Alterations of Gut Microbiota Composition in Severe Acute Respiratory Syndrome Coronavirus 2 Infection: A Brief Review
Fauzi Yusuf1,2*, Azzaki Abubakar1,2, Desi Maghfirah1,2, Muhsin Muhsin1,3, Marhami Fahriani4, Muhammad Iqhrammullah6,7
1Department of Internal Medicine, School of Medicine, Universitas Syiah Kuala, Banda Aceh, Aceh, Indonesia
2Department of Internal Medicine, Dr. Zainoel Abidin Hospital, Banda Aceh, Aceh, Indonesia
3Department of Parasitology, School of Medicine, Universitas Syiah Kuala, Banda Aceh, Aceh, Indonesia
4Medical Research Unit, School of Medicine, Universitas Syiah Kuala, Banda Aceh, Aceh, Indonesia
5Graduate School of Mathematics and Applied Sciences, Universitas Syiah Kuala, Banda Aceh, Indonesia
6Department of Chemistry, Faculty of Mathematics and Applied Sciences, Universitas Syiah Kuala, Banda Aceh, Indonesia
ABSTRACT
Respiratory diseases are strongly connected to the richness and composition of gut microbiota as reported in asthma and influenza A infection. Gut commensal microbiota produces short-chain fatty acids (SCFAs) that regulate the physical barrier in gastrointestinal tract, host immune response, and homeostasis. As one of the respiratory diseases, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), causes coronavirus disease 2019 (COVID-19), has been reported affecting the composition of intestinal microbiome. Herein, we discuss the current research of gut microbiota composition in SARS-CoV-2 cases.
The evidence of changing the composition of SCFAs-producing bacteria and pathogenic bacteria in SARS- CoV-2 infected patients are presented. Additionally, the roles of SARS-CoV-2 infection and gut-lung axis against the dysbiosis and its implication are discussed.
Keywords:COVID-19, SARS-CoV-2, gut microbiota, gut microbiota composition, gut-lung axis
Introduction
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), causes coronavirus disease 2019 (COVID-19) pandemic, targets the respiratory tract in human causing mild symptoms such as cough and fever up to lethal symptoms including pneumonia, hyperinflammation, respiratory failure and multiple organ failure.1 COVID-19 pandemic has caused a wide array of adverse impacts including environmental pollution,2, 3 economic crisis and energy consumption,4 and healthcare disruption.5, 6 To control the pandemic, vaccination program has been taken in place and shown a positive progress in slowing down the viral transmission in small groups of community.7, 8 Unfortunately, the global vaccination program is still far from success, where in fact, countries like India and its neighbors are facing the ‘tsunami’ of SARS-CoV-2 infection cases.9, 10
During the hospitalization, COVID-19 patients were treated pharmacologically using antivirals, antibiotics, antipyretics, and steroids along with ventilation.11 However, highly effective specific treatment for COVID-19 has not yet available, with antiviral candidates still being investigated.12 It is due to our lack of understanding upon the pathogenesis of COVID- 19 including the role of gut microbiota. The mutualistic interaction between the host and gut bacteria holds a significant function, especially in regulating immune response, absorbing nutrients, metabolism, and inhibiting the expansion of enteric pathogens.13-15 Moreover, intestinal bacteria have systemic influence outside the digestive system, in which its disruption could trigger inflammation in lung.16
Studies using animal models have revealed the importance of gut microbiota richness and composition in the development and progression of respiratory diseases. Occurrence of gut microbiota dysbiosis was observed in mouse model upon the H1N1 infection, leading to acute infection.17 Alteration of gut microbiota with increasing Bacteroidetes in infected murine have been also reported.18 The systemic spread of overgrown Bacteroidetes has been reported correlated with acute lung injury in mouse.19 Additionally, some fungi species, including Candida albicans and Saccharomyces cerevisiae, could reduce host’s susceptibility to influenza A (H1N1) infection.20
Changes in gut microbiota composition
Mutualistic relationship between the host and gut microflora holds multiple key functions in terms of metabolic, neurological, structural and, immunological landscapes21. For example, gut microbiomes are responsible in the secretion of proteins that induce the production of immunoglobulin A (IgA). These microbiomes include Akkermansiamuciniphila, Faecalibacteriumprausnitzii, Bacteroides spp., Roseburia spp., Lactobacillus spp., and Bifidobacterium spp.22 Furthermore, indigenous microbiota could provide a nourishment to host by producing essential vitamins and prevent the formation of colorectal cancer through the fermentation of non-digestible carbohydrate.23 Significant role of gut commensal microbiomes is also found in the homeostasis, reducing the chance of gut pathogens to be established either by releasing of a wide range of anti-microbial factors or competing of nutrients, space, and host cell receptors.24
In the case of SARS-CoV-2 infection gut microbiota dysbiosis were observed by several studies, in particular in group of butyrate-producing bacteria. At a family level, Ruminococcaceae and Lachnospiraceae had a significant depletion in patients with SARS- CoV-2.25 The alteration is not exclusive to SARS-CoV-2 infection, but it is also reported in other respiratory viral infections. Previously, viral lung infection had been found to alter the composition of gut microbiota in mouse17 and murine models.18 In this regard, several studies compared their findings with the influenza A (H1N1) infected group, showing similarities of the alteration in SARS-CoV-2 infection cases. Nonetheless, there were several differences such as the lower number of Candida glabrata26 and higher number of Streptococcus25 in SARS-CoV-2 group, compared to H1N1 group.
Different gut microbiota profile among studies can be attributed to many factors, among them are the demography,27 geography,28 dietary,29 medical treatment,30 and severity of the infection.31 Regardless the composition, the richness of gut microbiota was affected, where a depletion was shown.25, 31 However, the fungal burden was reported higher in SARS-CoV-2 group.26 A contradicting finding was reported by study investigating blood and stool samples from 100 SARS-CoV-2 confirmed patients, suggesting insignificant difference of gut microbiome richness compared to healthy group.30
Gastrointestinal infection symptoms present in SARS-CoV-2-infected patients
SARS-CoV-2 infected patients had been presented with gastrointestinal infection symptoms such as diarrhea, anorexia, and nausea.32 In this light, diarrhea is the most studied gastrointestinal infection symptom, where around 8.0 to 12.9% patients with SARS-CoV-2 suffered diarrhea.33 There has been a dispute whether the cause of the symptom is a direct SARS-CoV-2 infection or through gut microbiome dysbiosis. Currently, there is no specific and effective treatment for diarrhea during SARS-CoV-2 infection.34 It stresses further the importance of understanding the pathogenesis of SARS-CoV-2-related diarrhea.
A study investigating Clostridium difficile in SARS-CoV-2 patients, found no correlation with diarrhea occurrence.35 They argued, the infection of SARS-CoV-2 targets the gastrointestinal tract and consequently causes the inflammation-associated diarrhea. It was further substantiated by the correlation between the diarrhea and infectivity of fecal SARS-CoV-2.36 However, a screening of gut microbiome revealed the positive correlation of A. niger with SARS-CoV-2 infection.26 The intestinal inflammation and diarrhea might be caused by the loss functionality of colonic ACE2,33 which could be affected by the reduction of B.
stercorisduring SARS-CoV-2 infection.37 Furthermore, ACE2 holds a significant impact in the changed composition of gut microflora.38 The entry of inflammatory cells into the intestinal mucosa could be attributed to the depletion of non-digestible carbohydrate fermentation-associated bacteria.39
Role of intestinal ACE2 in SARS-CoV-2 infection-related alteration of gut microbiota It has been evidenced that SARS-CoV-2 infects the gastrointestinal tract, shown by the intracellular staining of the presence of SARS-CoV-2 RNA in duodenal, gastric, and rectal epithelia.40 This is supported by the finding of stool specimen with positivity of SARS-CoV- 2, regardless the gastrointestinal symptom.30, 37 The infection is due to the fact that ACE2 mRNA is abundantly expressed and stabilized on the surface cell of digestive tract.41 The expression of ACE2 mRNA is specifically high in duodenal enterocytes.33 As a consequence, downregulation of ACE2 by SARS-CoV-2 infection leads to the increase in inflammation susceptibility via angiotensin (Ang) II and AT1R-induced permeability of gut barrier.33, 42 Further, the disruption of ACE2/AngII/AT1R axis may contribute to the systemic cytokine storm and tissue damage.43, 44
Disrupted intestinal barrier may also cause systemic spread of bacteria, microbial metabolites, and endotoxins that adversely affect the host’s immunity.45 Cautious remarks have been made by several studies regarding the possible infection of enteric pathogens through blood circulation.25, 26, 37 Additionally, gut microbiome itself can affect the production of ACE2. For example, a study using gnotobiotic (germ-free) mice model revealed the expression of ACE2 is regulated by the gut microbial protein digestion.46
Role of gut–lung axis in SARS-CoV-2 infection-related alteration of gut microbiota The shared mucosal immune system, known as gut–lung axis, are associated by many reports to cause the development of pneumonia in COVID-19 patients suffering from colonic microflora dysbiosis. SCFAs produced by gut microbiomes, along with the lipopolysaccharides, could act as lung immune modulator.47 Gut-lung axis also covers the migration and circulation of immune cells (such as intestinal group 2 innate lymphoid cells), several hormones, and cytokines from gastrointestinal tract to the respiratory system.48
Gut barrier, a complex and dynamic intestinal interface, controls the interaction of gut microbiota and innate immune system.49 Bacteria from Bifidobacterium and Lactobacillus genus are lactic acid producer which is a regulating factor in gut barrier function and immune system.50, 51 The dysbiosis in intestinal microbiota activates innate immune system receptor, concomitant to the disruption of the epithelium lining permeability.52 As a consequence of this regulation effect, the population of extraintestinal T cells could also be affected. For example, allergic asthma is significantly correlated with gut microbiota via regulatory T cells abundance and activities.53
There are several cases indicating the role gut-lung axis in the alteration of gut bacteria. In child patients, the risk of asthma along with cystic fibrosis increases as the result of
significant depletion of SCFAs-producing bacteria.54 For that reason, several approaches have been tested to increase the production of SCFAs through diet changes which could improve the severity of respiratory diseases via IL-8, IL-6 and C-reactive protein55 along with natural killer (NK) cells.56
Other than the immune modulation mechanism by SCFAs-producing bacteria, systemic spread of gut bacteria to the lung may also contribute to the development of acute lung injury.
In mice model, the translocation of gut microbiome (especially Bacteroides spp.) was correlated with the lung damage where the indication of systemic inflammation was also found.19 The systemic spread of pathogenic bacteria through gut-lung axis was substantiated by the finding of S. infantis, a common respiratory tract bacterial species, in fecal samples.37 Moreover, the bacterial biosynthesis pathway of L-serine was found in fecal samples of SARS-CoV-2 infected patients.37 It could further lead the expansion of enteric pathogens in inflamed gastrointestinal tract.57 The schematic illustration summarizing the discussion in this review can be seen in Figure 1.
Figure 1. Schematic summary of gut microbiota alteration upon SARS-CoV-2 infection.
SARS-CoV-2 ( ) enters the host through angiotensin-converting enzyme 2 (ACE2) ( ) that is highly expressed in respiratory and gastrointestinal tracts. Gut-lung axis allows the
dysbiosis of gut microbiota resulting in systemic inflammation, immune modulation, and pathogen infection.
Conclusion
Results from various researches revealed that patients suffering SARS-CoV-2 infection have their gut microbiome composition altered. The common trend of increasing enteric pathogens and decreasing anti-inflammatory bacteria was observed. This alteration may contribute in the
pathogenesis of SARS-CoV-2 diseases, including that of cytokine storm and acute lung injury. Considering its significant role, careful attention should be given to the alteration of gut microbiome during the SARS-CoV-2 treatment. However, it is still unclear whether the abnormality of microbiota profile occurs before the SARS-CoV-2 infection (thus, contribute to the susceptibility of the infection) or after the infection (having a role in SARS-CoV-2 infection development and progression). Moreover, heterogenous composition of gut microbiota among individuals might be significant, which suggest the alteration might not cause by SARS-CoV-2 infection.
Acknowledgement We would like thanks Narra Studio Journal for the assistance.
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