owen, Andrew
name: Gupta, Ravindra K.
name: Williams, Thomas L.
name: Swift, Lisa
name: Moon, Andrew M.
name: Kuc, Rhoda E.
name: Curley, Paul
name: Kijak, Edyta
name: Forrest, Sally
name: Pertinez, Henry
name: Upponi, Sara S.
name: Brown, Stephanie
name: Corbett, Gareth
name: Melum, Espen
name: Ferreira, Raphaella D.
name: Gelson, William T. H.
name: Bastaich, Dustin R.
name: Dougan, Gordon
name: Gibbs, Paul
name: Davenport, Anthony P.
name: Neary, Megan
name: Humphreys, Peter
name: Lohse, Ansgar W.
name: Tysoe, Olivia C.
name: Crozier, Thomas W. M.
name: Mulcahy, Victoria L.
name: Wester, Axel
name: Rossetti, Davide
name: Valentijn, Anthony
name: Sinha, Sanjay
name: Fuchs, Claudia D.
name: Darvish-Damavandi, Mahnaz
name: Varankar, Sagar S.
name: Dahman, Bassam
name: Fisher, Andrew J.
name: Bramwell, Chloe
name: Maes, Mailis
name: Brevini, Teresa
name: Buczacki, Simon J. A.
name: Stewart, James
name: Vila-Gonzalez, Marta
name: Barnes, Eleanor
name: Davies, Susan E.
name: Marjot, Thomas
name: Heslop, James A.
name: Illingworth, Christopher J. R.
name: Matheson, Nicholas J.
name: John, Binu V.
name: Pereyra-Gerber, Pehuén
name: Hagström, Hannes
name: Webb, Gwilym J.
name: Mells, George F.
name: Sharp, Jo
name: Mlcochova, Petra
name: Brown, Marnie L.
name: Baker, Stephen
name: Griffiths, Chelsea
name: Watson, Christopher J. E.
name: Tatham, Lee
name: Sampaziotis, Fotios
name: Saeb-Parsy, Kourosh
name: Box, Helen
name: Lee, Joo-Hyeon
name: Barritt, Alfred S.
name: Herriott, Jo
name: Vallier, Ludovic
name: Galanakis, Vasileios
name: Scott, William E.
name: Bargehr, Johannes
Publisher: name: Springer Nature
Year: 2022

description: <p>Preventing SARS-CoV-2 infection by modulating viral host receptors, such as angiotensin-converting enzyme&thinsp;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.</p>