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

Brevini et al., Nature, doi:10.1038/s41586-022-05594-0

Dec 2022

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Retrospective study from two registries of 1,096 COVID-19 patients with chronic liver disease, including 31 treated with ursodeoxycholic acid (UDCA). Propensity score matching was used to compare outcomes between UDCA-treated and untreated patients. The analysis found that UDCA treatment was associated with reduced hospitalization, ICU admission, ventilation, and death from COVID-19. The authors suggest that UDCA may decrease susceptibility to SARS-CoV-2 infection by downregulating the host receptor ACE2 through inhibition of the farnesoid X receptor.

Authors also show that 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; and that UDCA reduces the expression of ACE2 in the nasal epithelium in humans.

3 preclinical studies support the efficacy of ursodeoxycholic acid for COVID-19:

2 In Vitro studies1,2

1 In Vivo animal study3

Ursodeoxycholic acid reduced ACE2 expression and blocked pseudovirus infection in Calu-3 cells1, protected against Omicron infection in hamsters by downregulating ACE2 expression via FXR inhibition, leading to reduced viral load in the upper respiratory tract and prevention of weight loss3, and inhibited SARS-CoV-2 infection by downregulating ACE2 expression via FXR inhibition in multiple tissues (respiratory, biliary, and intestinal), reduced viral transmission in a hamster model, and decreased viral replication in human organ perfusion models2.

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risk of death, 94.4% lower, RR 0.06, p = 0.13, treatment 0 of 31 (0.0%), control 14 of 155 (9.0%), NNT 11, relative risk is not 0 because of continuity correction due to zero events (with reciprocal of the contrasting arm), propensity score matching.

risk of mechanical ventilation, 66.7% lower, RR 0.33, p = 0.48, treatment 1 of 31 (3.2%), control 15 of 155 (9.7%), NNT 16, propensity score matching.

risk of ICU admission, 75.0% lower, RR 0.25, p = 0.21, treatment 1 of 31 (3.2%), control 20 of 155 (12.9%), NNT 10, propensity score matching.

risk of hospitalization, 39.6% lower, RR 0.60, p = 0.03, treatment 11 of 31 (35.5%), control 91 of 155 (58.7%), NNT 4.3, propensity score matching.

Effect extraction follows pre-specified rules prioritizing more serious outcomes. Submit updates

1. Tong et al., Ursodeoxycholic acid reduces ACE-2 activity in COVID-19 patients and Calu- 3 cells, Research Square, doi:10.21203/rs.3.rs-5317838/v1.researchsquare.com, doi.org.

2. Brevini et al., FXR inhibition may protect from SARS-CoV-2 infection by reducing ACE2, Nature, doi:10.1038/s41586-022-05594-0.nature.com, doi.org.

3. Lee et al., Ursodeoxycholic acid may protect from severe acute respiratory syndrome coronavirus 2 Omicron variant by reducing angiotensin‐converting enzyme 2, Pharmacology Research & Perspectives, doi:10.1002/prp2.1194.wiley.com, doi.org.

Brevini et al., 5 Dec 2022, retrospective, United Kingdom, peer-reviewed, 80 authors.

This Paper UDCA All

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

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

Nature, doi:10.1038/s41586-022-05594-0

prophylaxis against COVID-19 2 . Therefore, there is a pressing need for novel prophylactic agents that reduce the risk of severe disease 3 , are less susceptible to viral resistance and are compatible with healthcare systems in low-and middle-income countries. Viral host receptors represent logical therapeutic targets, because they are essential for SARS-CoV-2 cellular entry and infection 1 . Among these, ACE2 is particularly appealing 1 . ACE2 is a transmembrane carboxypeptidase with a broad substrate specificity, including angiotensin II, that acts as the main receptor for SARS-CoV-2. It directly binds to the spike proteins of different coronaviruses, with a high affinity for SARS-CoV-2, rendering it indispensable for viral entry 11 . Accordingly, COVID-19 predominantly affects tissues that express ACE2, such as the lungs, the cardiovascular system, the digestive tract and the biliary tree 12, 13 . Modifying the expression of ACE2 could impede viral entry and protect against infection with SARS-CoV-2 and potentially other coronaviruses that use the same receptor. Furthermore, because ACE2 is a host-cell protein, its expression is not likely to be affected by mutations in the virus. Therefore, therapies that modulate ACE2 expression may be effective against multiple SARS-CoV-2 variants with a higher genetic barrier to resistance. However, the mechanisms that control ACE2 expression remain unclear. Here we use human cholangiocyte organoids as a proof-of-principle system to demonstrate that the bile acid receptor FXR controls the expression of ACE2. We show that this mechanism applies in several SARS-CoV-2-affected tissues, including gastrointestinal and respiratory epithelia. Subsequently, we demonstrate that suppressing FXR signalling, by using the approved drug UDCA or the over-the-counter phytosteroid z-guggulsterone (ZGG), reduces ACE2 expression and SARS-CoV-2 infection in vitro and in an airborne transmission model in golden Syrian hamsters. We repeat our experiments in human lungs and livers perfused ex situ and show that administering UDCA at physiologically relevant concentrations reduces ACE2 and viral infection in both organs ex vivo. We then demonstrate a reduction in the levels of ACE2 in the nasal epithelium of volunteers receiving clinically approved doses of UDCA. Finally, we interrogate an international registry cohort of patients with COVID-19 and chronic liver disease, identify a correlation between UDCA therapy and better clinical outcomes from COVID-19 and reproduce these results in a second independent cohort of liver-transplant recipients.

Publisher's note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. Reporting summary Further information on research design is available in the Nature Portfolio Reporting Summary linked to this article. Cambridge BRC Cell Phenotyping Hub for their help with flow cytometry and processing of samples; the building staff of the Jeffrey Cheah Biomedical Centre for maintaining the institute open and safe during the period of lockdown; K. Füssel for coordinating the volunteer study and sample collection at the University Medical Centre Hamburg-Eppendorf; J. Hails

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EMBO J. 38, e100300 (2019).', 'journal-title': 'EMBO J.'}, { 'key': '5594_CR61', 'doi-asserted-by': 'publisher', 'first-page': '1335', 'DOI': '10.1016/j.jhep.2021.01.021', 'volume': '74', 'author': 'T Marjot', 'year': '2021', 'unstructured': 'Marjot, T. et al. SARS-CoV-2 infection in patients with autoimmune ' 'hepatitis. J. Hepatol. 74, 1335–1343 (2021).', 'journal-title': 'J. Hepatol.'}], 'container-title': 'Nature', 'original-title': [], 'language': 'en', 'link': [ { 'URL': 'https://www.nature.com/articles/s41586-022-05594-0.pdf', 'content-type': 'application/pdf', 'content-version': 'vor', 'intended-application': 'text-mining'}, { 'URL': 'https://www.nature.com/articles/s41586-022-05594-0', 'content-type': 'text/html', 'content-version': 'vor', 'intended-application': 'text-mining'}, { 'URL': 'https://www.nature.com/articles/s41586-022-05594-0.pdf', 'content-type': 'application/pdf', 'content-version': 'vor', 'intended-application': 'similarity-checking'}], 'deposited': { 'date-parts': [[2023, 2, 8]], 'date-time': '2023-02-08T05:06:20Z', 'timestamp': 1675832780000}, 'score': 1, 'resource': {'primary': {'URL': 'https://www.nature.com/articles/s41586-022-05594-0'}}, 'subtitle': [], 'short-title': [], 'issued': {'date-parts': [[2022, 12, 5]]}, 'references-count': 61, 'alternative-id': ['5594'], 'URL': 'http://dx.doi.org/10.1038/s41586-022-05594-0', 'relation': { 'has-review': [ { 'id-type': 'doi', 'id': '10.3410/f.742438702.793597353', 'asserted-by': 'object'}]}, 'ISSN': ['0028-0836', '1476-4687'], 'subject': ['Multidisciplinary'], 'container-title-short': 'Nature', 'published': {'date-parts': [[2022, 12, 5]]}, 'assertion': [ { 'value': '3 May 2021', 'order': 1, 'name': 'received', 'label': 'Received', 'group': {'name': 'ArticleHistory', 'label': 'Article History'}}, { 'value': '23 November 2022', 'order': 2, 'name': 'accepted', 'label': 'Accepted', 'group': {'name': 'ArticleHistory', 'label': 'Article History'}}, { 'value': '5 December 2022', 'order': 3, 'name': 'first_online', 'label': 'First Online', 'group': {'name': 'ArticleHistory', 'label': 'Article History'}}, { 'value': 'F.S., L.V. and K.S.-P. are founders and shareholders of Bilitech. L.V. is a ' 'founder and shareholder of DEFINIGEN. The remaining authors declare no ' 'competing interests.', 'order': 1, 'name': 'Ethics', 'group': {'name': 'EthicsHeading', 'label': 'Competing interests'}}]}

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