The coronavirus disease 2019 (COVID-19) pandemic, triggered by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has caused over 5.5 million deaths amidst hundreds of millions of infections worldwide. Without specific treatments, the outlook is bleak as new variants emerge, mocking the immunity gained from infection by earlier variants or vaccination based on the ancestral spike antigen.
Study: Potential Associations Between Microbiome and COVID-19. Image Credit: Rost9/Shutterstock
To better understand how the disease progresses, a recent paper in the journal Frontiers in Medicine discusses the role of the human microbiota in this condition.
The human organism includes about 1.5-3 kg of microbes, parasitic, symbiotic, or commensal. These occur mainly in the gut, mouth, skin, and vagina, among other sites. These microbes affect human physiology via their contribution to digestion and nutrition within the human gut, vitamin synthesis, immunomodulation, regulation of energy production and storage, and the production of a diverse range of active compounds.
The human microbiome is also being examined for its role in COVID-19 severity and symptomatology and may provide a novel target for treating or preventing this condition. Changes have been documented in the intestinal and lung microbiome in these patients, with fewer beneficial and more pathogenic bacteria.
Gut microbiota in COVID-19
The severity of COVID-19 was found to be related to alterations in the fecal microbiome, with increases in some species coupled with declines in others. Some species were inversely related to the viral load in fecal samples and the angiotensin-converting enzyme 2 (ACE2) receptor expression in host tissues.
An analysis of the changes turned up a five-genus marker that predicted the presence of COVID-19 with high accuracy - Intestinibacter, Fusicatenibacter, Actinomyces, Romboutsia, and Erysipelatoclostridium. When compared with flu patients harboring the H1N1 virus, there were seven biomarkers that differentiated the two groups.
The gut microbiome changes also correlated with other clinical markers such as the white cell and platelet count, D-dimer levels, and other inflammatory mediators.
The fungal composition of the stool in COVID-19 also changed significantly, with hospitalized patients showing increased yeast particles (Candida albicans) and an increase in fungal diversity by 2.5 times compared to healthy controls. Many opportunistic pathogens showed higher levels, such as Candida albicans, Auris candida, and Aspergillus flavus.
The latter persisted in stool samples in a small subset of patients, while the gut took several days to return to the normal fungal microbiome.
The lung microbiome
The lung microbiome in COVID-19 patients did not show a difference from that seen in patients with community-acquired pneumonia. Nasopharyngeal and lung bacteria seem to be protective against the growth and attachment of SARS-CoV-2 to the host tissues. However, patients admitted in the intensive care unit (ICU) with COVID-19 lose two genera, Bifidobacterium and Clostridium. At the same time, another set are found only in these patients – Salmonella, Scardovia, Serratia, and fruit bacilli.
Such findings may help screen patients with SARS-CoV-2 infection by the severity of infection.
The oral microbiome
The oral microbiome shows reduced diversity in confirmed patients compared with healthy controls, especially among butyrate-producers, while lipopolysaccharide-producers were increased. A set of 8 oral microbes or seven fecal microbes showed the ability to diagnose over 85% of patients with COVID-19.
Some bacteria predict a higher susceptibility to the virus, such as Fusobacterium periodonticum. While some species are found at higher levels, others decrease in COVID-19 patients. Severe COVID-19 is associated with declining Fusobacterium levels.
Microbial mechanism in COVID-19
Some patients with COVID-19 showed an abundance of opportunistic bacteria correlated with high infectivity in the gut. These microbes are known to be very active in synthesizing nucleotides and amino acids and in glycolysis. Less- or non-infective patients showed higher amounts of short-chain fatty acid (SCFA) producers, such as certain Lachnospiraceae bacteria and Alistipes onderdonkii.
One study reported the isolation of active infectious SARS-CoV-2 particles from the stool of a COVID-19 patient, showing that the virus produces gut infection.
ACE2 expression in intestinal epithelium makes this a putative site of viral attachment in the gut, which may cause the loss of ACE2 and the overactivity of angiotensin II receptor type 1. Gut permeability may be abnormally increased following a decrease in ACE2.
This molecule is key to immune function, amino acid homeostasis, protection against colitis, and maintaining a healthy gut microbiome. In turn, its expression depends on the gut microbiome. As a result, COVID-19 is likely to cause changes in the lung and intestine, starting with the loss of ACE2.
The resulting loss of protection from ACE2 leads to renin-angiotensin-system impairment, resulting in hyper-inflammation and the cytokine storm, with multi-organ damage. The altered intestinal microbiota, loss of intestinal epithelial integrity, and the poor immune response at local and systemic levels are all exacerbated by the lack of normal ACE2 expression.
Microbiome and mitochondria
Reactive oxygen species (ROS) of mitochondrial origin are part of the immune-inflammatory response, but in excess, they may disrupt the normal microbial signal pathways mediated by ROS. This may weaken the intestinal epithelial barrier.
Conversely, microbial metabolites may interfere with mitochondrial respiratory processes involved in ATP production. The loss of microbial-mitochondrial balance may trigger colitis.
Gut dysbiosis can occur due to SARS-CoV-2 colonization and may interfere with the normal inflammatory response to the pathogen, leading to severe COVID-19. But gut dysbiosis may also make the individual more susceptible to the virus by virtue of gut inflammation. Mitochondria can contribute to abnormal immune responses to worsen inflammation and change the gut microbiome's composition.
Meanwhile, the gut microbiota can target host mitochondria, using endocrine, immune and humoral pathways. Microbial SCFAs are, in contrast, beneficial to the host by reducing ROS production and thus relieving oxidative stress.
Gut-lung axis and severe COVID-19
The gut-lung axis allows the virus colonizing the lungs to reach the gut, causing symptoms like diarrhea and nausea, while the reduced gut microflora diversity with age may explain why older people are at higher risk for severe disease. Migration in the reverse direction may be favored by intestinal dysbiosis as intestinal permeability increases.
Another explanation is that the gut symptoms are due to crosstalk between the gut and the infected lung, mediated by the immune system.
Microbiome and COVID-19 management
The current evidence points to the potential utility of the human microbiome in detecting and treating COVID-19. For instance, changes in the lung microbiome, such as an increased bacterial presence, especially with gut-associated bacteria, predicted a poor outcome. This corroborates earlier findings in patients with acute respiratory distress syndrome (ARDS), a common final pathway in fatal cases of COVID-19.
The use of fecal microbiome transplantation (FMT) has been explored in many clinical situations where the integrity of the gut mucosa has been compromised, as in burns, sepsis, and inflammatory bowel disease. The gut-lung axis can maintain homeostasis with the host immune system by modulating the immune response.
Researchers envisage restoring gut microbiome composition in COVID-19 to prevent hyper-inflammation via FMT, but further work is required. This can be promoted by the addition of probiotics containing Lactobacillus casei. Studies have demonstrated that these can reduce the incidence and severity of respiratory infections.
Probiotics also modulate the TLR3-induced coagulation pathway in the lungs that occur in response to inflammation following a viral infection. This could be useful in reducing the chances of severe COVID-19 by the immunomodulatory function of probiotics.
The restoration of gut ecology by probiotics could also help manage COVID-19 by preventing disease progression, as orally administered bacterial strains can repair the gut barrier and prevent systemic inflammation. They can also migrate into other body parts, including the gut-lung axis.
Regulation of gut microbiota dysregulation may reduce inflammation or complications associated with COVID-19, leading to new breakthroughs in the prevention and treatment of the disease."
This area requires further research to probe its clinical usefulness in the management of COVID-19.