Farnesoid X receptor enhances epithelial ACE2 expression and inhibits viral-induced IL-6 secretion: implications for intestinal symptoms of SARS-CoV-2.

BACKGROUND: Intestinal inflammation and diarrhea are often associated with SARS-CoV-2 infection. The ACE2 receptor plays a key role in SARS-COV-2 pathogenesis, facilitating entry of the virus into epithelial cells, while also regulating mucosal inflammatory responses. Here, we investigated roles for the nuclear bile acid receptor, farnesoid x receptor (FXR), in regulating ACE2 expression and virally-mediated inflammatory responses in intestinal epithelia.

METHODS: Human colonic or ileal enteroids and cultured T84 and Caco-2 monolayers were treated with the FXR agonists, obeticholic acid (OCA) or GW4064, or infected with live SARS-CoV-2 (2019-nCoV/USA_WA1/2020). Changes in mRNA, protein or secreted cytokines were measured by qPCR, western blotting, and ELISA.

RESULTS: Treatment of undifferentiated colonic or ileal enteroids with OCA increased ACE2 mRNA by 2.1 ± 0.4 (n = 3; p = 0.08) and 2.3 ± 0.2 (n = 3; p < 0.05) fold, respectively. In contrast, ACE2 expression in differentiated enteroids was unaltered. FXR activation in cultured epithelial monolayers also upregulated ACE2 mRNA, accompanied by increases in ACE2 expression and secretion. Further experiments revealed FXR activation to inhibit IL-6 release both from Caco-2 cells infected with SARS-CoV-2 and T84 cells treated with the viral mimic, polyinosinic-polycytidylic acid by 46 ± 12% (n = 3, p < 0.05) and 35 ± 6% (n = 8; p < 0.01), respectively.

CONCLUSION: By virtue of its ability to modulate epithelial ACE2 expression and inhibit virus-mediated pro-inflammatory cytokine release, FXR represents a promising target for development of new approaches to prevent intestinal manifestations of SARS-CoV-2.