Abstract
COVID-19 is a pandemic disease caused by the novel coronavirus severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). This new viral infection was first identified in China in December 2019, and it has subsequently spread globally. The lack of a vaccine or curative treatment for COVID-19 necessitates a focus on other strategies to prevent and treat the infection. Probiotics consist of single or mixed cultures of live microorganisms that can beneficially affect the host by maintaining the intestinal or lung microbiota that play a major role in human health. At present, good scientific evidence exists to support the ability of probiotics to boost human immunity, thereby preventing colonization by pathogens and reducing the incidence and severity of infections. Herein, we present clinical studies of the use of probiotic supplementation to prevent or treat respiratory tract infections. These data lead to promising benefits of probiotics in reducing the risk of COVID-19. Further studies should be conducted to assess the ability of probiotics to combat COVID-19.
Introduction
The evolution and emergence of viruses have significantly increased in the last two decades because of their rapid mutation. The emergence or re-emergence of viruses is attributable to several factors including increased numbers of immunocompromised patients, climate change, the absence of anti-viral agents, the increased geographical movement of people and goods, and genetic modification of viruses1,2. Respiratory infections represent a major cause of death and disability worldwide in both developing and developed countries3. It has been estimated that acute respiratory infections including pneumonia, influenza, enterovirus, adenovirus, and respiratory syncytial virus infections are responsible for millions of deaths every year. In addition, they have a substantial economic and social impact because of their associated high hospitalization rate, high medical costs, and losses of productivity associated with time missed from work or school. It has been estimated that the annual cost of viral respiratory tract illnesses is approximately US $40 billion in the United States1. The majority of these infections are caused by more than 200 different types of viruses that may contain RNA or DNA as genetic material. Infections related to RNA viruses are more remarkable than those caused by DNA viruses. In particular, coronaviruses represent a highly important emerging RNA virus family2.
Coronavirus disease 2019 (COVID-19)
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a novel coronavirus that causes coronavirus disease (COVID-19) in humans, a respiratory infection that was first reported in Wuhan, China in December 2019. This SARS-related coronavirus is a member of the zoonotic beta-coronavirus family4,5. SARS-CoV-2 is an enveloped virus with a single-stranded positive sense RNA genome6. Coronaviruses are named for their crown-like shapes associated with their long surface spikes7. Coronaviruses are hosted by humans and several other vertebrate reservoirs such as camels, bats, masked palm civets, mice, dogs, and cats8,9. It has been suggested that COVID-19 was initially hosted by bats and then transmitted to humans via wild animals; however, the subsequent spread of the virus occurred through human-to-human transmission7.
Coronaviruses may cause respiratory, gastrointestinal (GI), and neurologic disorders8. Most of the identified coronaviruses cause mild human disease excluding SARS-CoV-1 and Middle East respiratory syndrome coronavirus (MERS-CoV), which are highly pathogenic viruses associated with severe infections and fatalities9,10. SARS-CoV-1 appeared in 2002 in China, whereas MERS-CoV was identified in 2012 in Saudi Arabia4,8. Although SARS-CoV-2 is more transmissible than MERS-CoV and SARS-CoV-1, it has lower fatality rates than either virus8. COVID-19 is highly pathogenic, and the number of affected patients has drastically increased globally. Therefore, COVID-19 was declared pandemic by WHO, which confirmed at least 32.5 million cases and more than 986.000 deaths through September 26, 202010.
The incubation period for COVID-19 is 1–14 days10. The clinical manifestations of COVID-19 are variable, ranging from asymptomatic to severe illness. Asymptomatic patients can serve as sources of disease dissemination5,8. Common symptoms of COVID-19 include fever, dry cough, shortness of breath, myalgia, and fatigue. Headache, rhinorrhea, sneezing, sore throat, loss of odor and pneumonia are other reported symptoms of COVID-198. Other uncommon manifestations of the disease include gastrointestinal symptoms such as diarrhea, nausea, vomiting, and abdominal pain7,8.
The majority of cases are self-limiting and result in complete recovery5. Conversely, SARS-CoV-2 can cause severe infections and result in septic shock, acute respiratory distress syndrome, acute cardiac injury, acute kidney injury, and multi-organ failure, which necessitate intensive care unit admission. Extremely severe cases of COVID-19 can lead to death5,7,8. Adults and children usually develop mild self-limiting disease. Meanwhile, more severe COVID-19 can occur in elderly people with underlying medical conditions such as cardiovascular diseases and diabetes5. Pregnant women usually develop a disease status similar to that in non-pregnant adult patients. Although COVID-19 was initially considered uncommon in children11, increasing numbers of pediatric cases have been reported worldwide, suggesting that children have the same susceptibility to COVID-19 as adults but exhibit mild or asymptomatic disease12.
A history of contact with infected patients within 2 weeks should raise the suspicion of COVID-19 infection7. Real-time reverse-transcription–polymerase-chain-reaction is the gold standard diagnostic tool for COVID-19. Moreover, chest computed tomography is another modality supporting the clinical diagnosis of COVID-197.
COVID-19 is mainly transmitted from person-to-person via sneeze- or cough-induced respiratory droplets from the mouths or noses of infected persons5,8. Disease transmission through the eyes has also been suggested. Contact with surfaces contaminated by the virus is another mode of COVID-19 transmission4,9. Recently, SARS-CoV-2 was detected in stools, suggesting the possibility of fecal–oral transmission13. This was later confirmed in some cases in the US and China which indicated that SARS-CoV-2 can multiply in both respiratory and digestive tracts14. Furthermore, the fecal samples of some infected patients were found positive for the RNA of SARS-CoV-2 after their respiratory samples became negative for the viral RNA15. It seems that COVID-19 infection negatively affect the anatomy and physiology of the GI tract for a long period and thus, attacking the gut microbiota16,17. Nowadays, a solid body of available evidence confirmed that the gut microbial community of COVID-19 patients had been changed. It was obvious that growth of opportunistic pathogens and reduction of beneficial bacteria in gut microbiota positively correlated with the severity of COVID-19 infections18,19.
Gut microbiota
Vaccines are promising treatments for preventing viral infectious disease; however, their efficacy can be limited by mutations in RNA viruses, as observed for the influenza virus as a representative pathogenic virus20,21. This increases the risk of infection, making these viruses serious threats to public health because of recurrent widespread outbreaks.
The microbial communities (bacteria, fungi, archaea, viruses, and protozoa) in the human GI tract, lungs, skin, and mouth exist in a commensal relationship with host cells, thereby playing a major role in human health22,23. The commensal bacteria (1 × 1013 CFU) that are present in the GI tract are equivalent to the number of human cells24. This colonization starts shortly after birth and their profiles and numbers stabilize by the age of 1 year with more than 1000 bacterial species25,26. The GI microbiota has the ability to interact with human cells, including specific immune cells. These interactions produce different health benefits in the host including regulating GI motility; activating and destroying toxins, genotoxins, and mutagens; transforming bile acid and steroids; producing vitamins; absorbing minerals; metabolizing xenobiotic substances; influencing intestinal permeability and barrier functions; and modulating mucosal and systemic immunity; as well as beneficial effects on the skin and upper respiratory tract26,27.
Recently, the presence of beneficial microbes was reported in the upper (nasal cavity, nasopharynx, oropharynx, and larynx above the vocal cords) and lower respiratory tracts (larynx below the vocal cords, trachea, bronchi, and bronchioles and alveoli of the lungs) of both healthy people and those with pulmonary diseases such as cystic fibrosis and chronic obstructive pulmonary disease20,28. The microbiota populated the lungs mostly via the upper respiratory tract or diffusion along the mucosal surface28,29.
These beneficial microorganisms compete with pathogens concerning the colonization of human cells in different organs to promote host health. This requires high numbers of beneficial microorganisms, and any imbalance or disruption of this system may cause dysbiosis, which can allow pathogens to cause diseases such as respiratory tract infections20,22. Dysbiosis can also be caused by long-term antibiotic use. Therefore, probiotics are also usually recommended for patients who have recently used antibiotics for treating any disease. Other causes of dysbiosis in the human GI tract include exposure to toxins, stress, disease, insufficient diet, and age26.
Gut-lung axis and COVID-19
The gastrointestinal tract and lung are among the body compartments that host microbiota; however, the lung has a small number of microbiota when compared to that of the gut30. There is accumulating evidence that bidirectional communications exist between gut and lung, which is called the gut-lung axis. This bidirectional crosstalk is involved in the support of immune homeostasis31. It is believed that the gastrointestinal inflammation results in lung inflammation through this connection32. The exact mechanism underlying this inflammatory shift from the gut to the lung is not yet completely revealed; however, dysbiosis of gut and lung microbiota is one of the implicated factors in this event. It has been shown previously that dysbiosis of gut microbiota is linked with several respiratory pathological conditions32,33, and shifts in the composition of the lung microbiota toward the gut microbiota have been observed in several respiratory disorders30,34. One of the suggested mechanisms behind the bidirectional interaction between lung and gut microbiota systems is that increased permeability of the GI tract allows the leakage and migration of the gut microbiota to the lung, modulating its microbiota and thus its immune responses30. Furthermore, gut microbial components and metabolites like lipopolysaccharides (LPS) and short-chain fatty acids (SCFA), respectively, are also involved in this gut-lung bidirectional communication. Additionally, blood- or lymphatic-mediated circulation of immune cells or inflammatory mediators from the GI tract to the lung results can in lung inflammatory responses30,35.
In addition to the most frequently described respiratory symptoms such as fever, cough and severe respiratory syndrome caused by COVID-19 infection, it has also been reported that patients exhibited GI symptoms including diarrhea, vomiting, nausea, loss of appetite, GI bleeding, and abdominal pain36. It was found that COVID-19 patients with GI symptoms such as diarrhea experienced more severe respiratory disorders than those without GI symptoms37. Although the impact of the gut on lung health is well established, the available knowledge about the opposite role of the lung on the gut health is still scarce. Therefore, it is unknown why would COVID-19 influence the GI tract integrity. Dysbiosis is potentially one of the contributing mechanisms. Little knowledge is available about the effect of lung microbiome on the gut one. Acute lung injury mediated-lung dysbiosis was associated with blood-mediated modulation of the gut microbiota38,39, and the gut microbiota population is modulated in cases of pulmonary allergy40. As a result, COVID-19 may induce lung microbiota disruption that modulates the GI tract microbiota, resulting in GI tract symptoms.
Furthermore, studies revealed that the GI symptoms generated in patients infected with COVID1-9 might be attributed to the damaged tissues and organs caused by the immune responses41. Alternatively, angiotensin-converting enzyme 2 (ACE2) is the main host cell receptor of COVID-19