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. 2022 Aug 12;13:963488. doi: 10.3389/fmicb.2022.963488

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Copyright © 2022 Gang, Wang, Xue and Zhang.

This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

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Schematic diagram of the relationships among SARS-CoV-2, ACE2, host immunity, and microorganisms. (1) Microbiota metabolites such as butyrate exert anti-inflammatory effects by up-regulating arginase 1 (Arg1) expression, down-regulating Nos2, IL6, and IL-12, and inhibiting tumor necrosis factor (TNF) activity. In addition, short-chain fatty acids inhibit histone deacetylases and increase the expression of foxp3 through the GPR43 receptor, thereby enhancing the regulatory function of FOXP3 + Treg cells resulting in anti-inflammatory effects. On the other aspect, short-chain fatty acids can inhibit TMPRSS2 gene expression and up-regulate antiviral pathways to inhibit viral entry. (2) The SARS-CoV-2 is activated by TMPRSS2, binds to ACE2 and enters the gut, can destroy the gut barrier and causes microbiota dysbiosis. (3) SARS-CoV-2 infection suppresses the JAK-STAT pathway of type I and type III interferon responses, and the protein encoded by ISGF3 that limits viral infection will be diminished. Besides, SARS-CoV-2 infection downregulates the expression of ACE2, weakens its ability to regulate the RAS system, and over activates the immune response. Dysregulated gut microbes and their metabolites can also stimulate the production of cytokines, causing a cytokine storm. (4) SARS-CoV-2 spike protein activates the Ras-Raf-MEK-ERK-VEGF pathway in intestinal epithelial cells and promotes vascular endothelial growth factor (VEGF) production, which leads to vascular permeability and inflammation. (5) ACE2 regulates the expression of the amino acid transporter B0AT1, which affects microbiota composition through mTOR-mediated antimicrobial peptide production.