Covid-19: is microbiota the missing clue?
After three years of Covid-19, there is accumulating evidence that gut microbiota but also oral, nasal and lung are significantly altered in patients with COVID-19. How does it work? Is there a link between the virus, immunity and the microbiota?
Irina Spacova & Sarah Lebeer (respectively Senior postdoctoral researcher and Professor at Antwerp University in Belgium) review the latest major findings.
About this article
Table of contents
Table of contents
Which role may play the microbiota in Covid-19 infection?
Prof. Irina Spacova and Prof. Sarah Lebeer: COVID-19 does not have the same effect on everyone: some of us remain asymptomatic, while others suffer for months or even years from residual symptoms such as fatigue and muscle weakness. In addition to sociodemographic factors such as age, recent studies suggest that individual differences in our microbiota play an important role in determining COVID-19 outcomes. Indeed, our bodies are inhabited by diverse microbial communities in the gastrointestinal tract and the airways where the SARS-CoV-2 infection takes place. Many of the (sidenote: Microorganisms Living organisms that are too small to be seen with the naked eye. They include bacteria, viruses, fungi, archaea and protozoa, and are commonly referred to as “microbes”. What is microbiology? Microbiology Society. ) within the microbiota play a protective gatekeeper function against invading (sidenote: Pathogen A pathogen is a microorganism that causes, or may cause, disease. Pirofski LA, Casadevall A. Q and A: What is a pathogen? A question that begs the point. BMC Biol. 2012 Jan 31;10:6. ) .
Some microbiota members are themselves (sidenote: Opportunistic infection An infection caused by a microorganism that is normally non-pathogenic, but which becomes so when the host microbiota loses its balance (through factors such as a weakened immune system, disease, age, certain medication, etc.). ) that can cause bacterial or fungal superinfections and additional inflammation when the barrier and immunological defenses are disrupted. Thus, a balanced microbiota is key for respiratory and gastrointestinal health, especially during viral infection.
Does the virus impact the gut, oral, nasal and lung microbiota in the same way?
I. S. & S. L.: COVID-19 is linked to microbiota disruptions (sometimes also named dysbiosis) of the gut, oral, nasal and lung microbiota, with many studies reporting less diverse microbial communities in infected patients at these major sites of infection and multiplication of the virus. However, not all studies observe the same alterations in microbiota diversity.
We summarize the main overall findings in what follows:
- The nasal passage, the mouth and especially the throat (the ENT microbiota) are two key sites of SARS-CoV-2 infection and multiplication. Patients with confirmed COVID-19 have generally a lower microbial diversity in nasopharyngeal swabs. The microbial community richness also seems to decrease with increasing disease severity 1. An increased abundance of a specific bacterium, for example bacterial pathogens such as Pseudomonas aeruginosa is also found in the nasal microbiota of hospitalized patients with COVID-19 2. This indicates that SARS-CoV-2-induced inflammation could promote the growth of opportunistic pathogens in the nose, resulting in superinfection. In the mouth, the oral microbiota also seems to be less diverse associated with the severity of the COVID-19 symptoms. Finally, opportunistic fungal pathogens Candida and Aspergillus, as well as bacteria associated with poor oral hygiene and periodontitis, are more abundant in COVID-19 patients 3.
The ENT microbiota
- Severe COVID-19 can result in acute respiratory distress syndrome (ARDS) associated with widespread inflammation in the lungs (pulmonary microbiota), often requiring prolonged mechanical ventilation in hospital settings. There appears to be a significant association between severe COVID-19 requiring mechanical ventilation and a lower microbial community diversity compared to a healthy lung samples 4. Furthermore, lung samples from these patients are frequently dominated by single bacterial genera that contain potential pathogens such as Staphylococcus and Enterococcus.
The pulmonary microbiota
- In the gastrointestinal tract (gut microbiota), COVID-19 is associated with symptoms such as diarrhea and loss of appetite. Therefore, it is not surprising that it has been linked with an intestinal dysbiosis. Notably, Candida and Aspergillus (opportunistic fungal pathogens) appear to also increase in the fecal microbiota of COVID-19 patients 5 and potentially beneficial bacteria such as Faecalibacterium prausnitzii to decrease 6. A striking research finding was that the composition of gut microbiota at admission might be predictive of long-term complications of COVID-19. At admission compared to long-term COVID-19 at 6 months, a total of 13 bacteria species, including Bifidobacterium longum were negatively correlated with long COVID-19: that means that the more these bacteria are present in your gut, the less risk you will have to develop long term COVID-19, indicating a putative protective role of these species in the recovery from the infection 6. Other species such as Atopobium parvulum were positively correlated with symptoms: the more we found this bacteria in your gut, the more you will suffer severe infection. These differences open up possibilities for better monitoring and predicting of long COVID-19 symptoms.
The gut microbiota
What is the link between the virus, immunity and the microbiota?
I. S. & S. L.: It is still not well understood whether these observed microbiota changes are cause or consequence of the disease. To better understand this, it is also important to take the immune system into account. Effective immune responses need to be generated upon SARS-CoV-2 infection to clear the virus and prevent future reinfections.
Even before the COVID-19 infection takes place, the resident microbiota can serve a protective function by training our immune system, enhancing the barrier function 7 or even directly inhibiting adherence or infectivity of the virus 8. Conversely, a disrupted gut microbiota can increase susceptibility to viral disease through disrupting the intestinal mucosal barrier function, impaired antiviral responses and increase in pathogen colonization and adhesion 9.
May healthy diet or probiotics protect against the virus by modulating the gut microbiota?
I. S. & S. L.: As you can understand, disentangling the complex relationship between the microbiota and COVID-19 is a challenging task, since our microbiota composition and immune functioning are affected by many different factors (health, genetics, lifestyle). However, since diet is an important determinant of the human gut microbiota composition, dietary changes hold some promise against COVID-19. For example, a smartphone-based study with more than 30.000 COVID-19 cases in the UK and the USA has suggested that plant-based foods consumption is linked with lower risk and severity of COVID-19 10. An interesting theory has been proposed that eating large quantities of fermented vegetables potentially containing beneficial microorganisms might be helpful in mitigating COVID-19 disease severity 11. This is a plausible approach, considering that gut microbiota modulation with (sidenote: Probiotics Live microorganisms that, when administered in adequate amounts, confer a health benefit on the host. FAO/OMS, Joint Food and Agriculture Organization of the United Nations/ World Health Organization. Working Group. Report on drafting guidelines for the evaluation of probiotics in food, 2002. Hill C, Guarner F, Reid G, et al. Expert consensus document. The International Scientific Association for Probiotics and Prebiotics consensus statement on the scope and appropriate use of the term probiotic. Nat Rev Gastroenterol Hepatol. 2014;11(8):506-514. ) bacteria often found in fermented foods may prevent or treat acute respiratory infections based on evidence from clinical research 12.
A small-scale study administering oral probiotic mix of bacteria in patients infected with SARS-CoV-2 reported a decreased risk for respiratory failure and quicker resolution of diarrhea 13.
Overall, the World Health Organization recommends that COVID-19 patients adhere to a healthy diet with fresh and unprocessed foods every day and less salt and sugar, which could support a balanced gut microbiota and optimal general health. Yet, this is a general true for all of us at all time: if only eating healthy could be this easy!
Discover Prof. Sarah Lebber's interview:
2. Rhoades NS, Pinski AN, Monsibais AN, et al. Acute SARS-CoV-2 infection is associated with an increased abundance of bacterial pathogens, including Pseudomonas aeruginosa in the nose. Cell Rep. 2021 Aug 31;36(9):109637
3. Soffritti I, D'Accolti M, Fabbri C, et al. Oral Microbiome Dysbiosis Is Associated With Symptoms Severity and Local Immune/Inflammatory Response in COVID-19 Patients: A Cross-Sectional Study. Front Microbiol. 2021 Jun 23;12:687513.
11. Bousquet J, Anto JM, Czarlewski W, et al. Cabbage and fermented vegetables: From death rate heterogeneity in countries to candidates for mitigation strategies of severe COVID-19. Allergy. 2021 Mar;76(3):735-750
13. d'Ettorre G, Ceccarelli G, Marazzato M, et al. Challenges in the Management of SARS-CoV2 Infection: The Role of Oral Bacteriotherapy as Complementary Therapeutic Strategy to Avoid the Progression of COVID-19. Front Med (Lausanne). 2020 Jul 7;7:389.