Ursodeoxycholic Acid Reduces Angiotensin-Converting Enzyme 2 Activity and Suppresses Cytokine Storm Syndrome in Patients With Coronavirus Disease 2019.

Ursodeoxycholic acid (UDCA) decreases angiotensin-converting enzyme 2 (ACE2) activities by inhibiting farnesoid X receptor (FXR). To investigate the role of UDCA in decreasing SARS-CoV-2 infection and affecting COVID-19 cytokine levels, COVID-19 patients (n = 142, male = 72, female = 70) were divided into UDCA-free (n = 53) and UDCA (n = 89) groups and treated with nirmatasvir/ritonavir or molnupiravir for 5 days. Patients in the UDCA group were additionally administered UDCA for 10 days. On Day 0 (before treatment), 3, 6, and 9 (after anti-viral drug and/or UDCA treatment), levels of ACE2 in serum and plasma or ACE2 mRNA in blood cells in the UDCA groups were significantly lower than those in the UDCA-free group. In Calu-3 cells, UDCA reduced ACE2 protein and mRNA, and blocked the COVID-19 spike (XBB.1.5) pseudovirus infection. Serum cytokines have been detected in COVID-19 patients with or without taking UDCA. Among the 46 cytokines analyzed, luminex profiling revealed that 21 proinflammatory cytokines, including CTACK, bFGF, G-CSF, GM-CSF, GRO-α, IL-1β, IL-1Ra, IL-2, IL-2Rα, IL-6, IL-10, IL-16, IP-10, MCP-1, MCP-3, MIG, TNF-α, TRAIL, VEGF, IL-9, and IL-18, were significantly lower with UDCA treatment (p < 0.01), whereas only eotaxin levels increased (p < 0.05). Therefore, UDCA reduces ACE2 activity, improves clinical outcomes, and suppresses cytokine storm syndrome (CSS) in COVID-19 patients.