The last two years have been like no other. A dystopian novel brought to life, the recent pandemic has wreaked havoc across the world, changing not only the way we live and work, but perhaps the human microbiome too. 

Coronavirus, also known as COVID-19, is a respiratory disease caused by SARS-CoV-2 which ranges from mild symptoms such as cough and fever to severe pneumonia with multiple organ failure and acute respiratory disease syndrome (ARDS). Predominantly affecting the lungs, respiratory disorders have also been linked to the human microbiome; the full array of microorganisms (the microbiota) that live on and in humans.

Because COVID-19 is a new disease, little is known about the relationship between the respiratory condition and the microbiome. That said, recent studies have started to delve into the topic, looking at differences in microbial compositions of COVID-19 patients and their healthy counterparts, links between disease severity and dysbiosis, as well as the chicken and egg conundrum that still baffles microbiome researchers today: are changes to the microbiome a cause or a consequence of diseases such as COVID-19?

This blog post highlights current findings in the relationship between COVID-19 and the human microbiome, and discusses the ways in which  ‘COVID normal’ may inadvertently be affecting the microscopic creatures living within us. 

What does the microbiome of COVID-19 patients look like?

When COVID-19 first hit, it was thought the disease primarily affected the respiratory system. However, evolving research shows that the virus impacts other parts of the body, including the microbiome. 

Often described as the largest immune organ in the body, the microbiome contains both ‘good’ and ‘bad’ bacteria. The microbial communities work together to maintain a state of homeostasis, keeping the body running optimally. When there is a decrease in ‘good’ bacteria or an increase in ‘bad’ bacteria however, disease can ensue, an outcome that has been observed in patients with COVID-19.

Microbial patterns

According to research, respiratory disorders are directly or indirectly associated with specific microorganism patterns (1). For example, people suffering from influenza have a disturbed upper respiratory tract microbiome, carrying an abundance of Pseudomonadales; an order of Proteobacteria. Interestingly, COVID-19 is also associated with particular microbiome patterns.

A study of ICU patients with COVID-19, including ARDS (a syndrome caused by a cytokine cascade), showed these patients had a profusion of proinflammatory cytokines, which correlated with a specific pattern of the gut microbiome (1). These patterns included stimulus specific microbe-cytokine interactions, cytokine production connected to the abundance of a specific gut microbial species or function, and microbial components affecting only the response of a particular cytokine and only in connection with a specific stimulation (4).

Dysbiosis in the fecal and respiratory tract microbiome of COVID-19 patients

Studies looking at associations between the microbiome and COVID-19 sampled the microbiome using stool, nose or throat swab, bronchoalveolar lavage fluid (sample from the lungs) and lung tissue. 

What the samples showed was that the human fecal and respiratory tract microbiome changed in COVID-19 patients. Specifically, there appeared to be a reduction in bacterial diversity in patients with COVID-19 or influenza compared to healthy controls (1). 

Evidence so far suggests changes to the microbiome in COVID-19 and influenza patients may be location dependent. While studies show that the airway microbiome was different from healthy controls, there was little difference seen in the nasopharyngeal microbiome compared to control individuals. 

Along with dysbiosis, COVID-19 patients were also seen to have increased numbers of opportunistic pathogens (1); types of commensal bacteria that given the chance, such as in the case of dysbiosis or when the immune system is compromised, may become pathogenic. Almost half of the covid patients were found to have an enriched number of potentially pathogenic microorganisms, the most abundant being Candida albicans and human alpha-herpesvirus as well as a number of viral pathogens including the human influenza virus, compared to healthy controls (1). 

Alarmingly, research has found that COVID-19 patients who have been treated with broad spectrum antibiotics have an almost 2-fold higher mortality from septic shock, thought to be associated with the higher risk of secondary infections by drug-resistant pathogenic bacteria (2).

While there appears to be a relationship between opportunistic bacteria and the microbiome, more research is needed to understand the mechanisms by which these opportunistic bacteria adversely affect health.

Curiously, one study showed that pharyngeal microbiome diversity decreased in older covid infected adults compared to younger covid infected adults; a possible explanation for the differences in severity observed between the two age groups (1).

Does the microbiome influence severity of COVID-19?

A potential connection between the severity of COVID-19 and microbiome dysbiosis has recently been established.

Dysbiosis is when there is a reduction in microbial diversity, as well as an imbalance between beneficial and harmful microbial populations. Studies have found that the microbiomes of patients infected by SARS-Cov-2 differ according to the severity of the condition, the idea being that SARS-CoV-2 may be disrupting microbial populations.

For example, one study showed that there was a negative correlation with severe covid and Faecalibacterium abundance (a genus of bacteria reported to be associated with reducing intestinal inflammation), showing how the dysbiosis of the microbiome could be a factor contributing to severe COVID-19 (1). 

Highlighting that opportunistic bacteria may pose a threat to immunity and increased opportunistic infections in proportion to SARS-COV-2 infection severity, one study showed that the number of specific opportunistic pathogens were increased in fecal samples with high SARS-CoV-2 infectivity compared to those in fecal samples with low to no SARS-COV-2 infectivity. Conversely, fecal samples with low or no SARS-CoV-2 infectivity had increased levels of the type of bacteria which produce short-chain-fatty acids (especially butyric acid), a metabolite that plays an important role in boosting immunity (1). 

Finally, another paper reported no significant difference in gut microbiota abundance and diversity between patients with mild and severe covid, demonstrating the need for more research to be conducted in this area (1). 

While it’s still not known whether preexisting dysbiosis contributes to more severe COVID-19 or whether COVID-19 is the cause of dysbiosis, a clue to the connection might be in the fact that conditions such as diabetes, obesity and high blood pressure which have higher risk of severe COVID-19 development (3), have also been associated with unhealthy microbiomes. Studies exploring the microbiota before and after COVID-19 will hopefully help resolve the chicken or the egg conundrum.  

Can we manipulate the microbiome to prevent covid?

Microbes play an important role in our immune response to respiratory viral infection. In the future, the composition of the microbiome may be used as a tool for predicting COVID-19 disease progression. If that is the case, early control of the microbiome, through means such as probiotics, fermented food and/or fecal transplants, might be effective in preventing and managing the disease (1). 

Several trials testing the efficacy of probiotics for COVID-19 are currently underway. As of yet, the effects of manipulating the gut microbiome remain uncertain, and it’s hoped that the results of such trials will shed more light on the subject.

What impact does pandemic life have on the microbiome?

Given that the microbiome plays an important role in immunity, anything that acts to reduce diversity of the microbiome may have a knock-on effect on health. 

The pandemic has forced many people to adopt new behaviours, ones which unfortunately don’t always align with good gut health. Social distancing and increased antibacterial use, while good measures for avoiding the virus, could be detrimental to microbial diversity; a key indicator of good health. That’s not to mention the increase in stress as well as consumption of carb-rich / low fibre comfort food that tend to go hand-in-hand with challenging times. Whether these COVID-19 related behavioral and dietary changes impact health later down the road, only time will tell. 

Conclusion

From public health and travel to the global economy and office hours, COVID-19 has had a far-reaching effect on the world in which we live. 

Limited evidence suggests that COVID-19 patients have altered gut and respiratory tract microbiomes along with an increased abundance of opportunistic bacteria and pro-inflammatory cytokines; all of which could be determiners of disease severity. As of now, the question of causality remains unresolved, and only further research will help to determine whether microbial changes can be added to COVID-19’s long list of effectors.

It is with great hope that scientists may one day better understand the relationship between respiratory virus infections and the human microbiome, a result which might lead to healthier outcomes for those inflicted by this terrible disease. 

Brigid xx

References

1.) Yamamoto, Shinya et al. “The human microbiome and COVID-19: A systematic review.” PloS one vol. 16,6 e0253293. 23 Jun. 2021, doi:10.1371/journal.pone.0253293

2.) Venzon M, Bernard-Raichon L, Klein J, Axelrad J, Hussey G, Sullivan A, Casanovas-Massana A, Noval M, Valero-Jimenez A, Gago J, Wilder E, Team YIR, Iwasaki A, Thorpe L, Littman D, Dittmann M, Stapleford K, Shopsin B, Torres V, Ko A, Cadwell K, Schluter J. Gut microbiome dysbiosis during COVID-19 is associated with increased risk for bacteremia and microbial translocation. Res Sq [Preprint]. 2021 Jul 27:rs.3.rs-726620. doi: 10.21203/rs.3.rs-726620/v1. PMID: 34341786; PMCID: PMC8328072.

3.) Medical Conditions. CDC. https://www.cdc.gov/coronavirus/2019-ncov/need-extra-precautions/people-with-medical-conditions.html#MedicalConditionsAdults. November 16, 2021

4.) Schirmer, Melanie et al. “Linking the Human Gut Microbiome to Inflammatory Cytokine Production Capacity.” Cell vol. 167,4 (2016): 1125-1136.e8. doi:10.1016/j.cell.2016.10.020