How gut microbes influence the immune response to SARS-CoV-2

Article published in Critical Reviews in Food Science and Nutrition The journal provides an overview of the role of the gut microbiota in shaping the host immune response to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).

Study: Gut Microbiome and Antiviral Immunity in COVID-19.  Image credit: Design_Cells/Shutterstock

Stady: The gut microbiome and antiviral immunity in COVID-19. Image credit: Design_Cells/Shutterstock


SARS-CoV-2, the pathogen causing pandemic coronavirus 2019 (COVID-19), is an RNA virus that primarily affects the upper and lower respiratory tracts. It is also known that the virus potentially targets the gastrointestinal (GI) tract and impairs the composition and diversity of the gut microbiota.

The gut microbiota is a collection of microbes that normally live in the digestive tract. The digestive system contains trillions of microbes that interact with each other to regulate various physiological processes, including the immune system. A change in the composition and diversity of the gut microbiota is called dysbiosis, which impairs the immune and inflammatory response.

Gut microbiota and COVID-19

Gastrointestinal symptoms, including nausea, vomiting and diarrhea, are observed in 60% of COVID-19 patients. An imbalance of the intestinal microbiota has been observed in COVID-19 patients, regardless of the presence of gastrointestinal symptoms. Importantly, dysbiosis has been observed to persist for up to 6 months after clinical clearance of SARS-CoV-2 from the respiratory tract.

Changes in the gut microbiota commonly observed in patients with COVID-19 include decreased numbers of bacteria commensal with immune-modulating functions that help maintain gastrointestinal barrier integrity and immune homeostasis.

A significant proportion of COVID-19 patients develop long-term symptoms, which are medically termed long-term COVID. Studies have shown that people who have had COVID for a long time have reduced numbers of commensal bacteria and altered overall gut bacteria. In addition, a decrease in the number of bacteria is associated with an increased serum concentration of inflammatory mediators in these patients.

The decrease in the number of commensal bacteria is accompanied by the enrichment of pathogenic bacteria and a reduction in the diversity of microorganisms in the intestine. Studies have suggested that these changes in the composition and diversity of gut microbiota may be associated with increased intestinal permeability, microbial translocation, excessive inflammation, and poor prognosis for COVID-19.

Besides bacteria, SARS-CoV-2 infection is known to alter the gut flora population. Enrichment in opportunistic fungal pathogens was observed in COVID-19 patients. Pathogens such as these are associated with pneumonia and respiratory symptoms and affect the pool of gut bacteria.

The gut microbiome and host cell entry of SARS-CoV-2

spike glycoprotein of SARS-CoV-2 interacts with the host cell membrane receptor angiotensin-converting enzyme 2 (ACE2) to initiate the virus entry process. Besides respiratory epithelial cells, ACE-2 is expressed at a high level in the stomach, ileum, and colon, highlighting the possibility of direct viral entry into the gastrointestinal tract.

It is known that the abundance of some bacterial species that downregulate ACE2 expression is negatively associated with the severity of COVID-19. People with diabetes or obesity show lower abundances of these bacteria and are at higher risk of COVID-19-related deaths.

Gut microbiome and immune response to SARS-CoV-2 infection

The gut microbiota is known to stimulate the antiviral immune response by modulating type I interferon signaling. In severe COVID-19 patients, an impaired antiviral response and a suppressed adaptive immune response are known to cause lung damage. The change caused by SARS-CoV-2 in the gut microbiota may be associated with these diseases.

The Inflammasome, a cytosolic multiprotein complex, is known to be associated with COVID-19 disease. Recent evidence has indicated that inflammatory particles induce release of neutrophil extracellular traps by neutrophils in severe COVID-19 patients, which in turn is associated with impaired lung function.

Altered gut bacteria may contribute to the pathogenesis of COVID-19 by promoting inflammasome activation. For example, in COVID-19 patients with cardiac disorders, increased activation of inflammatory particles and elevated markers of leaky gut, such as lipopolysaccharide binding protein, were observed.

The gut microbiome is vital to regulating the adaptive immune system. For example, in response to a viral infection, the gut microbiota stimulates the activation of B cells and T cellsthus participating in the production of antibodies and the production of immune memory cells to the virus.

Administration of specific commensal bacteria has been found to increase levels of neutralizing antibodies in the blood in response to viral vaccination. Similar effects have been seen in patients with COVID-19.

The gut-lung immune axis

Gut bacteria play an essential role in regulating lung health. Immune cells travel from the gut to the respiratory tract to destroy invading pathogens. This is called the gut-lung immune axis.

A change in the composition of the gut microbiota increases the risk of developing respiratory diseases, such as asthma. In COVID-19 patients, opportunistic upper respiratory tract bacteria have been identified in the gut microbiota. Similarly, an abnormality in the lung microbiota has been observed in COVID-19 patients with dysbiosis. These observations highlight that bidirectional transmission of microbes occurs between the gut and the lung.

Modulation of the gut microbiota as a therapeutic intervention for COVID-19

Given the significant association between dysbacteriosis and the anti-SARS-CoV-2 immune response, modulation of the gut microbiota has been considered as a potential therapeutic intervention for COVID-19.

Transplantation of fecal microbiota, which represents the whole gut microbiota, from a healthy donor into the recipient’s gastrointestinal tract is a potential strategy for the treatment of bacterial infection. This strategy is currently under clinical investigation in COVID-19 patients.

Dietary prebiotics are non-digestible fibers used to increase commensal bacteria and reduce pathogenic bacteria. There is evidence to suggest health benefits of prebiotics in COVID-19 patients.

Probiotics are live organisms that have immunomodulatory effects. In addition, the peptides produced by the probiotics showed ACE-2 inhibitory effects. Thus, probiotics are a potential adjuvant strategy in the treatment of COVID-19 patients.

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