A New Butyrate Releaser Exerts a Protective Action against SARS-CoV-2 Infection in Human Intestine.

Lorella Paparo,Pellegrino Cerino,Maddalena Cortese,Vito Alessandro Lasorsa,Maria Antonia Maglio,Riccardo Troncone,Cristina Bruno,Alessia Romano,Erika Punzo,Veronica Ferrucci,Maurizio Viscardi,Massimo Zollo,Mario Capasso,Giovanna Fusco

doi:10.3390/molecules27030862

Abstract

Butyrate is a major gut microbiome metabolite that regulates several defense mechanisms against infectious diseases. Alterations in the gut microbiome, leading to reduced butyrate production, have been reported in patients with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. A new butyrate releaser, useful for all the known applications of butyrate, presenting physiochemical characteristics suitable for easy oral administration, (N-(1-carbamoyl-2-phenyl-ethyl) butyramide (FBA), has been recently developed. We investigated the protective action of FBA against SARS-CoV-2 infection in the human small intestine and enterocytes. Relevant aspects of SARS-CoV-2 infection were assessed: infectivity, host functional receptor angiotensin-converting enzyme-2 (ACE2), transmembrane protease serine 2 (TMPRSS2), neuropilin-1 (NRP1), pro-inflammatory cytokines expression, genes involved in the antiviral response and the activation of Nf-kB nuclear factor (erythroid-derived 2-like) 2 (Nfr2) pathways. We found that FBA positively modulates the crucial aspects of the infection in small intestinal biopsies and human enterocytes, reducing the expression of ACE2, TMPRSS2 and NRP1, pro-inflammatory cytokines interleukin (IL)-15, monocyte chemoattractant protein-1 (MCP-1) and TNF-α, and regulating several genes involved in antiviral pathways. FBA was also able to reduce the number of SARS-CoV-2-infected cells, and ACE2, TMPRSS2 and NRP1 expression. Lastly, through the inhibition of Nf-kB and the up-regulation of Nfr2, it was also able to reduce the expression of pro-inflammatory cytokines IL-15, MCP-1 and TNF-α in human enterocytes. The new butyrate releaser, FBA, exerts a preventive action against SARS-CoV-2 infection. It could be considered as an innovative strategy to limit COVID-19.

Highlights

There is a global pandemic of coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) [1]
In a first set of experiments, we investigated the direct effect of FBA on the expression of the main molecular players of SARS-CoV-2 infection: angiotensin-converting enzyme-2 (ACE2), transmembrane protease serine-2 (TMPRSS2), NRP1 [4,5,6,7] and inflammatory cytokines
We found that ACE2, TMPRSS2 and NRP1 expression, the cellular mediators that facilitate SARS-CoV-2 entry into host cells, were significantly reduced by FBA

Summary

Introduction

There is a global pandemic of coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) [1]. The gastrointestinal tract is a major target organ for SARS-CoV-2 infection, with many patients presenting with gastrointestinal symptoms, such as nausea/vomiting, diarrhea and abdominal pain. These symptoms are even more frequent in severe COVID-19 patients [2,3]. As consequence of SARS-CoV-2 infection, host defenses launch a counterattack, releasing inflammatory cytokines, resulting in a “cytokine storm” [8]. The inflammation induced by SARS-CoV-2 infection is reflected by high blood levels of several inflammatory cytokines [10]. Phosphate food additives, including long chain PolyP, have been proven at low doses to inhibits SARS-CoV-2 infection and “the cytokine storm” [13]

Methods

Results

Conclusion