Microbiota and COVID-19: Long-term and complex influencing factors

Abstract

The coronavirus disease 2019 (COVID-19) is an infectious disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). According to the World Health Organization statistics, more than 500 million individuals have been infected and more than 6 million deaths have resulted worldwide. Although COVID-19 mainly affects the respiratory system, considerable evidence shows that the digestive, cardiovascular, nervous, and reproductive systems can all be involved. Angiotensin-converting enzyme 2 (AEC2), the target of SARS-CoV-2 invasion of the host is mainly distributed in the respiratory and gastrointestinal tract. Studies found that microbiota contributes to the onset and progression of many diseases, including COVID-19. Here, we firstly conclude the characterization of respiratory, gut, and oral microbial dysbiosis, including bacteria, fungi, and viruses. Then we explore the potential mechanisms of microbial involvement in COVID-19. Microbial dysbiosis could influence COVID-19 by complex interactions with SARS-CoV-2 and host immunity. Moreover, microbiota may have an impact on COVID-19 through their metabolites or modulation of ACE2 expression. Subsequently, we generalize the potential of microbiota as diagnostic markers for COVID-19 patients and its possible association with post-acute COVID-19 syndrome (PACS) and relapse after recovery. Finally, we proposed directed microbiota-targeted treatments from the perspective of gut microecology such as probiotics and prebiotics, fecal transplantation and antibiotics, and other interventions such as traditional Chinese medicine, COVID-19 vaccines, and ACE2-based treatments.

Keywords: ACE2; COVID-19; SARS-CoV-2; diagnostic model; microbiota; microbiota transplantation; traditional Chinese medicine.

FIGURE 1

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.

FIGURE 2

Potential COVID-19 therapies associated with microbiota such as prebiotics and prebiotics, fecal microbiota transplantation, antibiotics, traditional Chinese medicine, SARS-CoV-2 vaccine, and treatment based on ACE2, etc.