key: cord-0932954-kj4urpcu
authors: Gohil, Kushal; Samson, Rachel; Dastager, Syed; Dharne, Mahesh
title: Probiotics in the prophylaxis of COVID-19: something is better than nothing
date: 2020-11-26
journal: 3 Biotech
DOI: 10.1007/s13205-020-02554-1
sha: 1b164ceac82f56c539ebd059dd98b57c0ae3d04b
doc_id: 932954
cord_uid: kj4urpcu

The new viral pandemic of COVID-19 is caused by a novel coronavirus (SARS-CoV-2) that has brought the world at another unprecedented crisis in terms of health and economy. The lack of specific therapeutics necessitates other strategies to prevent the spread of infection caused by this previously unknown viral etiological agent. Recent pieces of evidence have shown an association between COVID-19 disease and intestinal dysbiosis. Probiotics comprise living microbes that upon oral administration benefit human health by reshaping the composition of gut microbiota. The close kinship of the gastrointestinal and respiratory tract suggests why the dysfunction of one may incite illness in others. The emerging studies suggest the capability of probiotics to regulate immune responses in the respiratory system. The efficacy of probiotics has been studied previously on several respiratory tract viral infections. Therefore, the purpose of this review is to comprehend existing information on the gut mediated-pulmonary immunity conferred by probiotic bacteria, in the course of respiratory virus infections and administration as a prophylactic measure in COVID-19 pandemic in managing intestinal dysbiosis as well.

Acute respiratory tract infections (pneumonia, influenza, enterovirus, adenovirus, and respiratory syncytial virus infections) accounts for one of the major causes of death and debility worldwide (Soriano et al. 2020) . A majority of these infections are caused by DNA/RNA viruses. Infections associated with RNA viruses are notable than those caused by DNA viruses (Zolnikova et al. 2018) . Coronaviruses, in particular, represent a highly important emerging RNA virus family causing respiratory infections (Su et al. 2016) . The recent 'Coronavirus disease 2019' (COVID-19) pandemic causes Severe Acute Respiratory Syndrome (SARS). Some patients with COVID-19 showed a striking dysbiosis in the probiotic group of intestinal microbes such as Lactobacillus and Bifidobacterium (Xu et al. 2020 ). In addition, some reports have confirmed a relationship between gut microbiota, secondary gut infection, and COVID-19 disease (Gu et al. 2020; Yeo et al. 2020; Gao et al. 2020) . Furthermore, some reports have shown the presence of RNA of SARS-CoV-2 in fecal samples of some infected patients that tested negative for the presence of SARS-CoV-2 RNA in their respiratory samples Xiao et al. 2020; Kopel et al. 2020) . These shreds of evidence suggest crosstalk between the gut-lung axis, which to some extent may be modulated by probiotics, by favorably altering the gastrointestinal symptoms and shielding the respiratory system (Gu et al. 2020; Bottari et al. 2020) . Therefore, this review article emphasizes to provide insights into the possible role of probiotics in COVID-19 prevention, in so doing, providing a starting point for future studies on it. Using keywords like COVID-19; SARS-CoV-2; probiotics in the respiratory tract infection; probiotics and antiviral activity; gut-lung axis; probiotics and coronavirus, we have derived the articles and reviewed for this review article.

Kushal Gohil and Rachel Samson contributed equally. Page 2 of 10

One of the major cause of worldwide mortality is acute viral respiratory infections (Fonkwo 2008) . The most important viral pathogens in this front consist of rhinovirus, adenovirus, influenza virus, respiratory syncytial virus (RSV), and coronavirus. The clinical manifestations of these viruses range from mild symptoms to severe infection in the upper, middle, and lower respiratory tract (Lysholm et al. 2012) . Adenovirus and rhinovirus have lower mortality but they are related to substantial morbidity (Pfeiffer and Virgin 2016) .

There is an annual increase in the global mortality rate as a result of influenza and RSV infection (Sahadulla 2018) .

The clinical manifestation upon infection with these respiratory viruses include common cold, bronchiolitis, croup, and pneumonia (Lehtoranta et al. 2014) . Different viruses responsible for these clinical manifestations are enlisted in Table 1 . Prevention of these infections poses a major challenge, since the available antivirals and vaccines for treatment are limited to influenza viruses and adenoviruses (Lee et al. 2018 ). Besides, a highly pathogenic group of viruses called coronaviruses cause a broad spectrum of respiratory tract infections (Zhang et al. 2020b ).

Coronaviruses (CoV) are enveloped and highly diverse RNA viruses comprising of a large (25-32 kb), single-stranded, positive-sense RNA genome (Zhu et al. 2020 ). There are four subfamilies of coronavirus, namely alpha-; beta-(originating mainly from mammals, particularly from bats); gamma-and delta-(originating from pigs and birds) (Zhang and Holmes 2020) . The alpha and beta-coronaviruses are known to cross animal-human barriers and cause severe disease and fatalities (Coleman and Frieman 2014) . These coronaviruses can infect humans and as well as several other vertebrates and cause respiratory, enteric, hepatic, and neurologic diseases (Jiang et al. 2020) . So far, six species of human coronaviruses have been identified. Among them, SARS-CoV and the Middle East Respiratory Syndrome Coronavirus (MERS-CoV) both having a zoonotic origin, can cause severe respiratory illness with high mortality (Fehr et al. 2017 (Zhai et al. 2005) . Later in 2012, another respiratory infection-Middle East respiratory syndrome (MERS), caused by MERS-CoV emerged with more than 30% mortality in the Middle East countries (Luo and Gao 2020) . To date, three highly pathogenic and lethal coronaviruses that infect humans are SARS-CoV, MERS-CoV and the recently reported one is SARS-CoV-2 (Meo et al. 2020 ).

In December 2019, a new type of Coronavirus, causing a cluster of pneumonia cases and deaths, emerged in the city of Wuhan, China, and spread out to other countries in the world rapidly, to become the current pandemic outbreak. The etiological agent behind the current pandemic of COVID-19 is Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) (Zhou et al. 2020 ). The isolated SARS-CoV-2 viral genome showed 88% and 50% genetic homology with SARS-CoV and MERS-CoV, respectively (Park et al. 2020 . As of 24th October 2020, there are over 42 million cases, with more than one million deaths worldwide (https ://www.world omete rs.info/coron aviru s). SARS-CoV-2 is the seventh known species of coronaviruses responsible for the COVID-19 disease, characterized by acute pathological outcomes, including pneumonia and acute respiratory distress syndrome (ARDS) (Velavan and Meyer 2020) . In addition, this virus can also cause severe infections resulting 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 death (Guan et al. 2020) . Presently, with the SARS-CoV-2 virus, the mortality rate is not as high as MERS, but the infectious rate of SARS-CoV-2 has challenged the specific development of therapeutics against COVID-19 disease (Seo et al. 2020) . The temporary precautionary measures include hand-washing, use of masks, gloves, and isolation (Singhal 2020) . Several efforts to develop vaccines against COVID-19 are underway, but the WHO estimates it will take 18 months for the COVID-19 vaccines to be available (Man Yi 2020). SARS-CoV-2 is mainly transmitted via respiratory droplets from the infected persons, contact with surfaces contaminated by the virus, and through the eyes. The peculiar respiratory symptoms of SARS-CoV-2 include fever, cough, and severe respiratory syndrome (Hamid et al. 2020) . Besides respiratory illness, some patients also exhibited gastro-intestinal (GI) symptoms such as diarrhea, vomiting, nausea, loss of appetite, GI bleeding, and abdominal pain (Kopel et al. 2020) . Recent, detection of SARS-CoV-2 virus in stools, suggested the possibility of fecal-oral transmission. This was later confirmed by the fact that SARS-CoV-2 can multiply in both respiratory and digestive tracts (Lamers et al. 2020) . Furthermore, it was also reported that COVID-19 infection affects the anatomy and physiology of the gastro-intestinal tract thereby modulating gut microbiota for a long period (Dhar and Mohanty 2020) . In addition, COVID-19 patients with GI symptoms did experience severe respiratory disorders than those without GI symptoms (Olaimat et al. 2020 ).

The term microbiome encompasses the entire microbial community such as bacteria, archaea, fungi, and viruses. Advances in research have led to the understanding that there is a dynamic cross-talk between the microbes of the gut-lung axis. This breakthrough quivered the ancient dogma of the sterile lung environment (Marsland et al. 2015) . Linking of the gut and the lung niche is mediated through this axis as it is a route for the passage of hormones, microbial metabolites, cytokines, and endotoxins into the bloodstream. A balanced gut community is of vital importance in pulmonary immunity. Several studies suggest that dysbiosis in gut microbiota influence pulmonary dysfunction by modulating the immune responses of neutrophils (Enaud et al. 2020) , T cell subsets (Ohnmacht 2016; Luu et al. 2017) , inflammatory cytokines (Scales et al. 2016 ) Toll-like receptors (Wang et al. 2018 ) and many more. The local or distal immune modulation of the commensal microbes in the lungs and gut affects the onset of the infection process. However, the indigenous gut commensals confer colonization resistance from the microbial pathogens by the concept of 'barrier effect' and thus, aid in protecting the gut niche from being altered (George Kerry et al. 2018) . The role of the gut microbiome and its effect on respiratory disease is summarized in Table 2 .

During infection of the respiratory tract, the commensal organisms of our body stimulate the local (from lungs) and the adjacent distal immune response (at the sites of the gut) (Chang and Kao 2019). The gut-lung axis is assumed to be bidirectional, meaning infection by SARS-CoV-2 at the lungs trigger an immune response in the GI tract. The infection of the lungs with SARS-CoV-2 causes an epithelial disruption in the gas exchange areas and the associated airways (Fanos et al. 2020) . Epithelial cells of the alveoli with angiotensin-converting enzyme 2 (ACE2) receptor serve as the binding site for SARS and SARS-CoV-2. The concentration of pro-inflammatory cytokines [Interferon gamma-induced protein 10 (IP-10); monocyte chemoattractant protein 1 (MCP1) and Interleukin 8 (IL-8)] (Sinha et al. 2020 ). Overproduction of cytokines and chemokines, activation of T helper cell-mediated immunity, and host inflammatory response was observed during the acute phase of SARS and SARS-CoV-2 infection (Qian et al. 2013) . Recent studies suggest that the involvement of the gut in COVID-19 is even greater and more prolonged compared with the lung (Xu et al. 2020) . Strikingly, it has been reported that probiotics show significant microbial inhibitory properties through alveolar macrophage, neutrophils, natural killer cells, and increased levels of Page 4 of 10 Page 5 of 10 1 pro-inflammatory cytokines like TNF-α and IL-6 in the lung (Dumas et al. 2018 ). In addition, probiotic bacteria can bind the invading virus and inhibit the pathogen-host cell receptor interaction. Therefore, the use of probiotics as medication restricts respiratory viral infections by fortifying the mucosal immunity (Marsland et al. 2015) .

Given the fundamental importance of gut microbiota in influencing lung diseases, the targeted manipulation of gut bacteria using certain dietary supplements, propose a promising therapeutic approach. Emerging studies suggest the use of probiotic bacteria in the treatment or prevention of a wide range of human diseases, medical conditions, and syndromes. Probiotics are live microorganisms that, when administered in adequate amounts, confer a health benefit to the host (FAO and WHO, UN). Probiotic mechanisms in preventive and therapeutic approaches consist of amending the intestinal microbial communities, immunomodulation, clamping down the pathogens, and protection of the intestinal barrier. They have already been used in the treatment of antibiotic-associated diarrhea, inflammatory bowel disease, and different chronic inflammatory diseases (Mortaz et al. 2013) .

Immune system modulation is a key factor in the prevention of infectious diseases. Probiotic microbes have demonstrated their ability to stimulate and modulate the immune system and also to reduce inflammation (Hardy et al. 2013) . Probiotics are known to decrease the severity of infections in the GI tract and the upper respiratory tract by acting on both the innate and the adaptive immune systems. Currently, the use of probiotic microorganisms and their metabolic products represents a promising approach for the treatment of viral diseases (Ryan et al. 2015) . Colonization of intestinal epithelium by the probiotic bacteria has been shown to reduce the incidences and symptoms of viral respiratory infections. This is achieved by the upsurge of IgA expressing B cells in the colon and lymph nodes in conjunction with the increasing population of the T follicular helper cells and IL-23-expressing dendritic cells. Furthermore, probiotics also comprise of immunostimulatory constituents such as peptidoglycan, lipoteichoic acid, Toll-like receptor (TLR) ligands, and muramyl dipeptide, which accentuates their immunomodulatory potency (Kanauchi et al. 2018) . The recent study of Ji et al., demonstrated that the supplementation of probiotics to RSV-infected mice has significantly elevated the abundance of short-chain fatty acid (SCFA) producing gut microbiota which in turn up-regulate the production of interferon β. Besides, they have also reported the upsurge of Corynebacterium and Lactobacillus species in the lung due to higher SCFA production, consequently leading to the activation of interferon β production in alveolar macrophages (Ji et al. 2020) . A randomized, double-blind and placebo-controlled human study of 109 adults demonstrated the enhanced level of anti-inflammatory cytokines IL-4 and IL-10 and reduced plasma peroxidation and oxidative stress upon administration of L. plantarum DR7.

The COVID-19 infection affects the lung tissues and gut, thus activating the inflammatory response. It increases the proinflammatory cytokines (IFN-γ, TNF-α) which lead to the emergence of the cytokine storm. This response is probably because of the activation of T helper cells (T h1 ) cell response in the lung tissue (Lehtoranta et al. 2014 ). In the case of the human gut environment, dysbiosis in the gut microbiota results in the imbalance of T h1 and T h2 which further results in the activation of proinflammatory cytokine and eventually the cytokine storm in the lungs as well (Qian et al. 2017) . Upon administration of probiotics, there is colonization of so-called "good bacteria" in the gut which leads to a shift in the balance between T h1/ T h2 cells that reduces the cytokine storm and reduces the severity of diseases (Qian et al. 2017) . Recently it has been found that medication with probiotic bacteria using Bifidobacteria and Lactobacillus provides a significant chance of recovery against COVID-19 (Fanos et al. 2020) . Previously, these probiotic bacteria Probiotics were reported to have beneficial effects against respiratory infection by the influenza virus (Zelaya et al. 2016) . Administration and consumption of probiotics advance the immune system by enhancing the level of type I interferons, antigen-presenting cells (APC), Natural Killer cells (NK cells), and B and T cells of the lungs (Dhar and Mohanty 2020). Probiotic administration can also improve the pro-and anti-inflammatory cytokines, helping to clear the viral infection by minimizing the cell damage in the lungs (Baud et al. 2020 ).

By maintaining the gut homeostasis probiotics are beneficial in preventing antibiotic-associated diarrhea, also prevent the adhesion and colonization of pathogenic microbes (Guo et al. 2019) . Hence, protect from infections in the gastrointestinal tract and various other body sites. The respiratory tract is one of them. Several animal model studies have reported the beneficial effects of L. plantarum species that, reduce the symptoms of influenza viral infection and increases the body weight and survival rate of mice (Maeda et al. 2009; Kawashima et al. 2011; Park et al. 2013) . Similarly, the anti-viral activity of L. casei was reported by Hori et al. (2001) against the H 1 N 1 virus, they observed a reduction in viral titer (Hori et al. 2001) . L. rhamnosus is reported for its ability to stimulate the host immune system and anti-influenza viral activity. With Lactobacillus species, Bifidobacterium species are also commensal bacterium of the human gut and reported for their beneficial effects to host. It promotes good digestion, boosts the immune system, and inhibits intestinal pathogens (Mayo and Sinderen 2010) . In many studies, bifidobacterial strains were used in combination with lactic acid bacteria to assess their anti-vital potential. A double-blind, placebo-controlled, randomized trial of 201 healthy infants aged between 4 and 10 months was administered with a combination of L. reuteri DSM 1793 and B. animalis spp. Lactis BB12. The combination reduced the RTI symptoms, fever, and antibiotic consumption (Weizman et al. 2005) , while a similar effect was also observed with only B. animalis spp. and Lactis BB12 strain (Taipale et al. 2011) .

The use of L. plantarum, L. salivarius, L. rhamnosus GG, and L. casei Shirota is well reported for their antiviral activity against rotavirus, transmissible gastroenteritis coronavirus (Maragkoudakis et al. 2010; Rejish Kumar et al. 2010) . Furthermore, the in vitro antiviral activity of probiotic strain Enterococcus faecium NCIMB 10,415 demonstrated the 3-log reduction in the viral titer. The authors also reported that the E. faecium alters the expression of interleukins, IL-6, and IL-8 and induces the production of Nitric oxide which might be the reason for its antiviral activity (Chai et al. 2012) . The study of Wang et al. (2019) also reported the antiviral activity of Lactobacillus plantarum against transmissible gastroenteritis virus, which in turn activates the antiviral proteins via JAK-STAT signalling pathway and up-regulate the expression of interferon genes, resulting in anti-transmissible gastroenteritis virus activity ). These reports further indicate the efficacy of probiotic strains to treat the infection of coronavirus.

Besides the oral intake of probiotics, the nasopharynx sprays have also shown promising results in terms of reduced viral infections (Lehtoranta et al. 2014) . The topical application of probiotics has been proved effective against Chronic Rhinosinusitis (CRS) and asthma, redefining the futuristic research (Cervin 2018) . The ability of probiotics to combat viral infections can be a solution to the lack of antiviral agents (Kassaa et al. 2015) . Lactobacillus and Bifidobacterium genus are the most studied genus concerning anti-respiratory virus activity specifically against H 1 N 1 , Influenza, and RSV viruses ( Table 3) .

All these studies found that the administration of probiotics shortens the duration of infections, reduces the severity, (de Vrese et al. 2006; Boge et al. 2009 ) improves immunity and gut health (Akatsu et al. 2013) . Hence, we believe that these probiotics can be good neutraceutical and promising immunobiotic agents to treat the infection of COVID-19.

Lactic acid bacteria (LAB) are known to produce a variety of antimicrobial substances such as acids, peptides or proteins, non-ribosomal peptides (NRP), hydrogen peroxide, and other metabolites. Hydrogen peroxide is toxic to many non-catalase microorganisms; however, their antirespiratory tract viral activity is not known but their activity against human immunodeficiency virus HIV-1 and Herpes simplex virus HSV-2 were reported earlier (Klebanoff and Coombs 1991; Conti et al. 2009 ). Lactic acid, the product of carbohydrate metabolism is an important microbicidal compound, it kills acid-sensitive microbes. It helps the host cells in preventing viral replication (Conti et al. 2009 ). Furthermore, the study of Verma et al. 2019 , demonstrated the expression and secretion of Human (Angiotensin-Converting Enzyme) ACE-2 (a receptor required by COVID-19 virus for its binding) in Lactobacillus paracasei (Verma et al. 2019 ).

Binding of this secreted ACE-2 with COVID-19 binding protein can prevent its entry into the cell and thus reduced the chances of infection (Rizzo et al. 2020) . Antimicrobial peptides are produced by probiotics organisms are the molecules most characterized for their antimicrobial activity and anti-viral activity. Bacteriocins are the antimicrobial peptides produced by genera Lactobacillus and Enterococcus spp. having broad-spectrum activity against various Gram-positive and Gram-negative bacteria. It can be used as alternatives to antibiotics or in combination with antibiotics. Bacteriocin compounds such as staphylococcin 188, enterocin AAR-74, erwiniocin NA4 have been evaluated for antiviral activity. Their activity is reported against HIV, HSV, Coliphage, influenza virus, and particularly H1N1 virus (Klebanoff and Coombs 1991; Quereshi et al. 2006; Conti et al. 2009; Lange-Starke et al. 2014) . Similarly, the nonribosomal peptides (NRPs) are also the secondary metabolites produced by probiotic microbes that have very broad clinical applications. Their uses are reported as antibiotics (daptomycin), anti-tumor drugs (bleomycin), antifungal drugs, and immunosuppressants (cyclosporin) (Walsh 2008) .

There is no specific antiviral treatment or vaccine recommended for COVID-19. Oxygen therapy, non-invasive (NIV), and invasive mechanical ventilation (IMV) is used in cases with severe respiratory outcomes (Carter et al. 2020) . To date, only one anti-viral drug-remdesivir, an RNA-dependent RNA-polymerase (RdRp) inhibitor of SARS-CoV-2 is used as the first drug for the treatment of COVID-19 patients (Beigel et al. 2020 ). However, with the increased mutation rate of SARS-CoV-2, the susceptibility of the virus to remdesivir drugs has been challenged. In addition, there are certain cases across 30 different countries associated with the failure of this antiviral agent (Martinot et al. 2020) . Therefore, until the availability of specific treatment against COVID-19, prevention is the only measure. Different types of immunity-boosting foods such as fruits, vitamins, antioxidants, prebiotics, and probiotics are considered to have beneficiary effects on the host (Arshad et al. 2020; Olaimat et al. 2020) . Probiotic bacteria are generally recognized as safe (GRAS) (Gerritsen et al. 2011) . Upon administration, they benefit the host by ameliorating the gut health and immune system functioning. The probiotic strains and their metabolites such as bacteriocins have been studied as potential anti-viral agents. Hence, knowing the fact of the high mutational rate of RNA viruses and a major challenge of restricted antibiotic efficacy, we believe that the administration of probiotics will help in boosting the host-immunity, and similar to other anti-viral studies it might reduce the symptoms of the novel coronavirus. Consequently, in a view of prevention being better than cure, probiotics have become a neutraceutical and promising immunobiotic agents to possibly treat the infection of COVID-19 in the wake of the absence of a vaccine or proven therapeutic intervention.

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The authors are thankful to the director, CSIR-