@article{Brevini_T-2022_104247,
title = {FXR inhibition may protect from SARS-CoV-2 infection by reducing ACE2},
author = {Brevini, T. and Maes, M. and Webb, G. and John, B. and Fuchs, C. and Buescher, G. and Wang, L. and Griffiths, C. and Brown, M. and Scott III, W. and Pereyra-Gerber, P. and Gelson, W. and Brown, S. and Dillon, S. and Muraro, D. and Sharp, J. and Neary, M. and Box, H. and Tatham, L. and Stewart, J. and Curley, P. and Pertinez, H. and Forrest, S. and Mlcochova, P. and Varankar, S. and Darvish-Damavandi, M. and Mulcahy, V. and Kuc, R. and Williams, T. and Heslop, J. and Rossetti, D. and Tysoe, O. and Galanakis, V. and Vila-Gonzalez, M. and Crozier, T. and Bargehr, J. and Sinha, S. and Upponi, S. and Fear, C. and Swift, L. and Saeb-Parsy, K. and Davies, S. and Wester, A. and Hagström, H. and Melum, E. and Clements, D. and Humphreys, P. and Herriott, J. and Kijak, E. and Cox, H. and Bramwell, C. and Valentijn, A. and Illingworth, C. and UK-PBC Research Consortium and Dahman, B. and Bastaich, D. and Ferreira, R. and Marjot, T. and Barnes, E. and Moon, A. and Barritt IV, A. and Gupta, R. and Baker, S. and Davenport, A. and Corbett, G. and Gorgoulis, V. and Buczacki, S. and Lee, J. and Matheson, N. and Trauner, M. and Fisher, A. and Gibbs, P. and Butler, A. and Watson, C. and Mells, G. and Dougan, G. and Owen, A. and Lohse, A. and Vallier, L. and Sampaziotis, F.},
month = {dec},
year = {2022},
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.},
journal = {Nature},
publisher = {Springer Nature},
url = {https://doi.org/10.1038/s41586-022-05594-0},
}
