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

Version 2 2023-11-06, 15:15
Version 1 2023-10-20, 13:09
journal contribution
posted on 2023-11-06, 15:15 authored by Jessica S Smyth, Jennifer K Truong, Anuradha Rao, Ruxian Lin, Jennifer Foulke-Abel, Luciano Adorini, Mark Donowitz, Paul A Dawson, Stephen KeelyStephen Keely

Intestinal inflammation and diarrhea are often associated with SARS-CoV-2 infection. The angiotensin converting enzyme 2 (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. 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. Treatment of undifferentiated colonic or ileal enteroids with OCA increased ACE2 mRNA by 2.1 ± 0.4-fold (n = 3; P = 0.08) and 2.3 ± 0.2-fold (n = 3; P < 0.05), respectively. In contrast, ACE2 expression in differentiated enteroids was not significantly altered. 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 from both 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. By virtue of its ability to modulate epithelial ACE2 expression and inhibit virus-mediated proinflammatory cytokine release, FXR represents a promising target for the development of new approaches to prevent intestinal manifestations of SARS-CoV-2. NEW & NOTEWORTHY Activation of the nuclear bile acid receptor, farnesoid X receptor (FXR), specifically upregulates ACE2 expression in undifferentiated colonic epithelial cells and inhibits virus-induced proinflammatory cytokine release. By virtue of these actions FXR represents a promising target for the development of new approaches to prevent intestinal manifestations of SARS-CoV-2 infection. 

Funding

National Institutes of Health Grant DK047987

NIH/NIDDK P30DK089502

NIH RO1DK116352

NIH RO16523

Science Foundation Ireland (SFI) Grants 16-IA-4445 and 17TIDA5050

History

Comments

The original article is available at https://journals.physiology.org/

Published Citation

Smyth JS. et al. Farnesoid X receptor enhances epithelial ACE2 expression and inhibits virally induced IL-6 secretion: implications for intestinal symptoms of SARS-CoV-2. Am J Physiol Gastrointest Liver Physiol. 2023;325(5):G446-G452.

Publication Date

10 October 2023

PubMed ID

37697930

Department/Unit

  • School of Pharmacy and Biomolecular Sciences

Publisher

American Physiological Society

Version

  • Accepted Version (Postprint)