COVID-19 Research: Disruption Of Gut Microbiome Could Be Also Be A Contributing Factor To Disease Severity In COVID-19 Patients
: More emerging study data is indicating that disruptions in the healthy functioning of the gut microbiome
could also be a contributing factor to disease severity in COVID-19 patients.
Typically the human gastrointestinal (GI) tract contains over 1,000 symbiotic and pathogenic microorganisms, which are known to play a key role in health via host metabolism, physiology, nutrition, and immune function. The GI tract is the primary site of interaction between the immune system and microorganisms, and disruption of the gut microbiota (known as dysbiosis) can lead to immune dysfunction and inflammation.
Dysbiosis has been linked to chronic conditions such as inflammatory bowel disease (IBD), diabetes, obesity, malnutrition, depression, and cardiovascular disease. Additionally, it has been shown that the diversity of the gut microbiota decreases with age. Gut microbiota has also been shown to affect respiratory health through a concept known as the “gut-lung axis,” where bi-directional crosstalk causes diseases in the gut to affect the lung and vice versa.
Numerous studies from China in the last one year have evaluated whether disruption of gut microbiota could be linked to the development of severe COVID-19 symptoms as a result of inflammation, particularly as elderly and immune-compromised patients have been shown to be at high risk of developing severe manifestations of the disease.
One such study investigated the correlation between changes in gut microbiota of 62 COVID-19 patients and interleukin (IL) 18 (a key pro-inflammatory factor produced by intestinal epithelial cells) and immunoglobulin A (IgA), which has been found to be linked to disease severity in COVID-19. https://www.sciencedirect.com/science/article/pii/S2590097820300203
The study findings showed that the virus caused changes in the composition of the gut microbiota in COVID-19 patients and suggested that this dysbiosis may contribute to disease severity. For example, higher levels of Streptococcus, Clostridium, Lactobacillus, and Bifidobacterium were seen, while lower levels of Bacteroidetes, Roseburia, Faecalibacterium, Coprococcus, and Parabacteroides were found in COVID-19 patients compared to seasonal flu patients and healthy controls.
Furthermore, the concentration of IL-18 was increased in both serum and fecal samples from COVID-19 patients, but not in seasonal flu patients, suggesting that it might serve as an indicator of intestinal infection in COVID-19 patients. The study noted that further studies would be needed to exclude the possibility that changes in the gut microbiota were caused by the administration of other drugs.
Yet another Chinese study, published in Clinical Infectious Diseases in June, compared the gut microbiota composition of 30 Covid-19 patients, 24 influenza A patients, and 30 matched healthy controls. https://academic.oup.com/cid/article/71/10/2669/5851452?searchresult=1
The study findings also
showed that COVID-19 patients had significantly reduced bacterial diversity, a significantly higher population of opportunistic pathogens, and a lower population of beneficial symbionts compared to healthy controls. Influenza A patients showed lower diversity and a different overall microbial composition compared with Covid-19 patients.
Also another study published in Gastroenterology by the Faculty of Medicine at the Chinese University of Hong Kong investigated whether changes in the gut microbiota of 15 hospitalized Covid-19 patients could be associated with disease severity and fecal shedding of the virus. Results showed that faecal microbiota alterations were associated with fecal levels of SARS-CoV-2 and COVID-19 severity. https://www.gastrojournal.org/article/S0016-5085(20)34852-6/fulltext#%20
This study found that patients with COVID-19 had significant alterations in fecal microbiomes compared with controls at the time of hospitalization and at all time points during hospitalization, with increased levels of opportunistic pathogens and depletion of beneficial symbionts.
An abundance of Coprobacillus, Clostridium ramosum, and Clostridium hathewayi was correlated with Covid-19 severity, while there was an inverse correlation between Faecalibacterium prausnitzii and disease severity. Depleted symbionts and dysbiosis were evident after clearance of SARS-CoV-2 and resolution of respiratory symptoms.
Many biotech companies are investigating live biotherapeutic products and diagnostic tests for COVID-19. For example, in April 2020, Persephone Biosciences announced that it was developing artificial intelligence (AI)-derived microbiome therapeutic to prevent and treat COVID-19, as well as a stool-based diagnostic to help predict which patients are at highest risk for developing severe COVID-19. https://www.prnewswire.com/news-releases/persephone-biosciences-announces-ai-driven-microbiome-therapeutic-and-diagnostic-programs-for-covid-19-301033668.html
Persephone Biosciences anticipates that the microbiome therapeutic could be used as an enhancer of the immune system to prevent infection, boost the immune system of those exposed to the virus, taken at the onset of symptoms, or given with a vaccine or antiviral to mount an effective immune response.
Persephone used its proprietary Decode. Design.Cure technology platform, which applies a combination of AI and next-generation genome sequencing technologies, to develop novel microbiome therapeutics and diagnostics. Lead candidates are expected to enter clinical trials in late 2020 as either monotherapy or in combination with other treatments, subject to FDA approval.
Interestingly in July 2020, ExeGi Pharma LLC announced the results of a clinical trial evaluating a microbiome drug candidate in hospitalized COVID-19 patients, which was published in Frontiers in Medicine. https://www.frontiersin.org/articles/10.3389/fmed.2020.00389/full
The researchers from the University of Rome hypothesized that a bacterial formulation could mitigate Covid-19 severity via modulation of the gut-lung axis.
This study enrolled 70 Covid-19 patients who had a fever, showed greater than 50% lung involvement on computed tomography (CT) scans and required non-invasive oxygen therapy. In the first study group, 42 patients received standard treatment of hydroxychloroquine, antibiotics, and tocilizumab. In the second study group, 28 patients received standard treatment, plus a high-dose, eight-strain bacteriotherapy.
Importantly of the patients in the bacteriotherapy group, all experienced elimination of diarrhoea within seven days, compared to less than half of the patients in the first study group.
The bacteriotherapy group also showed significant improvements in other COVID-19 symptoms, including fever, shortness of breath, physical weakness, and myalgia. Additionally, two patients not treated with bacteriotherapy were transferred to the intensive care unit (ICU) for mechanical ventilation.
Another four patients in the control group died as a result of Covid-19, although this was not statistically significant. No adverse events were recorded in the bacteriotherapy group.
In summary data from the research studies from China and Italy highlight the potential of using the gut microbiota as both a diagnostic marker for COVID-19 and as a therapeutic target by altering its composition to decrease inflammation and thus reduce disease severity.
Still more research is needed to fully understand the role of the gut-lung axis in COVID-19 in order to validate these study results.
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