Respiratory failure is one of the leading causes of death due to COVID-19 infection. It occurs when the capillaries in your lung fail to exchange oxygen and carbon dioxide with the alveoli in your lungs. Death effectively occurs due to suffocation.

The gut-lung axis is one of several axes in the body involving the gut and other organs/systems. Many are familiar with the gut-brain axis, and the gut-liver axis, but there are many more. I’ve covered why the bi-directional communication between these axes is crucial for health many times. (Check this blog for more info)

Interestingly, the gut and lungs are the only organs that take things essential to life from the environment and bring them into the body. The lung with oxygen and the gut with nutrients and water.

The gut-lung axis has new relevance in the age of COVID-19. First, it’s a lower respiratory infection which includes the lung. Additionally, respiratory failure may involve both the gut and lungs. Thus, it makes sense to briefly cover how gut health affects lung health.

Using this information, perhaps tending to the gut is a useful way to prevent respiratory failure due to COVID-19 infection. Or at the very least, prevent severe illness from the virus.

Mechanisms behind the gut-lung axis

There are a few ways the gut communicates with the lung and, from a distance, regulates lung health. Some are direct effects from microbial metabolites affecting the lung, while others involve an intermediary. Finally, bacterial members of the gut microbiome find their way into the lung, causing respiratory failure.

TMAO, SCFAs, and pulmonary hypertension

Pulmonary arterial hypertension(PAH) is a condition where narrowing of the arteries that supply blood to the lungs increases blood pressure there. As a result, people who suffer from PAH often experience shortness of breath.

This causes the right side of the heart to weaken due to overload. PAH is a complication of respiratory failure, and the extra workload on the right ventricle of the heart can lead to heart failure, another common cause of death in COVID-19.

A paper published earlier this year found that people with PAH have a distinct gut microbiome. Functionally, they had higher levels of bacteria that make trimethylamine N-oxide(TMAO) and process purines.

People without PAH had higher levels of bacteria that create the short chain fatty acids(SCFAs) butyrate and propionate. Furthermore, PAH could be predicted with 83% accuracy based on the gut microbial signature.

The gut microbiome in lung inflammation

A recent review covers the importance of SCFAs in maintaining lung health. The health of the lung is dependent on the microbiome there, much like the gut. Furthermore, the gut microbiome has long-reaching effects on the lung.

SCFAs produced in the gut “…act in the lungs as signaling molecules on resident antigen-presenting cells to attenuate the inflammatory and allergic responses.” A recent paper found that the SCFA butyrate, derived from the fermentation of fiber, decreased airway hyperreactivity by inhibiting inflammatory cells in the lung.

The gut is also a source of immune cells for the lung. “Recently, innate lymphoid cells, involved in tissue repair, have been shown to be recruited from the gut to the lungs in response to inflammatory signals upon IL-25.“

The gut-bone-lung axis

Very rarely do relationships in the body only work 2 ways. Since all systems within the body are interdependent, sometimes the effects work through an intermediary. In reference to the immune system, the bone marrow often acts as that intermediary.

Hematopoiesis is the generation of blood cells, including those of the immune system. It starts in the red bone marrow, but different steps occur in other tissues as well. While SCFAs do have direct effects on the lung, they also alter lung health through changes in hematopoiesis.

Many immune cells that populate the lungs originate in the bone marrow. Some of these cells are inflammatory cells that fight infection, but also cause damage if not balanced with anti-inflammatory cells. Anti-inflammatory cells do their work after the removal of infectious agents, repairing damage to tissues.

SCFAs created in the gut prime hematopoiesis in the bone marrow to produce anti-inflammatory cells. These cells migrate to the lungs to promote a healthy balance of the immune response there.

Proper immune function is about balance. You want inflammation to clear infection, but you don’t want it to damage your lungs. Furthermore, you don’t want to completely inhibit inflammation because that would impair your ability to fight infection.

Creation of SCFAs by the fermentation of fiber in the gut plays a role in creating this balance in the immune system. Generating this balance allows the lung to fight infections and repair any collateral damage from that fight.

The inflammation dance in respiratory failure

One final avenue where the gut has a direct effect on the lungs is in respiratory failure, also known as acute respiratory distress syndrome(ARDS). Researchers identified high levels of gut bacteria in the lungs of people with ARDS.

The researchers hypothesize that the bacteria traveled there through an increase of intestinal permeability. In other words, a leaky gut.

More recent evidence supports the notion that both immune dysregulation and the presence of gut bacteria in the lung are associated with acute respiratory distress syndrome. This study found that critically ill patients with higher bacterial burden in the lung as well as the presence of gut bacteria had fewer ventilator-free days than those with low burden.

As with all axes involving the gut, it works both ways. Damage in the lungs causes damage to the gut, likely through increased systemic inflammation. Therefore, this can lead to a vicious cycle where the gut amplifies inflammation in the lungs, which amplifies systemic inflammation, which amplifies inflammation in the gut, and so on.

In fact, this model indicates that inflammation in the lungs, gut, or systemic circulation have the potential to set this cycle in motion, leading to respiratory failure. This may explain why both sepsis and conditions with chronic systemic inflammation have an increased risk for poor outcomes in COVID-19 infection.

Conclusion

Respiratory failure is one of the leading causes of death due to COVID-19. Essentially, patients die by suffocation as gas exchange between the blood and lung become impaired.

The gut-lung axis is a multi-directional hub between the gut, lung, and intermediaries that help maintain health in all organs involved. The gut helps regulate the immune function in the lung directly by the generation of metabolites such as TMAO and short chain fatty acids that help balance the immune system.

Additionally, the gut creates immune cells that traffic to the lung and uses its metabolites to create immune balance with the bone marrow as an intermediary. Finally, bacteria from the gut meet up in the lung with members of the lung microbiome, creating an environment that can create respiratory failure.

This data indicates that maintaining healthy lungs, a healthy gut, and avoiding chronic systemic inflammation may be the keys to avoiding poor outcomes from COVID-19 infection.