Considering the link between microbiota health and COVID-19 severity

With the COVID-19 pandemic in its third year, it seems possible that SARS-CoV-2 might be here to stay. There are many unknowns¹ though, including the duration of immunity (natural and post-vaccination), the emergence of viral mutants, and the link between seasons and virus transmission.

It is prudent to devise alternative and complementary strategies to combat COVID-19. An example of this would be to address the biological and clinical implications of gut microbiota in SARS-CoV-2 infection, and how they could potentially influence therapeutic aspects of the disease.

The gut microbiota is an ecosystem of micro-organisms with defined roles in nutritional metabolism, for defence against pathogens and for modulation of the immune system. The variability of the microbiota between individuals is due² to genetic and phenotypic factors, such as diet, ageing, and environment. Gut microbial dysbiosis or a reduction in the microbial diversity is commonly linked to autoimmune diseases and immune-mediated inflammatory diseases. Therefore, the ability of the gastro-intestinal tract’s resident microbiota to regulate host immune³ responses is of clinical interest.

Through metabolites such as short chain fatty acids, healthy gut microbiota can regulate distal mucosal sites such as lungs, influencing the production and egress of immune cells and antibodies, thereby carrying out immunoregulatory activities. This cross-talk, between the gut and the lungs, has been well established⁴ in homeostatic conditions, as well as during influenza virus and respiratory syncytial virus infections. It has also been observed that a healthy gut microbiota can counter a respiratory infection.

In SARS-CoV-2 infection, increased severity of disease is attributed not only to the virus itself, but also an aggressive immune response marked by a cytokine storm leading to inflammation and tissue damage. Most observations point towards the virus’s active involvement in the gastro-intestinal tract, as evidenced by the detection of viral RNA in patient fecal samples⁵. Collectively, this suggests there could be a link⁶ between the composition of gut microbiota and severity of COVID-19, where an altered gut microbial ecosystem could contribute to severe disease.

Recently, Yeoh et al⁷ found that within a COVID-19 hospitalised group, depletion of bacterial species known to show immunomodulatory effects was linked to increased levels of pro-inflammatory mediators, TNF-α, IL-10, CXCL10, and CCL2. This indicates that commensal species, such as Faecalibacterium prausnitzii and Eubacterium rectale, which were prevalent in healthy subjects, may have a role in limiting or preventing inflammation. In addition, Zuo et al⁸ observed increased severity of disease accompanied by an increased abundance of opportunistic pathogens, Coprobacillus, Clostridium ramosum and Clostridium hathewayi in COVID-19 patients.

Studies have shown that the microbiome profile remains altered for up to 30 days post-viral clearance, suggesting it may increase susceptibility to reinfections or predispose individuals to long-term health issues. The influence of the microbiome configuration on susceptibility is an area under investigation, as studies have reported a reduced abundance of bacteroides species, which are thought to have a protective role in SARS-CoV-2 infection in patients with metabolic comorbidities as compared to healthy subjects.

It is likely that during infection, commensal bacteria are replaced by opportunistic ones. It remains unclear, however, whether it is the absence of beneficial bacteria or an active role played by dysbiotic bacteria that triggers and sustains excessive inflammation during severe COVID-19 infection.

The substrates for the immune system to monitor are derived from diet. Clinical trials are underway to determine the effectiveness of supplementary agents on disease progression and severity of symptoms. Preliminary studies indicate that administration of probiotics and prebiotics induces anti-viral activity and enhances lung and intestinal microbial diversity.

These studies highlight the importance of diet⁹ and adjunctive therapies to re-establish healthy gut microbiota in infected patients. A deeper understanding of the impact of nutrition on microbial diversity and their underlying effect on immune responsiveness will pave the way for personalised approaches to treating COVID-19.