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2. Mechanism of Alzheimer type II astrocyte development in hepatic encephalopathy

Author

Tong, Xiao Y., Norenberg, Michael D., Paidas, Michael J., Shamaladevi, Nagarajarao, Salgueiro, Luis, Jaszberenyi, Miklos, John, Binu, Hussain, Hussain, El hiba, Omar, Abdeljalil, El got, Bilal, El-Mansoury, Natarajan, Sampath, Romaguera, Rita, Papayan, Stanislav, Carden, Arianna K., Ramamoorthy, Rajalakshmi, Elumalai, Nila, Schally, Andrew V., Nithura, Jayakumar, Patrizio, Rebecca, and Jayakumar, Arumugam R.

Published
2024
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4. Hepatocellular Carcinoma Diagnosis and Management in 2021: A National Veterans Affairs Quality Improvement Project

Author

Rogal, Shari S., Taddei, Tamar H., Monto, Alexander, Yakovchenko, Vera, Patton, Heather, Merante, Monica, Spoutz, Patrick, Chia, Linda, Yudkevich, Jennifer, Aytaman, Ayse, Rabiee, Atoosa, John, Binu V., Blechacz, Boris, Cai, Cindy X., Gilles, HoChong, Shah, Anand S., McCurdy, Heather, Puri, Puneet, Jou, Janice, Mazhar, Khurram, Dominitz, Jason A., Anwar, Jennifer, Morgan, Timothy R., and Ioannou, George N.

Published
2024
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6. FXR inhibition may protect from SARS-CoV-2 infection by reducing ACE2

Author

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

Published
2023
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9. Direct-Acting Antiviral Therapy for Hepatitis C Virus Infection Is Associated With Increased Survival in Patients With a History of Hepatocellular Carcinoma

Author

Singal, Amit G, Rich, Nicole E, Mehta, Neil, Branch, Andrea D, Pillai, Anjana, Hoteit, Maarouf, Volk, Michael, Odewole, Mobolaji, Scaglione, Steven, Guy, Jennifer, Said, Adnan, Feld, Jordan J, John, Binu V, Frenette, Catherine, Mantry, Parvez, Rangnekar, Amol S, Oloruntoba, Omobonike, Leise, Michael, Jou, Janice H, Bhamidimarri, Kalyan Ram, Kulik, Laura, Ioannou, George N, Huang, Annsa, Tran, Tram, Samant, Hrishikesh, Dhanasekaran, Renumathy, Duarte-Rojo, Andres, Salgia, Reena, Eswaran, Sheila, Jalal, Prasun, Flores, Avegail, Satapathy, Sanjaya K, Kagan, Sofia, Gopal, Purva, Wong, Robert, Parikh, Neehar D, and Murphy, Caitlin C

Subjects
Biomedical and Clinical Sciences, Clinical Sciences, Liver Disease, Chronic Liver Disease and Cirrhosis, Digestive Diseases, Cancer, Emerging Infectious Diseases, Clinical Research, Hepatitis, Rare Diseases, Prevention, Infectious Diseases, Liver Cancer, Hepatitis - C, 6.1 Pharmaceuticals, Evaluation of treatments and therapeutic interventions, Infection, Good Health and Well Being, Aged, Antiviral Agents, Carcinoma, Hepatocellular, Female, Hepatitis C, Humans, Liver Neoplasms, Male, Middle Aged, North America, Protective Factors, Retrospective Studies, Risk Assessment, Risk Factors, Time Factors, Treatment Outcome, HCC, Survival, Neurosciences, Paediatrics and Reproductive Medicine, Gastroenterology & Hepatology, Clinical sciences, Nutrition and dietetics
Abstract

Background & aimsThere is controversy regarding the benefits of direct-acting antiviral (DAA) therapy for hepatitis C virus (HCV) infection for patients with a history of hepatocellular carcinoma (HCC). We performed a multicenter cohort study to compare overall survival between patients with HCV infection treated with DAAs and patients who did not receive DAA treatment for their HCV infection after complete response to prior HCC therapy.MethodsWe conducted a retrospective cohort study of patients with HCV-related HCC who achieved a complete response to resection, local ablation, transarterial chemo- or radioembolization, or radiation therapy, from January 2013 through December 2017 at 31 health care systems throughout the United States and Canada. We used Cox proportional hazards regression to determine the association between receipt of DAA therapy, modeled as a time-varying covariate, and all-cause mortality, accounting for informative censoring and confounding using inverse probability weighting.ResultsOf 797 patients with HCV-related HCC, 383 (48.1%) received DAA therapy and 414 (51.9%) did not receive treatment for their HCV infection after complete response to prior HCC therapy. Among DAA-treated patients, 43 deaths occurred during 941 person-years of follow-up, compared with 103 deaths during 526.6 person-years of follow-up among patients who did not receive DAA therapy (crude rate ratio, 0.23; 95% confidence interval [CI], 0.16-0.33). In inverse probability-weighted analyses, DAA therapy was associated with a significant reduction in risk of death (hazard ratio, 0.54; 95% CI, 0.33-0.90). This association differed by sustained virologic response to DAA therapy; risk of death was reduced in patients with sustained virologic response to DAA therapy (hazard ratio, 0.29; 95% CI, 0.18-0.47), but not in patients without a sustained virologic response (hazard ratio, 1.13; 95% CI, 0.55-2.33).ConclusionsIn an analysis of nearly 800 patients with complete response to HCC treatment, DAA therapy was associated with a significant reduction in risk of death.

Published
2019

13. Direct-Acting Antiviral Therapy Not Associated With Recurrence of Hepatocellular Carcinoma in a Multicenter North American Cohort Study

Author

Singal, Amit G, Rich, Nicole E, Mehta, Neil, Branch, Andrea, Pillai, Anjana, Hoteit, Maarouf, Volk, Michael, Odewole, Mobolaji, Scaglione, Steven, Guy, Jennifer, Said, Adnan, Feld, Jordan J, John, Binu V, Frenette, Catherine, Mantry, Parvez, Rangnekar, Amol S, Oloruntoba, Omobonike, Leise, Michael, Jou, Janice H, Bhamidimarri, Kalyan Ram, Kulik, Laura, Tran, Tram, Samant, Hrishikesh, Dhanasekaran, Renumathy, Duarte-Rojo, Andres, Salgia, Reena, Eswaran, Sheila, Jalal, Prasun, Flores, Avegail, Satapathy, Sanjaya K, Wong, Robert, Huang, Annsa, Misra, Suresh, Schwartz, Myron, Mitrani, Robert, Nakka, Sasank, Noureddine, Wassim, Ho, Chanda, Konjeti, Venkata R, Dao, Alexander, Nelson, Kevin, Delarosa, Kelly, Rahim, Usman, Mavuram, Meher, Xie, Jesse J, Murphy, Caitlin C, and Parikh, Neehar D

Subjects
Biomedical and Clinical Sciences, Clinical Sciences, Liver Disease, Emerging Infectious Diseases, Digestive Diseases, Rare Diseases, Hepatitis - C, Hepatitis, Chronic Liver Disease and Cirrhosis, Clinical Research, Liver Cancer, Cancer, Infectious Diseases, 6.1 Pharmaceuticals, Evaluation of treatments and therapeutic interventions, Good Health and Well Being, Aged, Antiviral Agents, Canada, Carcinoma, Hepatocellular, Female, Hepatitis C, Chronic, Humans, Liver Neoplasms, Male, Middle Aged, Neoplasm Recurrence, Local, Retrospective Studies, Sustained Virologic Response, Time Factors, United States, Hepatitis C Virus, Recurrence, Direct-Acting Antiviral, Neurosciences, Paediatrics and Reproductive Medicine, Gastroenterology & Hepatology, Clinical sciences, Nutrition and dietetics
Abstract

Background & aimsThere is controversy over the effects of direct-acting antiviral (DAA) therapies for hepatitis C virus (HCV) infection on hepatocellular carcinoma (HCC) recurrence and tumor aggressiveness. We compared HCC recurrence patterns between DAA-treated and untreated HCV-infected patients who had achieved a complete response to HCC treatment in a North American cohort.MethodsWe conducted a retrospective cohort study of patients with HCV-related HCC with a complete response to resection, local ablation, transarterial chemo- or radioembolization, or radiation therapy from January 2013 through December 2017 at 31 health systems throughout the United States and Canada. Cox regression was used to examine the association between DAA therapy and time to recurrence after a complete response, with DAA therapy analyzed as a time-varying exposure. We also estimated the association between DAA therapy and risk of early HCC recurrence (defined as 365 days after complete response).ResultsOf 793 patients with HCV-associated HCC, 304 (38.3%) received DAA therapy and 489 (61.7%) were untreated. HCC recurred in 128 DAA-treated patients (42.1%; early recurrence in 52 patients) and 288 untreated patients (58.9%; early recurrence in 227 patients). DAA therapy was not associated with HCC recurrence (hazard ratio 0.90, 95% confidence interval 0.70-1.16) or early HCC recurrence (hazard ratio 0.96, 95% confidence interval 0.70-1.34) after we adjusted for study site, age, sex, Child-Pugh score, α-fetoprotein level, tumor burden, and HCC treatment modality. In DAA-treated and untreated patients, most recurrences were within the Milan criteria (74.2% vs 78.8%; P = .23). A larger proportion of DAA-treated than untreated patients received potentially curative HCC therapy for recurrent HCC (32.0% vs 24.6%) and achieved a complete or partial response (45.3% vs 41.0%) but this did not achieve statistical significance.ConclusionIn a large cohort of North American patients with complete response to HCC treatment, DAA therapy was not associated with increased overall or early HCC recurrence. HCC recurrence patterns, including treatment response, were similar in DAA-treated and untreated patients.

Published
2019

24. Provider Attitudes and Practice Patterns for Direct-Acting Antiviral Therapy for Patients With Hepatocellular Carcinoma

Author

Rich, Nicole E., Yang, Ju Dong, Perumalswami, Ponni V., Alkhouri, Naim, Jackson, Whitney, Parikh, Neehar D., Mehta, Neil, Salgia, Reena, Duarte-Rojo, Andres, Kulik, Laura, Rakoski, Mina, Said, Adnan, Oloruntoba, Omobonike, Ioannou, George N., Hoteit, Maarouf A., Moon, Andrew M., Rangnekar, Amol S., Eswaran, Sheila L., Zheng, Elizabeth, Jou, Janice H., Hanje, James, Pillai, Anjana, Hernaez, Ruben, Wong, Robert, Scaglione, Steven, Samant, Hrishikesh, Kapuria, Devika, Chandna, Shaun, Rosenblatt, Russell, Ajmera, Veeral, Frenette, Catherine T., Satapathy, Sanjaya K., Mantry, Parvez, Jalal, Prasun, John, Binu V., Fix, Oren K., Leise, Michael, Lindenmeyer, Christina C., Flores, Avegail, Patel, Nayan, Jiang, Z. Gordon, Latt, Nyan, Dhanasekaran, Renumathy, Odewole, Mobolaji, Kagan, Sofia, Marrero, Jorge A., and Singal, Amit G.

Published
2020
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26. Alterations in Skin Microbiomes of Patients With Cirrhosis

Author

Bajaj, Jasmohan S., Fagan, Andrew, Sikaroodi, Masoumeh, Kakiyama, Genta, Takei, Hajme, Degefu, Yordanos, Pandak, William M., Hylemon, Phillip B., Fuchs, Michael, John, Binu, Heuman, Douglas M., Gavis, Edith, Nittono, Hiroshi, Patil, Rohan, and Gillevet, Patrick M.

Published
2019
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29. A Pilot Study of Electrocardiographic Features in Patients with Obesity from a Tertiary Care Centre in Southern India (Electron)

Author

Aditya John Binu, Sirish Chandra Srinath, Kripa Elizabeth Cherian, John Roshan Jacob, Thomas V. Paul, and Nitin Kapoor

Subjects
obesity, ECG, cardiovascular disease, Medicine
Abstract

Background: Obesity is associated with increased all-cause mortality and cardiovascular disease (CVD). An electrocardiogram (ECG) may be used to screen for subtle signs of CVD or altered cardiac morphology in the obese. Methodology: This observational cross-sectional analysed ECG changes in patients with obesity at a tertiary care centre in southern India. Results: One hundred and fifty adult patients with a mean (SD) BMI of 39.9 (6.7) kg/m2 were recruited in the study after excluding those with comorbidities (diabetes mellitus, systemic hypertension) or on chronic medications (ACE inhibitors). The cohort showed a female predominance (69.3%), with a mean (SD) age of 45.4 (11.2) years. Most patients exhibited a sinus rhythm (78%), with one patient showing features of first-degree conduction block. Sinus tachycardia was seen in 32 (21.3%) patients. We observed left and right ventricular hypertrophy in five (3.3%) and three (2%) patients, respectively. Observed ECG patterns included a prolonged QTc in 16 (10.7%) patients, inverted T-waves (mostly in the inferior leads) in 39 (26%) patients and ST-segment depression (predominantly in the lateral leads) in 14 (9.3%) patients. A greater prevalence was noted for morbid obesity. No deaths were reported in our cohort. Conclusions: The predominant ECG variations in this cohort included tachycardia, atrial enlargement, ventricular hypertrophy, conduction defects, LAD, features of ischemia or old infarction and repolarization abnormalities, with a greater prevalence in morbid obesity. Further studies are needed to assess the impact of weight reducing measures on reversibility of these changes and determine the association with outcomes in obese patients.

Published
2022
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35. Hepatocellular Carcinoma Diagnosis and Management in 2021: A National Veterans Affairs Quality Improvement Project

Author

Rogal, Shari S., primary, Taddei, Tamar, additional, Monto, Alexander, additional, Yakovchenko, Vera, additional, Patton, Heather, additional, Merante, Monica, additional, Spoutz, Patrick, additional, Chia, Linda, additional, Yudkevich, Jennifer, additional, Aytaman, Ayse, additional, Rabiee, Atoosa, additional, John, Binu, additional, Blechacz, Boris, additional, Cai, Cindy X., additional, Gilles, Hochong, additional, Shah, Anand S., additional, McCurdy, Heather, additional, Puri, Puneet, additional, Jou, Janice, additional, Mazhar, Khurram, additional, Dominitz, Jason, additional, Anwar, Jennifer, additional, Morgan, Timothy R., additional, and Ioannou, George N., additional

Published
2023
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36. Evidence of durable response to bepirovirsen in B-Clear responders: B-Sure first annual report

Author

Gadano, Adrian, primary, Arbune, Manuela, additional, Atsukawa, Masanori, additional, Fujiyama, Shigetoshi, additional, Urievna Gankina, Natalya Urievna Gankina, additional, John, Binu, additional, Komura, Takuya, additional, Kurosaki, Masayuki, additional, Kweon, Young Oh, additional, Lim, Seng Gee, additional, Mngqibisa, Rosie, additional, Piratvisuth, Teerha, additional, Sagalova, Olga, additional, Serfaty, Lawrence, additional, Stepanova, Tatyana, additional, Tsrancheva, Radoslava, additional, Xie, Qing, additional, Yuen, Man-Fung, additional, Macfarlane, Chelsea, additional, Corson, Stephen, additional, Dong, Jie, additional, Plein, Helene, additional, Quinn, Geoff, additional, Elston, Robert, additional, Kendrick, Stuart, additional, Paff, Melanie, additional, and Theodore, Dickens, additional

Published
2023
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40. The heart of the matter: Cardiac manifestations of endocrine disease

Author

Aditya John Binu, Kripa Elizabeth Cherian, Nitin Kapoor, Sujith Thomas Chacko, Oommen George, and Thomas Vizhalil Paul

Subjects
Cardiovascular disease, endocrine disorders, hypothyroidism, pheochromocytoma, Diseases of the endocrine glands. Clinical endocrinology, RC648-665, Diseases of the digestive system. Gastroenterology, RC799-869
Abstract

Endocrine disorders manifest as a disturbance in the milieu of multiple organ systems. The cardiovascular system may be directly affected or alter its function to maintain the state of homeostasis. In this article, we aim to review the pathophysiology, diagnosis, clinical features and management of cardiac manifestations of various endocrine disorders.

Published
2017
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41. Ursodeoxycholic acid is associated with a reduction in SARS‐CoV‐2 infection and reduced severity of COVID‐19 in patients with cirrhosis

Author

John, Binu V., primary, Bastaich, Dustin, additional, Webb, Gwilym, additional, Brevini, Teresa, additional, Moon, Andrew, additional, Ferreira, Raphaella D., additional, Chin, Allison M., additional, Kaplan, David E., additional, Taddei, Tamar H., additional, Serper, Marina, additional, Mahmud, Nadim, additional, Deng, Yangyang, additional, Chao, Hann‐Hsiang, additional, Sampaziotis, Fotios, additional, and Dahman, Bassam, additional

Published
2023
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45. LBP-15 - Evidence of durable response to bepirovirsen in B-Clear responders: B-Sure first annual report

Author

Gadano, Adrian, Arbune, Manuela, Atsukawa, Masanori, Fujiyama, Shigetoshi, Urievna Gankina, Natalya Urievna Gankina, John, Binu, Komura, Takuya, Kurosaki, Masayuki, Kweon, Young Oh, Lim, Seng Gee, Mngqibisa, Rosie, Piratvisuth, Teerha, Sagalova, Olga, Serfaty, Lawrence, Stepanova, Tatyana, Tsrancheva, Radoslava, Xie, Qing, Yuen, Man-Fung, Macfarlane, Chelsea, Corson, Stephen, Dong, Jie, Plein, Helene, Quinn, Geoff, Elston, Robert, Kendrick, Stuart, Paff, Melanie, and Theodore, Dickens

Published
2023
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46. FXR inhibition may protect from SARS-CoV-2 infection by reducing ACE2

Author

Brevini, Teresa, Maes, Mailis, Webb, Gwilym J, John, Binu V, Fuchs, Claudia D, Buescher, Gustav, Wang, Lu, Griffiths, Chelsea, Brown, Marnie L, Scott, William E, Pereyra-Gerber, Pehuén, Gelson, William TH, Brown, Stephanie, Dillon, Scott, Muraro, Daniele, Sharp, Jo, Neary, Megan, Box, Helen, Tatham, Lee, Stewart, James, Curley, Paul, Pertinez, Henry, Forrest, Sally, Mlcochova, Petra, Varankar, Sagar S, Darvish-Damavandi, Mahnaz, Mulcahy, Victoria L, Kuc, Rhoda E, Williams, Thomas L, Heslop, James A, Rossetti, Davide, Tysoe, Olivia C, Galanakis, Vasileios, Vila-Gonzalez, Marta, Crozier, Thomas WM, Bargehr, Johannes, Sinha, Sanjay, Upponi, Sara S, Fear, Corrina, Swift, Lisa, Saeb-Parsy, Kourosh, Davies, Susan E, Wester, Axel, Hagström, Hannes, Melum, Espen, Clements, Darran, Humphreys, Peter, Herriott, Jo, Kijak, Edyta, Cox, Helen, Bramwell, Chloe, Valentijn, Anthony, Illingworth, Christopher, UK-PBC Consortium, Dahman, Bassam, Bastaich, Dustin R, Ferreira, Raphaella D, Marjot, Thomas, Barnes, Eleanor, Moon, Andrew M, Barritt, Alfred S, Gupta, Ravindra K, Baker, Stephen, Davenport, Anthony P, Corbett, Gareth, Gorgoulis, Vassilis G, Buczacki, Simon JA, Lee, Joo-Hyeon, Matheson, Nicholas J, Trauner, Michael, Fisher, Andrew J, Gibbs, Paul, Butler, Andrew J, Watson, Christopher JE, Mells, George F, Dougan, Gordon, Owen, Andrew, Lohse, Ansgar W, Vallier, Ludovic, Sampaziotis, Fotios, Brevini, Teresa [0000-0002-3581-5379], Maes, Mailis [0000-0002-0266-6557], Wang, Lu [0000-0002-4418-8602], Brown, Marnie L [0000-0001-6463-0288], Scott, William E [0000-0003-1515-0514], Sharp, Jo [0000-0001-8482-5736], Neary, Megan [0000-0002-4960-2139], Tatham, Lee [0000-0001-9448-8876], Stewart, James [0000-0002-8928-2037], Darvish-Damavandi, Mahnaz [0000-0003-0226-2621], Williams, Thomas L [0000-0002-1051-0595], Crozier, Thomas WM [0000-0003-0951-4588], Bargehr, Johannes [0000-0002-9304-3573], Sinha, Sanjay [0000-0001-5900-1209], Saeb-Parsy, Kourosh [0000-0002-0633-3696], Wester, Axel [0000-0003-3634-6591], Melum, Espen [0000-0001-6903-6878], Bramwell, Chloe [0000-0001-8274-457X], Barnes, Eleanor [0000-0002-0860-0831], Moon, Andrew M [0000-0001-7163-2062], Gupta, Ravindra K [0000-0001-9751-1808], Baker, Stephen [0000-0003-1308-5755], Davenport, Anthony P [0000-0002-2096-3117], Gorgoulis, Vassilis G [0000-0001-9001-4112], Buczacki, Simon JA [0000-0002-2975-416X], Lee, Joo-Hyeon [0000-0002-7364-6422], Matheson, Nicholas J [0000-0002-3318-1851], Trauner, Michael [0000-0002-1275-6425], Fisher, Andrew J [0000-0003-4822-7223], Watson, Christopher JE [0000-0002-0590-4901], Owen, Andrew [0000-0002-9819-7651], Vallier, Ludovic [0000-0002-3848-2602], Sampaziotis, Fotios [0000-0003-0812-7586], and Apollo - University of Cambridge Repository

Subjects
Transcription, Genetic, SARS-CoV-2, Ursodeoxycholic Acid, COVID-19, Reproducibility of Results, COVID-19 Drug Treatment, Liver Transplantation, Organoids, Mice, Nasal Mucosa, Liver, Cricetinae, UK-PBC Consortium, Animals, Humans, Receptors, Virus, Angiotensin-Converting Enzyme 2, Registries, Lung, Retrospective Studies
Abstract

Acknowledgements: We thank the European Association for the Study of the Liver (EASL) and the American Association for the Study of Liver Disease (AASLD) for supporting the COVID-Hep and SECURE-Liver registries; S. Marciniak and P. J. Lehner for comments and feedback on the manuscript; I. Goodfellow for providing the viral isolate; M. Wills and S. Clare for all their work ensuring a safe CL-3 working environment; C. Cormie for general lab support; the NIHR 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, K.-I. Nikitopoulou and A. Ford for collecting blood samples; M. Colzani for advising on flow cytometry; A. Wiblin for advising on antibodies; and the Cambridge Biorepository for Translational Medicine for the provision of human tissue used in the study. T.B. was supported by an EASL Juan Rodès PhD fellowship. F.S. was supported by a UKRI Future Leaders fellowship, the Evelyn trust, an NIHR Clinical Lectureship, the Academy of Medical Sciences Starter Grant for Clinical Lecturers, the Addenbrooke’s Charitable Trust and the Rosetrees Trust. In addition, the F.S. laboratory is supported by the Cambridge University Hospitals National Institute for Health Research Biomedical Research Centre and the core support grant from the Wellcome Trust and Medical Research Council (MRC) of the Wellcome–Medical Research Council Cambridge Stem Cell Institute. The L.V. laboratory is funded by the ERC advanced grant New-Chol, the Cambridge University Hospitals National Institute for Health Research Biomedical Research Centre and the core support grant from the Wellcome Trust and MRC of the Wellcome–Medical Research Council Cambridge Stem Cell Institute. M.M., S.F. and G.D. are funded by the NIHR Cambridge Biomedical Research Centre and NIHR AMR Research Capital Funding Scheme (NIHR200640). The views expressed are those of the author(s) and not necessarily those of the NIHR or the Department of Health and Social Care. V.L.M. was funded by an MRC Clinical Research Training Fellowship. G.F.M. was funded by a post-doctoral fellowship from the National Institute for Health Research (NIHR) Rare Diseases–Translational Research Collaboration (RD-TRC) and by an MRC Clinical Academic Research Partnership (CARP) award. The UK-PBC Nested Cohort study was funded by an MRC Stratified Medicine award (MR/L001489/1). C.J.R.I. was supported by the Medical Research Council (MC_UU_12014). T.M. is funded by a Wellcome Trust Clinical Research Training Fellowship (102176/B/13/Z). The A.P.D. laboratory was supported by BHF TG/18/4/33770, Wellcome Trust 203814/Z/16/A and Addenbrooke’s Charitable Trust. The COVID-Hep.net registry was supported by the European Association for the Study of the Liver (EASL) and the SECURE-Liver registry was supported by the American Association for the Study of Liver Disease (AASLD). The lung perfusion experiment was supported by the National Institute for Health Research Blood and Transplant Research Unit (NIHR BTRU) in Organ Donation and Transplantation at Newcastle University and the University of Cambridge in partnership with NHS Blood and Transplant (NHSBT). The views expressed are those of the author(s) and not necessarily those of the NIHR, the Department of Health and Social Care or NHSBT. G.B. is funded by the European Reference Network for Hepatological Diseases (ERN RARE LIVER). A.O. acknowledges funding for preclinical research on treatment and prevention of COVID-19 from Unitaid (2020-38-LONGEVITY), the Engineering and Physical Sciences Research Council (EPSRC; EP/R024804/1), the Wellcome Trust (222489/Z/21/Z) and UK Research and Innovation (UKRI; BB/W010801/1). N.J.M. acknowledges funding from the MRC (CSF ref. MR/P008801/1 to N.J.M.), NHSBT (grant ref. WPA15-02 to N.J.M.) and Addenbrooke’s Charitable Trust (grant ref. to 900239 N.J.M.). This research was funded in whole, or in part, by the Wellcome Trust (203151/Z/16/Z, 203151/A/16/Z) and the UKRI Medical Research Council (MC_PC_17230). For the purpose of open access, the author has applied a CC BY public copyright licence to any Author Accepted Manuscript version arising from this submission., Preventing SARS-CoV-2 infection by modulating viral host receptors, such as angiotensin-converting enzyme 2 (ACE2)1, could represent a new chemoprophylactic approach for COVID-19 that complements vaccination2,3. 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 reveal that UDCA reduces the expression of ACE2 in the nasal epithelium in humans. Finally, we identify a correlation between UDCA treatment and positive clinical outcomes after SARS-CoV-2 infection using retrospective registry data, and confirm these findings in an independent validation cohort of recipients of liver transplants. In conclusion, we show that FXR has a role in controlling ACE2 expression and provide evidence that modulation of this pathway could be beneficial for reducing SARS-CoV-2 infection, paving the way for future clinical trials.

Published
2022

47. Reply

Author

John, Binu V., primary and Dahman, Bassam, additional

Published
2022
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