The gut bacteriome and virome in Covid-19 patients

By Madeleine Pramoedya

The bacteriome itself presents a subset of the microbiome which exclusively consists of bacteria. It is the most widely studied and characterised aspect of the gut microbiome.1 It has also long been suggested that the composition of the gut microbiome influences host physiology and plays a strong role in modulating the host’s immune system. The commensal host-microbiome interactions are an important aspect of the gut microbiome as a perturbation of this environment due to external factors (e.g., Excessive antibiotic use, diet, or geography), may have an adverse impact on commensal microorganisms. This may lead to susceptibility to pathogenic invasion and rogue immune responses.2

The virome is another subset of the overall microbiome and is extremely diverse. Despite the difficulty in quantifying the exact size of the human virome, its density has been estimated to be ~109 viral particles per gram found in human feces of which most were phages.3 However, this number would be a significant underestimation of the true density of the human virome, as any viruses outside of the GI tract are not considered. Hence, other studies have suggested through metagenomics methods, the density of the human virome is closer to ~1015 viral particles per gram.4

With the current global Covid-19 pandemic, it is interesting to consider how severe acute respiratory syndrome coronavirus 2 (SARs-CoV-2) infection interacts with the human gut virome and bacteriome. The virus infects several organs such as the lungs and the gastrointestinal tract, hence the microbiome found at these sites may respond and influence the progression of Covid-19 in the host. although it is widely known that Covid-19 primarily exhibits itself as a respiratory disease that causes pneumonia ,The gut microbiome is of interest as, a commonly reported symptom is oneassociated with the gastrointestinal tract, diarrhea, which tends to appear prior to respiratory symptoms.5 Furthermore, even once the virus is cleared from the respiratory system it has been reported to still be detected in fecal or rectal swabs for a few days.6 Thus, SARs-CoV-2 can be associated with affecting the gastrointestinal system.

The composition of the bacteriome of Covid-19 patients may also be used to interpret the severity of their infection. Several studies have shown that with Covid-19 infection there is a decrease in the diversity of the gut bacteriome. However, specific bacteria may be able to present as biomarkers for the severity of Covid-19’s clinical outcome. For example, the numbers of the bacteria Ruminococcus gnavus, Coprobacillus, and Clostridium ramosum were significantly enhanced in COVID-19 patients. R. gnavus is also implicated in Crohn’s disease as it produces an inflammatory polysaccharide inducing cytokine production (e.g., TNFα) by dendritic cells. The presence of these bacteria are positively correlated to the severity of COVID-19 in patients observed.2 Butyrate-producing bacterial groups such as Eubacterium were also found to be depleted in severe cases of Covid-19, whereas opportunistic pathogens such as Corynebacterium, Enterococcus, Campylobacter, Citrobacter, and Enterobacter increased in number.7 Supporting the concept of using bacteria as biomarkers for Covid-19 clinical outcome can also be seen as proteomic (studies of proteins expressed) and metabolomic (studies of chemical processes involving metabolites) profiling has predicted progression to severe Covid-19 both in infected and healthy individuals.8

Furthermore, recent research has suggested that specific gut microbiota compositions may allow healthy individuals to avoid the severe symptoms of Covid-19. In COVID-19 this has been observed as an increase in the level of pro-inflammatory cytokines which is correlated with an increase in disease severity. Disruptions to the microbiome-immune system dialogue have been suggested to cause chronic inflammatory conditions such as acute systemic multi-organ dysfunction. This implies that disruptions to the gut microbiome caused by the Covid-19 infection may lead to increased pro-inflammatory cytokine production (cytokine storm), which may increase the severity of Covid-19 cases.9 However, there are limitations to these studies, as they are still preliminary with cohorts used in the different studies varying in terms of geography as well as size.

In terms of the gut virome’s composition in response to Covid-19 infection, relative to normal individuals, infected patients showed an underrepresentation of Pepper mild mottle virus (RNA virus), multiple bacteriophage lineages (DNA viruses), and environment-borne eukaryotic DNA viruses in fecal samples. It was also seen upon the Covid-19 infection, that the fecal virome showed more stress, inflammation, and virulence-associated gene encoding mechanisms. Furthermore, studies have shown that the baseline fecal abundance of 10 virus species: 1 RNA virus, pepper chlorotic spot virus, and 9 DNA virus species, inversely correlated with Covid-19 severity. These viruses also had a negative correlation to blood levels of pro-inflammatory proteins, white cells, and neutrophils.7 Thus, this suggests that the composition of the gut virome in response to Covid-19 infection may impact the severity of the disease progression.

Furthermore, it has been suggested that the gut may be a reservoir for SARS-CoV-2. Specifically, the intestinal epithelial cells of Covid-19 patients express high amounts of the SARS-CoV-2 receptor ACE2 and transmembrane protease serine subtype 2 (TMPRSS2) – a cellular protease required for viral entry. This is notable as GI infection is a frequent symptom of Covid-19, with 30-70% of patients reporting such symptoms. Patients exhibiting these symptoms have shown limited or lack of signs for local inflammation and low mortality in Covid-19, suggesting that the GI tract may play a role in reducing the severity of the disease progression.11

In conclusion, the gut bacteriome and virome in Covid-19 patients may play a role in affecting the progression of the disease and may indicate the severity of infection. Specifically, the gut bacteriome’s composition may present as biomarkers for the severity of the Covid-19 infection, and disruptions to the composition may lead to more severe infections. The virome’s composition may also be affected by Covid-19, with certain viruses being more likely to be present in the fecal matter of patients. However, much research is still required as patient cohorts used for these studies vary in size and location, thus making it difficult to make comparisons of results.

References:

1. Hopson LM, Singleton SS, David JA, Basuchoudhary A, Prast-Nielsen S, Klein P, et al. Bioinformatics and machine learning in gastrointestinal microbiome research and clinical application. Progress in molecular biology and translational science. 2020; 176 141-178. 10.1016/bs.pmbts.2020.08.011.

2. Zheng D, Liwinski T, Elinav E. Interaction between microbiota and immunity in health and disease. Cell research. 2020; 30 (6): 492-506. 10.1038/s41422-020-0332-7.

3. KIM M, PARK E, ROH SW, BAE J. Diversity and Abundance of Single-Stranded DNA Viruses in Human Feces. Applied and Environmental Microbiology. 2011; 77 (22): 8062-8070. 10.1128/AEM.06331-11.

4. Mokili JL, Rohwer F, Dutilh BE. Metagenomics and future perspectives in virus discovery. Current opinion in virology. 2012; 2 (1): 63-77. 10.1016/j.coviro.2011.12.004.

5. Xiao F, Tang M, Zheng X, Liu Y, Li X, Shan H. Evidence for Gastrointestinal Infection of SARS-CoV-2. Gastroenterology (New York, N.Y. 1943). 2020; 158 (6): 1831-1833.e3. 10.1053/j.gastro.2020.02.055.

6. Wu Y, Guo C, Tang L, Hong Z, Zhou J, Dong X, et al. Prolonged presence of SARS-CoV-2 viral RNA in faecal samples. The lancet. Gastroenterology & hepatology. 2020; 5 (5): 434-435. 10.1016/S2468-1253(20)30083-2.

7. Zuo T, Liu Q, Zhang F, Yeoh YK, Wan Y, Zhan H, et al. Temporal landscape of human gut RNA and DNA virome in SARS-CoV-2 infection and severity. Microbiome. 2021; 9 (1): 91. 10.1186/s40168-021-01008-x.

8. Shen B, Yi X, Sun Y, Bi X, Du J, Zhang C, et al. Proteomic and Metabolomic Characterization of COVID-19 Patient Sera. Cell. 2020; 182 (1): 59-72.e15. 10.1016/j.cell.2020.05.032.

9. Mehta P, McAuley DF, Brown M, Sanchez E, Tattersall RS, Manson JJ. COVID-19: consider cytokine storm syndromes and immunosuppression. The Lancet (British edition). 2020; 395 (10229): 1033-1034. 10.1016/S0140-6736(20)30628-0.

10. Zuo T, Zhang F, Lui GCY, Yeoh YK, Li AYL, Zhan H, et al. Alterations in Gut Microbiota of Patients With COVID-19 During Time of Hospitalization. Gastroenterology (New York, N.Y. 1943). 2020; 159 (3): 944-955.e8. 10.1053/j.gastro.2020.05.048.

11. Neurath MF, Überla K, Ng SC. Gut as viral reservoir: lessons from gut viromes, HIV and COVID-19. Gut. 2021; 70 (9): 1605-1608. 10.1136/gutjnl-2021-324622.

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