FXR inhibition reduces ACE2 expression, SARS-CoV-2 infection and may improve COVID-19 outcome

Brevini, T.; Maes, M.; Webb, G. J.; Gelson, W. T. H.; Forrest, S.; Mlcochova, P.; Dillon, S.; Varankar, S.; Darvish-Damavandi, M.; Mulcahy, V. L.; Kuc, R. E.; Williams, T. L.; Galanakis, V.; Vila-Gonzalez, M.; Tysoe, O. C.; Muraro, D.; Crozier, T. W. M.; Bargehr, J.; Sinha, S.; Upponi, S. S.; Swift, L.; Saeb-Parsy, K.; Davies, S. E.; Marjot, T.; Barnes, E.; Lohse, A. W.; Moon, A. M.; Barritt, S. A.; Gupta, R. K.; Baker, S.; Davenport, A. P.; Corbett, G.; Buczacki, S. J. A.; Lee, J.-H.; Gibbs, P.; Butler, A. J.; Watson, C. J. E.; Mells, G. F.; Dougan, G.; vallier, L.; Sampaziotis, F.

doi:10.1101/2021.06.06.446781

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bioRxiv · 10.1101/2021.06.06.446781

FXR inhibition reduces ACE2 expression, SARS-CoV-2 infection and may improve COVID-19 outcome

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Abstract

Prevention of SARS-CoV-2 entry in cells through the modulation of viral host receptors, such as ACE2, could represent a new therapeutic approach complementing vaccination. 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 demonstrate that FXR antagonists, including the over-the-counter compound z-guggulsterone (ZGG) and the off-patent drug ursodeoxycholic acid (UDCA), downregulate ACE2 levels, and reduce susceptibility to SARS-CoV-2 infection in lung, cholangiocyte and gut organoids. We then show that therapeutic levels of UDCA downregulate ACE2 in human organs perfused ex situ and reduce SARS-CoV-2 infection ex vivo. Finally, we perform a retrospective study using registry data and identify a correlation between UDCA treatment and positive clinical outcomes following SARS-CoV-2 infection, including hospitalisation, ICU admission and death. In conclusion, we identify a novel function of FXR in controlling ACE2 expression and provide evidence that this approach could be beneficial for reducing SARS-CoV-2 infection, thereby paving the road for future clinical trials.

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Brevini, T., Maes, M., Webb, G. J., Gelson, W. T. H., Forrest, S., Mlcochova, P., Dillon, S., Varankar, S., Darvish-Damavandi, M., Mulcahy, V. L., Kuc, R. E., Williams, T. L., Galanakis, V., Vila-Gonzalez, M., Tysoe, O. C., Muraro, D., Crozier, T. W. M., Bargehr, J., Sinha, S., Upponi, S. S., Swift, L., Saeb-Parsy, K., Davies, S. E., Marjot, T., Barnes, E., Lohse, A. W., Moon, A. M., Barritt, S. A., Gupta, R. K., Baker, S., Davenport, A. P., Corbett, G., Buczacki, S. J. A., Lee, J.-H., Gibbs, P., Butler, A. J., Watson, C. J. E., Mells, G. F., Dougan, G., vallier, L., Sampaziotis, F.. 2021-06-07. FXR inhibition reduces ACE2 expression, SARS-CoV-2 infection and may improve COVID-19 outcome. https://doi.org/10.1101/2021.06.06.446781

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