ACE2 is a highly affinitive host receptor for SARS-CoV-2, functions as a key receptor-mediated internalization of virus and plays protective component during severe acute lung injury (4). Targeting ACE2 is emerging as a novel approach to prevent SARS-CoV-2 infection and brings a higher barrier to the emergence of resistance. Recently, Brevini T et al. identified the bile acid receptor farnesoid X receptor (FXR) as a direct regulator of ACE2 transcription, the use of UDCA or compound z-guggulsterone (ZGG) could reduce FXR signaling, downregulate ACE2 expression and limit SARS-CoV-2 infection [1]. The study identified UDCA as a novel potential clinical application for the prevention of SARS-CoV-2 infection or its use in the treatment of COVID-19. However, whether this new regulatory pathway has a clinical effect is still questionable and needs to be validated in the real-world clinical studies.
To clarify the role of UDCA in the clinical prevention and treatment of COVID-19, we conducted this cohort. We found that UDCA neither prevent infection with Omicron sub-variant BA.5.2 nor shorten the duration of infection. We also found that UDCA treatment failed to prevent or mitigate the severity of COVID-19, although we do not know if the severity of liver diseases impacted the effects of UDCA in treating COVID-19. This is not to deny the inhibitory efforts of UDCA in SARS-CoV-2 infection, but rather to tell that the clinical problem is far more complex than hypothesis or experiments, and that some other factors may dominate the course of the COVID-19 in the real world. In our opinion, some reasons are under consideration: (1) FXR is widely distributed in the liver, gallbladder, intestine, kidney, and lungs, with a broad variety of functions, including bile acid and lipid metabolism, glucose homeostasis, fibrosis and inflammation [5, 6]. There should be multiple pathways in modulating FXR and UDCA is likely one of them in modulating the FXR-ACE2 pathway. (2) ACE2 is widely expressed in renal, cardiovascular, and gastrointestinal systems, type I and type II alveolar epithelial cells; ACE2 is regulated by multiple signaling pathways and is not limited to FXR [4, 7]; Competitive inhibition affects the regulation effort of the UDCA -FXR-ACE2 pathway. (3) Liver damage has been confirmed to associated with severe COVID-19, particularly decompensated cirrhosis is supposed as a risk factor for severe COVID-19 and death. We demonstrated the severity of COVID-19 in this cohort was closely associated with the severity of hepatic illness, especially the TBil, ALP, γ-GT, liver cirrhosis and Child-Pugh classification, which may outweigh the positive effects of the UDCA-FXR-ACE2 pathway[8–10].
In summary, our findings demonstrated that UDCA failed to prevent SARS-COV-2 infection and had no appreciable therapeutic effect in shortening the course of COVID-19 or reduce the severity of the disease in this real-world clinical study. Many factors are likely to affect this novel UDCA-FXR-ACE2 pathway, and more in-depth mechanistic studies and clinical validation are needed in future.