v
Search
Advanced

Publications > Journals > Exploratory Research and Hypothesis in Medicine > Article Full Text

  • Review Article
  • OPEN ACCESS

Advances in the Interaction between Intestinal Microbiota and COVID-19

  • Zhi-Jun He,
  • Yun-Xiao Liang*  and
  • Lian-Ying Cai
 Author information  Cite
Exploratory Research and Hypothesis in Medicine   2021;6(1):1-8

doi: 10.14218/ERHM.2020.00055

Abstract

Coronavirus disease 2019 (COVID-19) is a global epidemic disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Many digestive symptoms have been reported in patients infected with this virus, however, the relationship between the intestinal microbiota and SARS-CoV-2 remains unknown. This review aims to elucidate the interaction between intestinal microbiota and SARS-CoV-2, and review the mechanism of interaction between these two items as well as the effects of probiotics. This review further discusses various studies on gastrointestinal symptoms and changes in intestinal microbiota in COVID-19 patients. To further understand the mechanism, we focused on the role of angiotensin converting enzyme 2 and transmembrane protease serine 2 in this viral infection. There is a correlation between many diseases and dysbiosis of intestinal microbiota. SARS-CoV-2 can lead to dysbiosis of intestinal microbiota through a variety of mechanisms, with a decrease in the abundance and diversity of probiotics and an increase in that of pathogenic bacteria. Dysbiosis of intestinal microbiota results in the translocation of intestinal flora, aggravation of systemic inflammation, and lung injury. Modulating the intestinal microbiota ameliorates digestive symptoms and pathology in infectious respiratory diseases. Intestinal microbiota and SARS-CoV-2 interact through a variety of mechanisms; SARS-CoV-2 can cause dysbiosis of the intestinal microbiota, while dysbiosis of intestinal microbiota, in turn, aggravates COVID-19.

Keywords

Intestinal microbiota, SARS-CoV-2, COVID-19, Angiotensin converting enzyme 2, Transmembrane serine protease 2

Introduction

There is a large number of microbial communities, approximately 500 to 2,000 species, present in the gastrointestinal tract. The intestinal microbiota performs many essential functions that help the host to maintain health.1 Studies indicate that host homeostasis and disease development are maintained by the immune system. Intestinal microbiota may contribute to the progression of coronavirus disease 2019 (COVID-19) due to the gut-lung interaction with the immune system.2 Dysbiosis of intestinal microbiota results in changes in the composition of intestinal flora, gut permeability, and bacterial translocation. These processes eventually lead to multiple organ failure and may also result in the translocation of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) from the lung into the intestinal tract.3

COVID-19 is a global epidemic that spreads acute respiratory infection caused by SARS-CoV-2. SARS-CoV-2 is a single-stranded RNA-enveloped virus belonging to the β-coronavirus genus. Full-genome analysis showed that SARS-CoV-2 shares 79.6% sequence identity with SARS-CoV and belongs to the same genus of coronaviruses.4 The main transmission modes are respiratory droplets and close contact with an infected patient.5 The clinical features of COVID-19 include high rates of transmission, destruction of multiple organs, and more serious symptoms in the elderly.6–8 Additionally, multiple other clinical manifestations may also be observed, such as fever, dyspnea to pneumonia, acute respiratory distress syndrome, multiple organ failure, all of which may lead to death.9 Digestive disorders appear to precede or follow respiratory symptoms7 as previous studies have reported the incidence of gastrointestinal symptoms in 2% to 50% of COVID-19 cases.10–13 The digestive system is not only a part of disease expression, but is also a potential driver of disease severity and viral transmission.9 This review highlights the relationship between intestinal microbiota dysbiosis and SARS-CoV-2 infection.

Structure and function of the human intestinal microbiota

The intestinal microbiota is established from infant birth status and is relatively stable and resilient in adults with temporal patterns.14,15 The intestinal microbiota of different individuals is relatively stable,16 however, the diversity of intestinal flora decreases with biological age.17 Most of the flora in the human intestinal tract is located in the colon, while the amount of bacteria in the jejunum, ileum, and duodenum decreases in turn. The intestinal flora of humans consists of approximately 100 trillion resident microorganisms, including bacteria, viruses, fungi, and chlamydiae.18 The healthy state is characterized by between 500 and 2,000 microbial species, which comprise the four most common bacteria phyla of Firmicutes, Bacteroidetes, Actinobacteria, and Proteobacteria.19

The intestinal microbiota provides many beneficial functions in modulating intestinal barrier function, supporting the host immune system, inhibiting tumors, promoting vitamin synthesis, aiding digestion and absorption, and enhancing primary alveolar macrophage function.20,21 Intestinal bacteria as well as products and metabolites of intestinal bacteria, play beneficial roles in the intestinal mucosal barrier by enhancing tight junctions and decreasing the permeability of the epithelium.20 Differentiation and maturation of intestinal T helper 17 cells and secretion of IgA can be induced by intestinal flora, which are important components of intestinal mucosal immunity and participate in the regulation of human autoimmune diseases.22,23 The intestinal microbiota directly or indirectly, through enzymes, makes an important contribution to the metabolism of dietary carbohydrates, proteins, bile acids, and vitamins.24

Intestinal microbiota dysbiosis and disease

Multiple factors can lead to changes in the intestinal microbiota, such as exercise, diet, obesity, drug utilization, host genetics, and disease.15,25 Exercise can enhance the number of beneficial microbial species and improve the development of commensal intestinal bacteria.26 A high-fat diet-induced intestinal microbiota dysbiosis increases intestinal permeability and causes an inflammatory response, whereas methionine-restricted diets can increase the abundance of Bifidobacterium, Lactobacillus, and Bacteroides.27 Overuse of antibiotics can also lead to intestinal microbiota dysbiosis and superinfection, which in turn can aggravate the primary disease.28,29

There is a correlation between intestinal microbiota imbalance and many diseases. Microbial dysbiosis contributes to the development of liver cirrhosis, increases carcinoma susceptibility, and aggravates inflammatory bowel disease.30 The number of Enterobacteriaceae, Enterococcus, and Saccharomyces was significantly greater in liver cirrhosis patients, but the number of Lactobacillus, Bacteroides, and Clostridium was significantly decreased.30Fusobacterium were also enriched in colorectal carcinomas, while Bacteroidetes and Firmicutes were significantly reduced in tumors.31 The characteristics of intestinal microbiota can be used to predict biological age and the prognosis of diseases, to treat diseases, and to develop new drugs.17 Intestinal microbiota plays an important role in the regulation of lung inflammation. The generation of metabolites of intestinal microbiota, such as short chain fatty acids, can suppress respiratory inflammation by activating G protein-coupled receptors.32 Type 2 diabetes has a significantly lower abundance of verrucomicrobiae, which may be a potential biomarker thereof.33 Based on a population view, the microbial synthesis potential of the dopamine metabolite 3,4-dihydroxyphenylacetic acid correlates positively with the mental quality of life, and microbial γ-aminobutyric acid production may play a role in the evolution of depression.34 Nevertheless, the mechanism of interaction between microbiota and the host, especially at the molecular and biochemical levels, needs further study. These studies suggest that maintaining a normal intestinal microecology is one of the most important treatment strategies to maintain the dynamic balance of the immune system and reduce the occurrence of diseases.

The alterations of intestinal microbiota in COVID-19 patients

Dysbiosis of the intestinal microbiota can lead to a variety of gastrointestinal symptoms, leading to multi-organ dysfunction, the symptoms of which include diarrhea (4.8–50.0%), nausea, and vomiting (3.9%).11,35,36 COVID-19 patients with gastrointestinal symptoms are also more likely to have higher rates of fever, fatigue, and shortness of breath, compared with patients without gastrointestinal symptoms.37 However, a study of 138 COVID-19 patients found that diarrhea was present in 10.1% of patients, but there was no significant correlation between the occurrence of diarrhea and the need for intensive care.38 Due to the limited data at present, medical staff should pay attention to COVID-19 patients who are complicated with gastrointestinal symptoms and who may be in a more severe condition. Whether gastrointestinal symptoms are a factor of poor prognosis remains to be studied further.

Dysbiosis of intestinal microbiota in COVID-19 exhibits a decrease in the abundance and diversity of probiotics and an increase in those of opportunistic pathogen bacteria. The probiotic bacteria, such as Bifidobacterium and Lactobacillus, decreased, and was dominated by pathogenic bacteria such as Streptococcus, Rothia, Veillonella, Erysipelatoclostridium, and Actinomyces.9,39Bifdobacteriumand Lactobacillus can enhance the secretion of IgA and maintain mucus-secreting goblet cells, which in turn benefit the defensive effect of mucosal barriers.20,24 Lu et al. found that Streptococcus and Rothia were likely to increase the risk of secondary bacterial lung infections in H7N9 patients.40 Dysbiosis of the intestinal microbiota causes deficiencies in nutrient absorption in the gut and immune regulation, as well as lung injury.41,42

In some COVID-19 patients who have needed to be administered antibiotics, the drugs generally affect the intestinal microbiota. Zuo et al.43 found that COVID-19 patients receiving empirical antibiotics or antibiotic-naïve therapy were characterized by the enrichment of opportunistic pathogens and the depletion of beneficial commensals. COVID-19 patients without antibiotic therapy had an enriched population of opportunistic pathogens, including Clostridium hathewayi, Actinomycesviscosus, and Bacteroidesnordii. These opportunistic pathogens are known to cause bacteremia.44 While receiving antibiotics, patients demonstrated a further depletion of probiotics such as F. prausnitzii, Lachnospiraceae bacterium 5_1_63FAA, Eubacteriumrectale, Ruminococcusobeum, and Doreaformicigenerans, which are symbionts beneficial to host immunity.43 This suggests that the use of antibiotics should be considered carefully as it may exacerbate intestinal flora disorders.

This dysbiosis of intestinal microbiota in patients with COVID-19 can persist in a subset up to 12 days after nasopharyngeal clearance of SARS-CoV-2.45 Although SARS-CoV-2 infection may be cured in the respiratory tract, loss of probiotics and gastrointestinal tract SARS-CoV-2 persisted in some COVID-19 patients.43,46 On the other hand, COVID-19 patients were enriched with fungal pathogens such as candida and aspergillus.45 Candida albicans caused by intestinal colonization aggravates inflammation in the gastrointestinal tract.47 Therefore, attention should be paid to the monitoring of intestinal microecological disorders in COVID-19 patients with gastrointestinal symptoms. Since these studies involved a small number of cases, more studies need to be conducted in the future, especially regarding the study of intestinal fungi.

Interaction and mechanism between COVID-19 and intestinal microbiota

There is evidence to suggest the presence of crucial cross-talk between the gastrointestinal microbiota and the lungs (gut-lung axis). The gut-lung axis mainly refers to the gastrointestinal microbiota, which can strengthen lung resistance, eliminate pathogenic bacteria and reduce or slow down the occurrence and development of respiratory diseases through the regulation of the immune response signal pathway. At the same time, disorders of the respiratory tract also impact the gastrointestinal tract through immune regulation.48 The main reason for this extrapulmonary phenomenon may be that the virus damages the intestinal mucosa and changes the intestinal flora, while dysbiosis of intestinal microbiota aggravates the severity of COVID-19.2 The RNA of SARS-CoV-2 can be detected in and be isolated from stool, and can be accompanied by intestinal microbiota disorders.49 However, Wolfel et al.50 reported that SARS-CoV-2 was isolated from samples derived from the throat or lung in COVID-19 patients, but not from stool samples despite high concentrations of virus RNA. This results suggests that whether the fecal-oral transmission route is utilized by SARS-COV-2 still needs more research.

Effects of SARS-CoV-2 on intestinal microbiota

COVID-19 can cause systemic inflammation syndrome, acute respiratory distress syndrome, shock, and antimicrobial use, all of which directly or indirectly cause dysbiosis of intestinal microbiota. Among these options, the combination of SARS-CoV-2 and angiotensin converting enzyme 2 (ACE2) plays a unique role in intestinal microecology. SARS-CoV-2 infects host cells by binding to the receptor of ACE2 and transmembrane serine protease 2 (TMPRSS2).51 ACE2 and TMPRSS2 are not only co-expressed in lung AT1 and AT2 cells but are also highly expressed in enterocytes from the ileum and colon.51,52 SARS-CoV-2 has four structural proteins, which are necessary for particle formation and include spike, membrane, envelope, and nucleocapsid proteins.53 The first step of viral infection is entry into host cells. The spike protein on the viral envelope can bind to the specific cellular receptor ACE2 on the membrane of host cells. Spike protein can then be cleaved into S1 and S2 subunits. S1 is the receptor binding domain that contributes to the SARS-CoV-2 attachment to the surface of the human cell, and thus promotes the S2-mediated fusion process of SARS-CoV-2 with host cell membrane.54 TMPRSS2 of host cell protease cleaves the spike protein, promoting the virus to release fusion peptides for membrane fusion.55

ACE2 is essential for neutral amino acid transporters in the gastrointestinal tract. Amino acid malnutrition can result in intestinal inflammation by ACE2, which plays an important role in innate immunity, amino acid homeostasis, and maintenance of intestinal microbiota.56,57 ACE2 is necessary for intestinal B(0) AT1 expression, which is involved in the absorption of amino acids. When ACE2 is decreased or knocked out, tryptophan cannot be effectively absorbed and the mTOR pathway activity in the small intestine is reduced. This results in decreased expression of antimicrobial peptides in intestinal Paneth cells, which can lead to changes in the composition of intestinal flora and increase the risk of bacterial translocation and endotoxemia.56,58–60

ACE2 is a negative regulator of the renin-angiotensin system (RAS) and converts angiotensin II (Ang II) to vasoprotective heptapeptide (Ang-(1-7)).61 Ang-(1-7) binds with the receptor Mas to construct the ACE2-Ang-(1-7)-Mas axis, which exerts beneficial effects by improving endothelial function, anti-oxidative stress, and inhibits the inflammatory response and alleviates intestinal inflammation.62–64 In addition, Yang et al. reported that colonized gut microbiota decrease in colonic ACE2 expression through the presence or absence of the microbiota rats. This suggests that the variability of gut microbial composition is one of factors for the susceptibility of COVID-19.57

TMPRSS2 is a protease that belongs to the type II transmembrane serine protease family. The cells expressing TMPRSS2 play a role in infecting and propagating SARS-CoV-2.65 TMPRSS2 knockout mice can reduce the primary sites of infection and increase virus spread within the respiratory tract and immunopathological injury after infection by SARS-CoV.66 This suggests that TMPRSS2 plays a critical role in coronavirus infection and will be one of the selected targets for drug therapy in the future.

Moreover, influenza pulmonary infection can change the intestinal microecology through type I interferons (IFNs). High levels of type I IFNs increase interlukin-17 production and Th17 cell activation, which promotes the production of pro-inflammatory cytokines and chemokines and destroys intestinal epithelial cells.67

The binding of SARS-CoV-2 to the ACE2 receptor results in ACE2 downregulation. TMPRSS2 enhances the spread of this virus, hindering the absorption of intestinal nutrients, aggravating intestinal inflammation, reducing the function of intestinal mucosal barrier, and causing intestinal flora translocation and abnormal composition. However, the exact mechanism by which SARS-CoV-2 interacts with intestinal microbiota is still unclear.

Effects of intestinal microbiota dysbiosison COVID-19

Normal intestinal microbiota play an important role in the regulation of lung immunity and host defense.21 Dysbiosis of the intestinal microbiota leads to deficient energy harvesting and immune protection, is correlated to diarrhea and systemic invasion by microbial pathogens, and increases the burden of lung infection patients.68 Dysbiosis of the intestinal microbiota therefore induces the translocation of intestinal flora, the aggravation of systemic inflammation and lung injury.

Respiratory influenza virus infection induces intestinal injury by microbiota-mediated Th17 cell-dependent inflammation,69 which increases the risk of bacterial translocation. Dickson et al. found that the lung microbiome is enriched with intestinal bacteria in a murine model of sepsis and in humans with established acute respiratory distress syndrome. Overall, the gut-lung translocation and disorder of the lung microbiome are associated with indices of systemic and alveolar inflammation, respectively.70 In contrast, the cytokine storm is caused by the massive release of cytokines and chemokines, leading to widespread and uncontrolled disorders of the host immune defense in COVID-19 patients.9,71,72

Dysbiosis of intestinal microbiota can result in the enhancement of pulmonary influenza virus amplification, leading to the aggravation of airway inflammation and the progression of sepsis.69,70,73,74 Through the BALB/c pulmonary influenza virus infection mouse model with dysbiosis of intestinal microbiota, Pang et al.74 found that the lung viral load significantly increased and suggested that intestinal dysbacteriosis might affect antiviral immunity in the lung.74 For intestinal dysbacteriosis COVID-19 patients, whether there is similar performance, and whether the virulence and infectivity of the virus change still need further research (Fig. 1).

A model for the process by which SARS-CoV-2 enters host cells in the lung and gastrointestinal tract.
Fig. 1  A model for the process by which SARS-CoV-2 enters host cells in the lung and gastrointestinal tract.

The spike glycoprotein of SARS-CoV-2 binds to the angiotensin converting enzyme 2 (ACE2) on host cells, allowing the virus enter. Transmembrane protease serine 2 (TMPRSS2) also participates in this process by cleaving the spike glycoprotein, promoting the virus to release fusion peptides for membrane fusion.

Effects of probiotics on COVID-19

Probiotics are living microorganisms that, when used at a reasonable dosage, are beneficial to the health of the host. Probiotics can improve intestinal flora disorders, reduce secondary infections, and improve immunity.75–78 About 12.3% of COVID-19 patients need invasive ventilation.7 Probiotics have been reported to reduce enteritis, the duration of intensive care unit stays, and ventilator-associated pneumonia in patients with sepsis.75,79 Modulating the intestinal microbiota has been reported to have ameliorated the symptoms and pathology in a sepsis mouse model.80 Studies have further found that probiotics can reduce the incidence of respiratory diseases in the elderly and children.81,82 d’Ettorre et al. found that from 28 COVID-19 patients the risk of developing respiratory failure was eight-fold lower in patients receiving oral bacteriotherapy, and the prevalence of patients transferred to the intensive care unit and mortality was lower.83 Previous studies have found that probiotics can produce exopolysaccharides, increase leukocyte and natural killer cell counts, decrease inflammatory cytokine expression, and influence both innate and adaptive immune responses.82 However, the potential mechanisms of probiotics on COVID-19 are not yet well defined.

Fecal microbiota transplantation (FMT) is one of the treatment strategies to restore the dynamic balance of intestinal microbiota. Considering that SARS-CoV-2 may be potentially transmitted through a fecal-oral route, the use of FMT should be conducted with caution during the epidemic of COVID-19.84 To preserve intestinal balance and reduce the risk of secondary bacterial infections, the use of probiotics is recommended for the treatment of patients with severe COVID-19 in China.9 Clinical trials testing probiotic treatments for COVID-19 are being undertaken, however, until reliable data is available against this approach, probiotic use should be recommended (Table 1).

Table 1

The latest literature sources on COVID-19 and intestinal microbiota

NoAuthorYearObjectsSample sizeConclusions
1Zuo et al.432020COVID-19 patients15Fecal microbiota alterations were associated with fecal levels of SARS-CoV-2 and COVID-19 severity, with persistent alterations during hospitalization.
2Zuo et al.452020COVID-19 patients30COVID-19 patients have enrichment of fungal pathogens from the genera Candida and Aspergillus. Up to 12 days after nasopharyngeal clearance of SARS-CoV-2, prolonged dysbiosis persisted in COVID-19 patients.
3Zuo et al.492020COVID-19 patients15Gut microbiota of patients with active SARS-CoV-2 gastrointestinal infection was characterised by enrichment of opportunistic pathogens, loss of salutary bacteria and increased functional capacity for nucleotide and amino acid biosynthesis and carbohydrate metabolism.
4Zhou et al.102020COVID-19 patients254The gastrointestinal symptom group appeared to have a similar rate of complications, treatment, and clinical prognosis as the non–gastrointestinal symptom group in COVID-19 patients
5Yang et al.572020ratGut microbiota colonized decrease in colonic ACE2 expression
6Xing et al.462020COVID-19 patients3SARS-CoV-2 may exist in children’s gastrointestinal tract for a longer time than the respiratory system.
7Wolfel et al.502020COVID-19 patients9Pharyngeal virus shedding was very high during the first week of symptoms, with a peak RNA copies per throat swab on day 4. Infectious virus was readily isolated from samples derived from the throat or lung, but not from stool samples.
8Wei et al.132020COVID-19 patients84A higher proportion of COVID-19 patients with diarrhea have virus RNA in the stool. Elimination of SARS-CoV-2 from stool takes longer than that from the nose and throat.
9Pan et al.362020COVID-19 patients204COVID-19 patients with digestive symptoms have a longer time from onset to admission, evidence of longer coagulation, and higher liver enzyme levels.
10Matsuyama et al.652020VeroE6/TMPRSS2 cells/TMPRSS2 may also play an important role in SARS-CoV-2 cell entry and is likely to be a key protease for SARS-CoV-2 replication.
11Gu et al.392020COVID-19 patients30COVID-19 patients had significantly reduced bacterial diversity, a significantly higher relative abundance of opportunistic pathogens, such as Streptococcus, Rothia, Veillonella and Actinomyces, and a lower relative abundance of beneficial symbionts
12d’Ettorre et al.832020COVID-19 patients70Using the specific bacterial formulation ameliorated the impact on the clinical conditions of COVID-19 patients

COVID-19, coronavirus disease 2019; SARS-CoV-2, severe acute respiratory syndrome coronavirus 2; ACE2, angiotensin converting enzyme 2; TMPRSS2, transmembrane protease serine 2.

Future direction

COVID-19 is a global epidemic that can cause multiple organ failure within the digestive system. It is necessary to confirm the mechanism and interaction between intestinal microbiota and COVID-19. SARS-CoV-2 infects host cells by binding to the receptor of ACE2, which is co-expressed in the lung and intestinal tract. Further studies are needed to identify other binding receptors by which this virus infects host cells. Dysbiosis of intestinal microbiota may occur in COVID-19 patients, but further studies on the gastrointestinal injury of these patients are needed. Noninvasive tests such as calprotectin, computerized tomography enterograph, magnetic resonance enterograph, may be used to assess the gastrointestinal injury. Moreover, the intestinal microbiota participates in helping the host to maintain homeostasis through a gut-lung interaction. Clinical attention should focus on the efficacy and mechanism of probiotic therapy in COVID-19 patients.

Conclusion

A variety of mechanisms are involved in the interaction between the intestinal microbiota and COVID-19. SARS-CoV-2 can cause dysbiosis of intestinal microbiota and intestinal damage, with dysbiosis of intestinal microbiota aggravating a systemic inflammatory response and lung injury. Modulating the intestinal microbiota improves digestive symptoms and the pathology of respiratory infectious diseases. Probiotics may have therapeutic value for COVID-19. Nevertheless, more studies on the interaction between intestinal flora and COVID-19 are needed in the future.

Abbreviations

COVID-19: 

coronavirus disease 2019

SARS-CoV-2: 

severe acute respiratory syndrome coronavirus 2

ACE2: 

angiotensin converting enzyme 2

TMPRSS2: 

transmembrane protease serine 2

RNA: 

ribonucleic acid

Ang II: 

angiotensin II

mTOR: 

mechanistic target of rapamycin

FMT: 

fecal microbiota transplantation

Declarations

Acknowledgement

The authors thank Editage (www.editage.cn) for English language editing.

Funding

This work was supported by Self-financing Project of the Health Commission of Guangxi Zhuang Autonomous Region (NO.Z20201334).

Conflict of interest

The authors declare that they have no conflict of interest.

Authors’ contributions

Study design (ZJH, LYC); manuscript writing (ZJH, YXL). The authors read and approved the final manuscript.

References

  1. Harmsen HJ, de Goffau MC. The Human Gut Microbiota. Adv Exp Med Biol 2016;902:95-108 View Article
  2. Aktas B, Aslim B. Gut-lung axis and dysbiosis in COVID-19. Turk J Biol 2020;44(3):265-272 View Article
  3. Perlot T, Penninger JM. ACE2 - from the renin-angiotensin system to gut microbiota and malnutrition. Microbes Infect 2013;15(13):866-873 View Article
  4. Zhou P, Yang XL, Wang XG, Hu B, Zhang L, Zhang W, et al. A pneumonia outbreak associated with a new coronavirus of probable bat origin. Nature 2020;579(7798):270-273 View Article
  5. Tu H, Tu S, Gao S, Shao A, Sheng J. Current epidemiological and clinical features of COVID-19; a global perspective from China. J Infect 2020;81(1):1-9 View Article
  6. Yuen KS, Ye ZW, Fung SY, Chan CP, Jin DY. SARS-CoV-2 and COVID-19: The most important research questions. Cell Biosci 2020;10:40 View Article
  7. Wang D, Hu B, Hu C, Zhu F, Liu X, Zhang J, et al. Clinical Characteristics of 138 Hospitalized Patients With 2019 Novel Coronavirus-Infected Pneumonia in Wuhan, China. JAMA 2020;323(11):1061-1069 View Article
  8. Zaim S, Chong JH, Sankaranarayanan V, Harky A. COVID-19 and Multiorgan Response. Curr Probl Cardiol 2020;45(8):100618 View Article
  9. Xu K, Cai H, Shen Y, Ni Q, Chen Y, Hu S, et al. Management of corona virus disease-19 (COVID-19): the Zhejiang experience (in Chinese). Zhejiang Da Xue Xue Bao Yi Xue Ban 2020;49(1):147-157 View Article
  10. Zhou Z, Zhao N, Shu Y, Han S, Chen B, Shu X. Effect of Gastrointestinal Symptoms in Patients With COVID-19. Gastroenterology 2020;158(8):2294-2297 View Article
  11. D’Amico F, Baumgart DC, Danese S, Peyrin-Biroulet L. Diarrhea During COVID-19 Infection: Pathogenesis, Epidemiology, Prevention, and Management. Clin Gastroenterol Hepatol 2020;18(8):1663-1672 View Article
  12. Rokkas T. Gastrointestinal involvement in COVID-19: a systematic review and meta-analysis. Ann Gastroenterol 2020;33(4):355-365 View Article
  13. Wei XS, Wang X, Niu YR, Ye LL, Peng WB, Wang ZH, et al. Diarrhea Is Associated With Prolonged Symptoms and Viral Carriage in Corona Virus Disease 2019. Clin Gastroenterol Hepatol 2020;18(8):1753-1759.e2 View Article
  14. Wopereis H, Oozeer R, Knipping K, Belzer C, Knol J. The first thousand days - intestinal microbiology of early life: establishing a symbiosis. Pediatr Allergy Immunol 2014;25(5):428-438 View Article
  15. Thursby E, Juge N. Introduction to the human gut microbiota. Biochem J 2017;474(11):1823-1836 View Article
  16. Faith JJ, Guruge JL, Charbonneau M, Subramanian S, Seedorf H, Goodman AL, et al. The long-term stability of the human gut microbiota. Science 2013;341(6141):1237439 View Article
  17. Maffei VJ, Kim S, Blanchard E4th, Luo M, Jazwinski SM, Taylor CM, et al. Biological Aging and the Human Gut Microbiota. J Gerontol A Biol Sci Med Sci 2017;72(11):1474-1482 View Article
  18. Dhar D, Mohanty A. Gut microbiota and Covid-19- possible link and implications. Virus Res 2020;285:198018 View Article
  19. Gupta A, Saha S, Khanna S. Therapies to modulate gut microbiota: Past, present and future. World J Gastroenterol 2020;26(8):777-788 View Article
  20. Michie L, Tucker HO. Influence of Commensal Microbiota in Barrier Function of Intestinal Mucosal Epithelium. Adv Res Endocrinol Metab 2019;1(1):33-36
  21. Schuijt TJ, Lankelma JM, Scicluna BP, de Sousa e Melo F, Roelofs JJ, de Boer JD, et al. The gut microbiota plays a protective role in the host defence against pneumococcal pneumonia. Gut 2016;65(4):575-583 View Article
  22. Cosorich I, Dalla-Costa G, Sorini C, Ferrarese R, Messina MJ, Dolpady J, et al. High frequency of intestinal T(H)17 cells correlates with microbiota alterations and disease activity in multiple sclerosis. Sci Adv 2017;3(7):e1700492 View Article
  23. Wu M, Xiao H, Liu G, Chen S, Tan B, Ren W, et al. Glutamine promotes intestinal SIgA secretion through intestinal microbiota and IL-13. Mol Nutr Food Res 2016;60(7):1637-1648 View Article
  24. Rowland I, Gibson G, Heinken A, Scott K, Swann J, Thiele I, et al. Gut microbiota functions: metabolism of nutrients and other food components. Eur J Nutr 2018;57(1):1-24 View Article
  25. Hou YP, He QQ, Ouyang HM, Peng HS, Wang Q, Li J, et al. Human Gut Microbiota Associated with Obesity in Chinese Children and Adolescents. Biomed Res Int 2017;2017:7585989 View Article
  26. Monda V, Villano I, Messina A, Valenzano A, Esposito T, Moscatelli F, et al. Exercise Modifies the Gut Microbiota with Positive Health Effects. Oxid Med Cell Longev 2017;2017:3831972 View Article
  27. Yang Y, Zhang Y, Xu Y, Luo T, Ge Y, Jiang Y, et al. Dietary methionine restriction improves the gut microbiota and reduces intestinal permeability and inflammation in high-fat-fed mice. Food Funct 2019;10(9):5952-5968 View Article
  28. Eljaaly K, Enani MA, Al-Tawfiq JA. Impact of carbapenem versus non-carbapenem treatment on the rates of superinfection: A meta-analysis of randomized controlled trials. J Infect Chemother 2018;24(11):915-920 View Article
  29. Ge X, Ding C, Zhao W, Xu L, Tian H, Gong J, et al. Antibiotics-induced depletion of mice microbiota induces changes in host serotonin biosynthesis and intestinal motility. J Transl Med 2017;15(1):13 View Article
  30. Mou H, Yang F, Zhou J, Bao C. Correlation of liver function with intestinal flora, vitamin deficiency and IL-17A in patients with liver cirrhosis. Exp Ther Med 2018;16(5):4082-4088 View Article
  31. Kostic AD, Gevers D, Pedamallu CS, Michaud M, Duke F, Earl AM, et al. Genomic analysis identifies association of Fusobacterium with colorectal carcinoma. Genome Res 2012;22(2):292-298 View Article
  32. McAleer JP, Kolls JK. Contributions of the intestinal microbiome in lung immunity. Eur J Immunol 2018;48(1):39-49 View Article
  33. Zhang X, Shen D, Fang Z, Jie Z, Qiu X, Zhang C, et al. Human gut microbiota changes reveal the progression of glucose intolerance. PloS one 2013;8(8):e71108 View Article
  34. Valles-Colomer M, Falony G, Darzi Y, Tigchelaar EF, Wang J, Tito RY, et al. The neuroactive potential of the human gut microbiota in quality of life and depression. Nat Microbiol 2019;4(4):623-632 View Article
  35. Li LQ, Huang T, Wang YQ, Wang ZP, Liang Y, Huang TB, et al. COVID-19 patients’ clinical characteristics, discharge rate, and fatality rate of meta-analysis. J Med Virol 2020;92(6):577-583 View Article
  36. Pan L, Mu M, Yang P, Sun Y, Wang R, Yan J, et al. Clinical Characteristics of COVID-19 Patients With Digestive Symptoms in Hubei, China: A Descriptive, Cross-Sectional, Multicenter Study. Am J Gastroenterol 2020;115(5):766-773 View Article
  37. Jin X, Lian JS, Hu JH, Gao J, Zheng L, Zhang YM, et al. Epidemiological, clinical and virological characteristics of 74 cases of coronavirus-infected disease 2019 (COVID-19) with gastrointestinal symptoms. Gut 2020;69(6):1002-1009 View Article
  38. Song Y, Liu P, Shi XL, Chu YL, Zhang J, Xia J, et al. SARS-CoV-2 induced diarrhoea as onset symptom in patient with COVID-19. Gut 2020;69(6):1143-1144 View Article
  39. Gu S, Chen Y, Wu Z, Chen Y, Gao H, Lv L, et al. Alterations of the Gut Microbiota in Patients with COVID-19 or H1N1 Influenza. Clin Infect Dis 2020:ciaa709 View Article
  40. Lu HF, Li A, Zhang T, Ren ZG, He KX, Zhang H, et al. Disordered oropharyngeal microbial communities in H7N9 patients with or without secondary bacterial lung infection. Emerg Microbes Infect 2017;6(12):e112 View Article
  41. Zhang CX, Wang HY, Chen TX. Interactions between Intestinal Microflora/Probiotics and the Immune System. Biomed Res Int 2019;2019:6764919 View Article
  42. Tan JY, Tang YC, Huang J. Gut Microbiota and Lung Injury. Adv Exp Med Biol 2020;1238:55-72 View Article
  43. 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 2020;159(3):944-955.e8 View Article
  44. Finegold SM, Song Y, Liu C, Hecht DW, Summanen P, Kononen E, et al. Clostridium clostridioforme: a mixture of three clinically important species. Eur J Clin Microbiol Infect Dis 2005;24(5):319-324 View Article
  45. Zuo T, Zhan H, Zhang F, Liu Q, Tso EYK, Lui GCY, et al. Alterations in Fecal Fungal Microbiome of Patients With COVID-19 During Time of Hospitalization until Discharge. Gastroenterology 2020;159(4):1302-1310.e5 View Article
  46. Xing YH, Ni W, Wu Q, Li WJ, Li GJ, Wang WD, et al. Prolonged viral shedding in feces of pediatric patients with coronavirus disease 2019. J Microbiol Immunol Infect 2020;53(3):473-480 View Article
  47. Sonoyama K, Miki A, Sugita R, Goto H, Nakata M, Yamaguchi N. Gut colonization by Candida albicans aggravates inflammation in the gut and extra-gut tissues in mice. Med Mycol 2011;49(3):237-247 View Article
  48. Ye Q, Wang B, Zhang T, Xu J, Shang S. The mechanism and treatment of gastrointestinal symptoms in patients with COVID-19. Am J Physiol Gastrointest Liver Physiol 2020;319(2):G245-G252 View Article
  49. Zuo T, Liu Q, Zhang F, Lui GC, Tso EY, Yeoh YK, et al. Depicting SARS-CoV-2 faecal viral activity in association with gut microbiota composition in patients with COVID-19. Gut 2020:gutjnl-2020-322294 View Article
  50. Wolfel R, Corman VM, Guggemos W, Seilmaier M, Zange S, Muller MA, et al. Virological assessment of hospitalized patients with COVID-2019. Nature 2020;581(7809):465-469 View Article
  51. Zhang H, Kang ZJ, Gong HY, Xu D, Wang J, Li ZX, et al. Digestive system is a potential route of COVID-19: an analysis of single-cell coexpression pattern of key proteins in viral entry process. Gut 2020;69(6):1010-1018 View Article
  52. Baughn LB, Sharma N, Elhaik E, Sekulic A, Bryce AH, Fonseca R. Targeting TMPRSS2 in SARS-CoV-2 Infection. Mayo Clin Proc 2020;95(9):1989-1999 View Article
  53. Peng M. Outbreak of COVID-19: An emerging global pandemic threat. Biomed Pharmacother 2020;129:110499 View Article
  54. Coutard B, Valle C, de Lamballerie X, Canard B, Seidah NG, Decroly E. The spike glycoprotein of the new coronavirus 2019-nCoV contains a furin-like cleavage site absent in CoV of the same clade. Antiviral Res 2020;176:104742 View Article
  55. Hoffmann M, Kleine-Weber H, Schroeder S, Krüger N, Herrler T, Erichsen S, et al. SARS-CoV-2 Cell Entry Depends on ACE2 and TMPRSS2 and Is Blocked by a Clinically Proven Protease Inhibitor. Cell 2020;181(2):271-280.e8 View Article
  56. Hashimoto T, Perlot T, Rehman A, Trichereau J, Ishiguro H, Paolino M, et al. ACE2 links amino acid malnutrition to microbial ecology and intestinal inflammation. Nature 2012;487(7408):477-481 View Article
  57. Yang T, Chakraborty S, Saha P, Mell B, Cheng X, Yeo JY, et al. Gnotobiotic Rats Reveal That Gut Microbiota Regulates Colonic mRNA of Ace2, the Receptor for SARS-CoV-2 Infectivity. Hypertension 2020;76(1):e1-e3 View Article
  58. Singer D, Camargo SM, Ramadan T, Schafer M, Mariotta L, Herzog B, et al. Defective intestinal amino acid absorption in Ace2 null mice. Am J Physiol Gastrointest Liver Physiol 2012;303(6):G686-G695 View Article
  59. Vuille-dit-Bille RN, Camargo SM, Emmenegger L, Sasse T, Kummer E, Jando J, et al. Human intestine luminal ACE2 and amino acid transporter expression increased by ACE-inhibitors. Amino Acids 2015;47(4):693-705 View Article
  60. He F, Wu C, Li P, Li N, Zhang D, Zhu Q, et al. Functions and Signaling Pathways of Amino Acids in Intestinal Inflammation. Biomed Res Int 2018;2018:9171905 View Article
  61. Kuba K, Imai Y, Penninger JM. Multiple functions of angiotensin-converting enzyme 2 and its relevance in cardiovascular diseases. Circ J 2013;77(2):301-308 View Article
  62. Jiang T, Gao L, Lu J, Zhang YD. ACE2-Ang-(1-7)-Mas Axis in Brain: A Potential Target for Prevention and Treatment of Ischemic Stroke. Curr Neuropharmacol 2013;11(2):209-217 View Article
  63. Khajah MA, Fateel MM, Ananthalakshmi KV, Luqmani YA. Anti-Inflammatory Action of Angiotensin 1-7 in Experimental Colitis. PloS one 2016;11(3):e0150861 View Article
  64. Meng Y, Yu CH, Li W, Li T, Luo W, Huang S, et al. Angiotensin-converting enzyme 2/angiotensin-(1-7)/Mas axis protects against lung fibrosis by inhibiting the MAPK/NF-kappaB pathway. Am J Respir Cell Mol Biol 2014;50(4):723-736 View Article
  65. Matsuyama S, Nao N, Shirato K, Kawase M, Saito S, Takayama I, et al. Enhanced isolation of SARS-CoV-2 by TMPRSS2-expressing cells. PNAS 2020;117(13):7001-7003 View Article
  66. Iwata-Yoshikawa N, Okamura T, Shimizu Y, Hasegawa H, Takeda M, Nagata N. TMPRSS2 Contributes to Virus Spread and Immunopathology in the Airways of Murine Models after Coronavirus Infection. J Virol 2019;93(6):e01815-18 View Article
  67. Deriu E, Boxx GM, He X, Pan C, Benavidez SD, Cen L, et al. Influenza Virus Affects Intestinal Microbiota and Secondary Salmonella Infection in the Gut through Type I Interferons. PLoS Pathog 2016;12(5):e1005572 View Article
  68. Million M, Diallo A, Raoult D. Gut microbiota and malnutrition. Microb Pathog 2017;106:127-138 View Article
  69. Wang J, Li F, Wei H, Lian ZX, Sun R, Tian Z. Respiratory influenza virus infection induces intestinal immune injury via microbiota-mediated Th17 cell-dependent inflammation. J Exp Med 2014;211(12):2397-2410 View Article
  70. Dickson RP, Singer BH, Newstead MW, Falkowski NR, Erb-Downward JR, Standiford TJ, et al. Enrichment of the lung microbiome with gut bacteria in sepsis and the acute respiratory distress syndrome. Nat Microbiol 2016;1(10):16113 View Article
  71. Catanzaro M, Fagiani F, Racchi M, Corsini E, Govoni S, Lanni C. Immune response in COVID-19: addressing a pharmacological challenge by targeting pathways triggered by SARS-CoV-2. Signal Transduct Target Ther 2020;5(1):84 View Article
  72. Akour A. Probiotics and COVID-19: is there any link?. Lett Appl Microbiol 2020;71(3):229-234 View Article
  73. Kim YG, Udayanga KG, Totsuka N, Weinberg JB, Núñez G, Shibuya A. Gut dysbiosis promotes M2 macrophage polarization and allergic airway inflammation via fungi-induced PGE2. Cell Host Microbe 2014;15(1):95-102 View Article
  74. Pang P, Yu B, Shi Y, Deng L, Xu H, Wu S, et al. Alteration of Intestinal Flora Stimulates Pulmonary microRNAs to Interfere with Host Antiviral Immunity in Influenza. Molecules 2018;23(12):3451 View Article
  75. Shimizu K, Yamada T, Ogura H, Mohri T, Kiguchi T, Fujimi S, et al. Synbiotics modulate gut microbiota and reduce enteritis and ventilator-associated pneumonia in patients with sepsis: a randomized controlled trial. Crit Care 2018;22(1):239 View Article
  76. He LH, Ren LF, Li JF, Wu YN, Li X, Zhang L. Intestinal Flora as a Potential Strategy to Fight SARS-CoV-2 Infection. Front Microbiol 2020;11:1388 View Article
  77. Sundararaman A, Ray M, Ravindra PV, Halami PM. Role of probiotics to combat viral infections with emphasis on COVID-19. Appl Microbiol Biotechnol 2020;104(19):8089-8104 View Article
  78. Angurana SK, Bansal A. Probiotics and COVID-19: Think about the link. Br J Nutr 2020:1-26 View Article
  79. Banupriya B, Biswal N, Srinivasaraghavan R, Narayanan P, Mandal J. Probiotic prophylaxis to prevent ventilator associated pneumonia (VAP) in children on mechanical ventilation: an open-label randomized controlled trial. Intensive Care Med 2015;41(4):677-685 View Article
  80. Wang W, Chen Q, Yang X, Wu J, Huang F. Sini decoction ameliorates interrelated lung injury in septic mice by modulating the composition of gut microbiota. Microb Pathog 2020;140:103956 View Article
  81. Wang B, Hylwka T, Smieja M, Surrette M, Bowdish DME, Loeb M. Probiotics to Prevent Respiratory Infections in Nursing Homes: A Pilot Randomized Controlled Trial. J Am Geriatr Soc 2018;66(7):1346-1352 View Article
  82. Wang Y, Li X, Ge T, Xiao Y, Liao Y, Cui Y, et al. Probiotics for prevention and treatment of respiratory tract infections in children: A systematic review and meta-analysis of randomized controlled trials. Medicine 2016;95(31):e4509 View Article
  83. d’Ettorre G, Ceccarelli G, Marazzato M, Campagna G, Pinacchio C, Alessandri F, et al. Challenges in the Management of SARS-CoV2 Infection: The Role of Oral Bacteriotherapy as Complementary Therapeutic Strategy to Avoid the Progression of COVID-19. Front Med 2020;7:389 View Article
  84. Nicco C, Paule A, Konturek P, Edeas M. From Donor to Patient: Collection, Preparation and Cryopreservation of Fecal Samples for Fecal Microbiota Transplantation. Diseases 2020;8(2):9 View Article
© 2021 Authors. This is an Open Access article distributed under the terms of the Creative Commons Attribution-Noncommercial 4.0 License (CC BY-NC 4.0), permitting all non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
  • Exploratory Research and Hypothesis in Medicine
  • pISSN 2993-5113
  • eISSN 2472-0712

Article Options

Metrics

Cite this Article

  • © 2024 Xia & He Publishing Inc.
  • Total visits : 2747692
  • Visits today : 1395
Back to Top

Advances in the Interaction between Intestinal Microbiota and COVID-19

Zhi-Jun He, Yun-Xiao Liang, Lian-Ying Cai
  • Reset Zoom
  • Download TIFF