FXR inhibition reduces ACE2 expression, SARS-CoV-2 infection and may improve COVID-19 outcome
Gwilym J Webb,
William T H Gelson,
Victoria L Mulcahy,
Rhoda E Kuc,
Thomas L Williams,
Olivia C Tysoe,
Thomas W M Crozier,
Sara S Upponi,
Susan E. Davies,
Ansgar W. Lohse,
Andrew M Moon,
Sidney A Barritt,
Ravindra K Gupta,
Anthony P Davenport,
Simon J A Buczacki,
Andrew J Butler,
Christopher J E Watson,
George F Mells,
Posted 07 Jun 2021
bioRxiv DOI: 10.1101/2021.06.06.446781
Posted 07 Jun 2021
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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