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

. 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…

• AA
  American Association for the Study of Liver Diseases
• NB
  NHS Blood and Transplant

  Award: WPA15-02
• WT
  Wellcome Trust

  Awards: 203151/A/16/Z, 203814/Z/16/A, 102176/B/13/Z, 203151/Z/16/Z, 222489/Z/21/Z, 102176, TG/18/4/33770, 203151
• UR
  UK Research and Innovation

  Awards: MC_PC_17230, EP/R024804/1
• NB
  NIHR Biomedical Research Centre, Royal Marsden NHS Foundation Trust/Institute of Cancer Research
• NI
  National Institute for Health and Care Research
• BH
  British Heart Foundation

  Awards: TG/18/4/33770, 203814/Z/16/A
• DO
  Department of Health and Social Care
• UO
  University of Cambridge

  Awards: 203814/Z/16/A, TG/18/4/33770
• NU
  Newcastle University
• RT
  Rosetrees Trust
• CU
  Cambridge University Hospitals
• ET
  Evelyn Trust
• EA
  European Association for the Study of the Liver
• MR
  Medical Research Council

  Awards: MC_PC_17230, MC_UU_12014, MC_PC_19026, MR/L001489/1, MR/P008801/1, MR/V002074/1, MC_PC_17230, MR/P008801/1, COVID-19, 203151/Z/16/Z
• EA
  Engineering and Physical Sciences Research Council

  Awards: EP/R024804/1, EP/R024804/1
• NC
  NIHR Cambridge Biomedical Research Centre