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. This 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.
Several studies from China over the past six months 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.
For example, one 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. Results found 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. Moreover, the concentration of IL-18 was increased in both serum and faecal 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. Similarly, 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. Results 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.
In September, a 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 hospitalised Covid-19 patients could be associated with disease severity and faecal shedding of the virus. Results showed that faecal microbiota alterations were associated with faecal levels of SARS-CoV-2 and Covid-19 severity. Patients with Covid-19 had significant alterations in faecal microbiomes compared with controls at the time of hospitalisation and at all time points during hospitalisation, 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.
Several 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. The company 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.
In July 2020, ExeGi Pharma LLC announced the results of a clinical trial evaluating a microbiome drug candidate in hospitalised Covid-19 patients, which was published in Frontiers in Medicine. Investigators at the University of Rome hypothesised that a bacterial formulation could mitigate Covid-19 severity via modulation of the gut-lung axis. The 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. 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. Furthermore, 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.
Overall, data from the 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. However, it was highlighted that further research is needed to fully understand the role of the gut-lung axis in Covid-19 in order to validate the study results.