In the past weeks, scientific journals have published an increasing number of clinical and laboratory studies highlighting the involvement of gut environment and gut microbiome in COVID-19 infection and severity.

Why and how is COVID-19 infection associated with gut and gut microbiome?

We often forget that our body’s largest immune organ is our gut. Because the gut is the most hazardous and longest border our immune system has to guard, about 70% of our immune system is located in and around our gut.

Numerous scientific studies have shown that our immune system and our gut with its microbiome influence each other to orchestrate whole-body physiology and regulate immune functions. An effective and balanced collaboration between them is essential for the development and maturation of our immunity.

Our gut microbiome is the signaling hub. It constantly integrates environmental inputs with immune and gene expression signals to regulate immune responses and homeostasis. It influences not only the gut, but also other organs throughout the body.

The gut microbiome is a potent influencer, regulator, communicator, and collaborator of our immune system, impacting its maturation, function, and regeneration. In fact, the composition and function of our gut microbiome influence the quality, strength, intensity, duration, and appropriateness of any immune reaction.

A healthy gut and gut microbiome protect, but a leaky gut and an unbalanced gut microbiome may create an inflammatory environment that the coronavirus can exploit. Inflammatory proteins (cytokines) can be amplified by more cytokines when coronavirus hits. In fact, a dysregulated, runaway immune reaction can cause more damage than the virus itself.

• Several clinical studies found that gut microbiome dysbiosis, characterized by larger numbers of harmful bacteria and depletions of beneficial bacteria in both diversity and abundance, occurred in COVID-19 patients.

• Changes in gut dysbiosis were associated with COVID-19 infection severity and hematological (blood-related) parameters.

• The gut microbiome changes in COVID-19 patients as compared to normal adults were significant enough that some researchers suggested that the shifts in specific bacteria groups may serve as biomarkers for COVID-19 and predict disease severity.

• Evidence suggests that COVID-19 patients’ gut barriers were altered, with evidence of bacterial translocation. Bacterial translocation occurs when the gut barrier becomes leaky and bacteria in the gut lumen passes through into the blood circulation. It is associated with uncontrolled inflammation and may induce secondary infections. It is also an important contributor to multiple organ dysfunction, which is commonly seen in COVID-19 mortality.

• Altered and abnormal gut microbiome during infection persisted even after the clearance of COVID-19 virus and resolution of respiratory symptoms. This may be associated with a weakened immune system and some lasting symptoms such as fatigue, discomfort, and loss of sleep and appetite.

• Since the patients’ gut microbiomes were not tested before infection, it is not known whether they already had gut microbiome dysbiosis and leaky gut before infection, or if the infection caused the changes.

• Suggestions made by researchers in the studies include:

• Microbiome-targeted therapies administered at the early stage of COVID-19 infection may help reduce the number of severe and critical cases.

• Preventing bacterial translocation from the gut is a priority in the treatment of COVID-19 and associated complications.

• Because many of the findings were from smaller studies, more research and larger clinical studies are urgently needed to clearly identify interactions between COVID-19 virus and gut microbiome, and the effects of these interactions on host response to the infection.

Previous studies indicate that the gut microbiome can boost host response to respiratory viral infections, while dysbiosis of the gut microbiome can worsen the outcome of infectious respiratory diseases.

The importance of gut microbiome on our whole-body immunity is now well established and indisputable. In the last decade, scientists have gradually discovered the surprisingly strong connection between the gut microbiome and respiratory health. This connection is called the gut microbiome-lung axis.

Lung and gut microbiota play several important roles in the development, regulation, and maintenance of healthy immune responses. Dysbiosis and subsequent dysregulation of microbiome-related immunological processes affect the onset of airway and gut diseases, their clinical characteristics, and our responses to treatment.

Over the last few years, mounting evidence shows that the gut microbiome protects against airway and lung infections, including virus infections and pneumonia. Current research is assessing the effects of selected gut microbes on improving respiratory immunity and health.

Studies also show that gut microbiome depletion and dysbiosis led to an impaired lung immune response, increased respiratory virus infection vulnerability and severity, and worsened disease outcomes. For example, researchers showed that within fifty hours of pneumonia infection, 20% of mice with depleted gut microbiome had died. In contrast, all of the infected mice with an intact gut microbiome survived.

Gut microbiome also helps to determine the effectiveness of some vaccines, including flu shots (influenza is a coronavirus). It seems that gut microbiome and gut microbial-derived signals may be necessary to induce an immune response to a flu vaccine.

Studies of the gut microbiome-lung axis may provide crucial new insights into the prevalence, etiology, and potential mechanisms of COVID-19 in the respiratory and digestive tracts. These findings will help to define prevention measures, clinical care, and treatment strategies. In the meantime, knowledge of the effects of gut microbiome on respiratory virus infections and pneumonia can inform how we may strengthen our immune defense against them.

• COVID-19 virus enters the body via the nose, throat, bronchial airway, eyes, lips, mouth, and gut. But what is common to these sites? They are all mucosal surfaces (warm, soft “skins”) lined with a layer of mucus. Mucosal integrity, especially of the mouth, bronchial walls, and gut wall is therefore an important defense against virus entry. It has been suggested that in some mild cases, COVID-19 infection might have stayed in the mucosal layers of the airway or gut wall and not gone farther.

• Gut microbiome contributes to mucosal defense. For example, the secretion of mucin, a major component of mucus, is influenced by the presence and composition of the gut microbiome.

• Increasing evidence supports a common mucosal response—gut microbiome influences not only mucosal defense in the gut, but also all mucosal surfaces of our body.

• It is known that the COVID-19 virus enters our cells by binding to the enzyme receptor called ACE2 (angiotensin-converting enzyme 2) on the cell surface. ACE2 is expressed in many organs of our body, including lungs, heart, blood vessels, kidneys, gut, and brain. This is why COVID-19 can attack any of these organs. Normally, ACE2 regulates blood pressure and gut inflammation, curbing excessive inflammation. This protective effect of ACE2 is mediated by gut microbiome. The COVID-19 virus may gain entry into gut cells by binding to ACE2, thereby reducing the amount of available ACE2 to regulate gut inflammation. Gut dysbiosis and leaky gut, if already present, would make the situation even worse, increasing the risk for uncontrolled inflammation in the gut and throughout the body.

• Cross talk between gut microbiome and the lungs is vital for maintaining lung immune homeostasis, inducing appropriate and well-balanced immune responses, and educating the immune system and training its armies. Major known mechanisms attributed to the protective effects of gut microbiome during respiratory infections include stimulating production of antibodies, inducing secretion of cytokines (chemical signaling molecules that guide immune responses) and immune T cells (which activate immune cells), increasing killer cell activities, and inhibiting overzealous immune response in lung infections.

• Immune regulatory and effector cells and factors travel between the gut and the respiratory system via our lymphatic and blood circulations to induce immune response. They establish a defense parameter against incoming viruses in the airways and lungs. Early and appropriate immune responses in the airway and lungs result in quicker resolution of infection before viruses can spread and cause more severe damage.

• Since 2015, research data has demonstrated that our respiratory system not only harbors a distinct microbiome, but it also changes when our gut microbiome is altered. Both respiratory and gut microbiomes contribute to our immunity in concert.

• Commensal gut microbes induce the production of antimicrobial and antiviral peptides, secretory immunoglobulin A (IgA, antibody), and cytokines when the virus starts to multiply. These immune armies and tools are mobilized to the sites of invasion to fight off and remove the virus.

• To effectively heal the body, immune response must be well orchestrated and well regulated. The gut microbiome regulates our immune system, which, in turn, controls inflammation and ensures appropriate immune responses in the airway and lungs.

• If the immune system overreacts, inflammatory cytokine levels soar and immune cells start to attack not only the viruses but also healthy tissues, causing serious consequences such as systemic inflammation, organ failure, and death. This condition is called cytokine storm.

• One method of communication between the gut and the respiratory system to ensure effective immune signaling is through gut microbial components and metabolites, such as short-chain fatty acids (SCFAs) derived from the fermentation of dietary fibers by the gut microbes. SCFAs promote lung immunity and protect against respiratory infections. Their protective effects against respiratory virus infections are mainly indirect, through their influence and recruitment of immune cells to the lungs.

• SCFAs also help to prime immune cells in the bone marrow against respiratory system infections, limit inappropriate inflammatory immune response, and mediate and refine antiviral immune responses. Because SCFA levels in our gut and blood circulation are dependent on the fermentation of fiber by gut microbes, diet and SCFAs represent a promising potential preventive approach to respiratory virus infection.

• The status of our gut microbiome impacts the functions of almost all major physiological systems and organs in our body, including all of the known possible sites of attack by COVID-19.

• Immune responses induced at these sites are all influenced by gut wall mucosal integrity and the composition and function of our gut microbes.

In a recent scientific study, researchers analyzed how different components of the immune system respond to COVID-19 in the infected cells of ferrets and human patients. They characterized the gene expression (transcriptional) signature underlying COVID-19 pathology and compared it to other coronavirus infections.

They discovered that despite COVID-19 virus replication, host levels of the antiviral proteins (interferons) consistently remained abnormally low. At the same time, levels of some pro-inflammatory cytokines that generate nonspecific immune responses were significantly, abnormally high. The coupling of these two immune dynamics greatly compromises our defense and fighting capacity against COVID-19, while causing immune overreactions.

The weak antiviral response failed to prevent COVID-19 spread at early stages of the infection. But simultaneously, the inappropriate, dysregulated immune responses drive uncontrolled inflammation, causing lung injuries, organ failures, and death, as seen in severe cases of COVID-19.

The researchers indicated that their findings are consistent with clinical observations of COVID-19 pathology and data from other studies. To address these imbalanced immune dynamics, they proposed targeting immune regulation (immunomodulation) as a strategy. Clinical studies of new therapeutics could consider including microbiome and metabolite analyses to determine whether microbiome features correlate with responses to COVID-19 treatments, they suggested.

Further research to determine the viability and infectivity of COVID-19 in feces is also needed to control the spread of the virus, especially in asymptomatic carriers. More research is needed to establish direct links and the effects of gut and gut microbiome on COVID-19 infection.

In any event, taken together, there is strong evidence that a healthy gut and balanced microbiome protect against respiratory virus infections, improve our capacity to fight them, reduce risk of complications, improve our chance of better disease outcomes, and enhance certain vaccines’ effectiveness.

Our most ignored body system is actually our most important immune influencer.

If robust immune engagement and balanced immune regulation are indeed keys to protect and fight against COVID-19, strengthening our gut with its microbiome may fortify our defense against it.

Besides being a predictor of COVID-19 infection severity in patients, as shown in recent clinical studies, perhaps gut microbiome may also predict our susceptibility to the disease; the healthier the gut and the gut microbiome, the stronger the defense and the better the disease outcomes.

• Defense from the Inside Out
• Defense from the Inside Out Webinar Recording
• Whether your flu shot is effective is determined in your gut
• Why GI symptoms often developed with flu?
• Can you look for protection in food against flu-related lung damage?

References on how immune system works and how gut microbiome impacts immunity