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IMPORTANCE OF PROBIOTICS IN THE PREVENTION AND TREATMENT OF COVID-19

of numerous respiratory illnesses is known to depend on the lung microbiota. Through microaspiration and inhalation, which bacteria, molds, and viruses can create, the healthy lung acquired its unique microbiota. Probiotic strains might be used to influence these microbiotas, contributing novel views in the managing of respiratory diseases. Returning gut microbiota has been revealed to recover resistance to virus or pathogenic invades moreover at the respiratory mucosal stages.


PROBIOTICS' IMPACT ON HEALTH AND DISEASE
According to WHO, FAO, and ISAPP, probiotics are live bacteria that improve the health of the host when given in excessive amounts (Hill, Guarner et al. 2014). The use has been considered ever since long, previously known as food components . Probiotic use has mostly been investigated for the prevention and treatment of gastrointestinal ailments. Still, other potential properties of these microorganisms have been considered for nutritional effects, inflammatory diseases, Helicobacter pylori infections, allergic diseases, and anti-tumor properties (Abdolshahi, Tabatabaiee

PROBIOTIC EFFECTS ON IMMUNE RESPONSES
Mucus, the movement of the cilia, and secretory IgA in the respiratory tract secretion are the primary mechanisms by which the host achieves protection. Dendritic cells (DC) are persuaded by viral infection to initiate a series of immunological responses, which are followed by the activation of CD4+/CD8+ cells and an improvement in specific T and B cell intermediated immunity (Madsen 2006). Microorganisms form a diverse and rich environment on the skin and mucosal surfaces. The correlation between gut microbiota and overall health has been confirmed. Gut microbiota is one of the greatest active sites of microorganisms playing a vital role in modifying the mucosal immune system (Milani, Duranti et al. 2017). Diet can alter the gut microbiome, which uses nutrients from eating foods, discharges harmful or helpful metabolites, and regulating the immune system. The intestinal mucosal surface is a significant location of the entrance of pathogenic microorganisms into the human body, but in a healthy individual's epithelium and its microbiota offer an effective barrier against invading microorganisms (Salek Farrokhi, Darabi et al. 2019). Different human diseases are linked to dysbiosis, a disruption of the gut microbiota's development and operation. Therefore, management of the gut microbiota has been nominated as a possible attitude for sustaining a healthy lifestyle and curing diseases. This approach can be it happens by stimulating favorable microbiota colonizing in the gastrointestinal tract (GIT) through the diet or probiotics administration. Probiotics were able to provide beneficial effects in reestablishing unbalanced microbiota and preserving gut immune homeostasis by improving immune system responses (Hathaway-Schrader, Steinkamp et al. 2019). Some investigations have revealed that these probiotics stimulate and modify innate immune responses through multiple membrane molecules that transfer signaling massages with the epithelial cells of the gut. Immune system modulation has been demonstrated since an excessive immune response because of pathogenic infection can cause unwanted immunopathogenesis, leading to considerable damage to host tissues (Taverniti 2013). Lungs and the stomach are anatomically distinct from one another. However, a gut-lung axis that might influence immune responses and the development of respiratory disorders has been supported by prospective anatomic correlation and multiple networks connecting their unique microbiota. By altering pro-and anti-inflammatory responses and sending out regulatory signals, the gut microbiota closely collaborates with the mucosal immune system (Kayama, Okumura et al. 2020). Leukocyte activation and recruitment to the site of infection is encouraged by the high concentration of SCFAs (acetate, propionate, and butyrate) generated and released into the bloodstream by gut bacteria through binding to certain receptors. These prepared cells secrete certain antibodies that help the host defend itself by clearing intracellular pathogens and virus-infected cells from the body. For microbiota-induced myelopoiesis to occur, Toll-like receptors (TLR) or G-protein-coupled receptors (GPR41/43) signaling is essential. This also has an impact on immune cells that express MAMPs or SCFAs. The lung microbiota's resident antigens must also be encountered for the resident memory B cells to organize, especially in terms of immunity to viruses (Zeng, Umar et al. 2019).

CLINICAL EVIDENCE OF PROBIOTIC IMMUNOMODULATION
Local and systemic immunological impacts are linked to interactions between different microbial components of the gut and lungs. These communications forcefully suggest that the GLA plays a key role in respiratory diseases. The gut microbiome clearly influences metabolic pathways, which is linked to altered cellular response. Communication between the immune system and the lung microbiota is comparably effective. For instance, inflammation in the lungs can change the makeup of the lung microbiota (Budden, Gellatly et al. 2017). Therefore, produced metabolites by the gut microbiota modify gut immunity and affects the lung and brain among other organs. The mesenteric lymphatic system is a vital corridor among the lungs and gut, completed by microbiota and their particles or metabolites products that pass the gastrointestinal barrier, enter the bloodstream, and alter the lung's immunological response (Parigi 2019). Due to a high-fiber diet, microbial dietary fiber metabolites act as signaling molecules for local antigen-presenting cells (APCs) in the lungs and through this way modulate inflammatory responses. Recently studies performed experimental models of asthma in SCFA receptor deficient Mice that revealed enhanced inflammatory responses. According to several research, the capacity for phagocytosis in the macrophages of germ-free mice is diminished and demonstrate a decreased cellular responsiveness concerning microbial antigens. However, amounts of monocytes and macrophages are enhanced. Still, they have a restricted aptitude to produce Chemokine C-X-C Motif Ligand 1 (CXCL1), and consequently caused tissue injury due to reduced neutrophil recruitment to the airways

PROBIOTICS: PREVENTION OF COVID-19
Besides the extensively investigated gut microbiota, microbiotas of other regions, lung microbiota is essential in various respiratory disorders' physiopathology. The lung microbiota has considerably smaller biomass in comparison to the gut microbiota. From birth all over the whole life period, a close association between the conformation the microbiome of the lungs and gut and the host's health condition can influence this gut-lung communication (Faner, Sibila et al. 2017). The oropharynx, upper respiratory tract, immigration, and host removal capacities of the microbes have an impact on the creation of the object (coughing and mucociliary clearance), immune system, local circumstances for microbial proliferation, like pH and amount oxygen concentration. The healthy individual's microbiota includes Prevotella, Veillonella, and Streptococcus, nevertheless the Veillonella and Prevotella while Proteobacteria can be found in the respiratory tract of intubated preterm newborns. The primary bacterial phyla in the lungs are identical to in the gut, mostly Firmicutes and Bacteroidetes, and in the next rank Proteobacteria and Actinobacteria (Milani, Duranti et al. 2017). The lung microbiota in acute respiratory distress syndrome (ARDS) resembles gut bacteria such Bacteroidetes and Enterobacteriaceae. Bacteria are able to travel through the colon wall and into the lungs due to a hyperpermeable gut. In addition to contributing to an inflammatory environment, gut microbiota dysbiosis has been linked to a number of lung diseases, including allergies, asthma, and cystic fibrosis, where it may be investigated by SARS-CoV-2 (Amornphimoltham, Yuen et al. 2019). Probiotic strains might be used to influence these microbiotas, contributing novel views in the managing of respiratory diseases. Returning gut microbiota has been revealed to recover resistance to the virus or pathogenic invades, moreover, at the respiratory mucosal stages

PROBIOTIC EFFECTS ON CORONAVIRUS INFECTIONS
There is increasing indication backing the benefit of probiotics as a preventive method to diminish, period and the need for drugs. A possible approach would be to modify the microbiome using probiotics, enabling inhibition or the treatment of respiratory illnesses like COVID-19. L. plantarum produces a variety of metabolites, such as: Gamma-aminobutyric acid (GABA), lactic acid, acetic acid, and plantaricin can all boost protection to viruses (Dhar and Mohanty 2020, Novik and Savich 2020). Receptor recognition is the primary period of host cell infection by the virus and one of the most critical features of the host cell. The binding affinity among SARS-CoV and hACE2 can associate with viral transfection and infection. Computational demonstration and molecular dynamics study validate the anti-viral action of Plantaricin combinations. Several mechanistic methods include blocking the entrance of COVID-19 through binding with RNA-dependent RNA polymerase (RdRp), residual binding domain (RBD) to ACE2. In this work, the Plantaricin family of probiotic metabolites is used to target both spikes (S) glycoprotein by impairing RBD and ACE2. This computational method was used to restrict the entry of COVID-19 and prevent the effects of Plantaricin compounds by binding to RdRp, RBD, and ACE2. In this investigation, plantaricin metabolites were identified as a potential novel antiviral treatment option for COVID-19 (Anwar, Altayb et al. 2020).

BACTERIOCINS AND GUT MICROBIOTA
The ability of metabolic products such lactic acid, H2O2, and bacteriocins delivered by LAB to reduce viral load has been studied. Bacteriocins can play a big part in host defense, according to another research. LAB probiotics have been found to create proteinaceous compounds synthesized by ribosomes that have bactericidal effect. These anti-microbial proteins have been shown to effectively combat potential pathogens by influencing the host microbiota and a variety of bodily functions. Maintaining gut homeostasis and biocontrolling harmful microorganisms are two potential uses for bacteriocins (Garcia-Gutierrez, Mayer et al. 2019). One of the primary anti-viral tools of probiotics, the inhibition of viral replication, has not yet been documented. Peptide CRL35 was produced by Enterococcus faecium by inhibiting the last phases of HSV-1/2 replication. L. delbrueckii, a very specific restriction on influenza virus H7N7 and H7N1 replication. This view's activity is probably more useful than in the inflammatory stages of the illness during the early stages of viral infection, when virus loads are relatively low. These factors support the idea that probiotics may be more beneficial as a preventative measure than the current standard of virus treatment.

THERAPEUTIC IMPLICATIONS
The current coronavirus disease outbreak (COVID-19) has sparked a flurry of research into ways to prevent, treat, and lower morbidity and fatality rates. Clinical tests showed the presence of cytokine storm symptoms and a significant amount of pro-inflammatory cytokines. IL-1, TNF, IFN, IL-2, IL-8, interferon-inducible protein 10 (IP-10), and macrophage inflammatory protein 1 (MIP-1) were among the chemokines present. Especially in severe patients may lead to more extended hospitalization and a rise in the mortality rate (Mahooti, Miri et al. 2020). Therefore, addressing the urgent need to control the cytokine storm may be helpful in COVID-19 treatment. Several modalities such as anti-microbial peptides, bacteriophages, and probiotics can be considered. According to the studies, probiotics have immunomodulatory effects and could improve the intestinal epithelial barrier features. Additionally, they generate anti-microbial compounds, alter the ratio of pro-to anti-inflammatory cytokines, boost T cell and NK cell activity, and raise levels of systemic and mucosal-specific antibodies in the lungs Several COVID-19 patients displayed lower levels of various probiotic species, including Bifidobacterium and Lactobacillus in their intestines, which may be related to weak immune system function. Re-normalization of the intestinal flora balance by consuming probiotics may lessen the likelihood of infection and the severity of illness (AKTAŞ and Aslim 2020). According to recent research, the most important probiotics that might be associated to reducing the impact of the B. bifidum,B. breve L. plantarum,L. casei,L. gasseri,L. rhamnosus,Pediococcus pentosaceus,and Leuconostoc mesenteroides (Baud, Agri et al. 2020, Khaled 2020). The therapeutic effects of probiotics against COVID-19 are not backed by any reliable research. Probiotics' immune-boosting and nutritional effects, as well as their antiviral abilities against a variety of respiratory viruses, point to probiotics as a supplemental treatment for COVID-19 disease that requires further clinical and laboratory research. Table 1 illustrated human studies that other probiotic strains assisted in the treatment of respiratory infections and effect of probiotics bacteria in respiratory infections shown in Table 2. IG: 5×10 7 cfu/tablet during two winter/spring seasons, of the spraydried probiotic bacteria along with vitamins and minerals (at least 3 months). CG: Tablet with vitamin minerals (1 tablet/day) -Days with fever during an episode and the length of the common cold bouts were shorter in IG (almost 2 days).
-A significantly higher enhancement of CD8+/CD4+ was observed in IG. IG: 1 g of lyophilized bacteria (1 10 9 cfu each day for 12 weeks) and 1 g of maltodextrin CG: 1.0 g maltodextrine -In IG, there was a considerably lower likelihood of developing one or more episodes of the common cold, as well as a shorter duration of time experiencing symptoms and pharyngeal symptoms. -B lymphocyte proliferation was considerably reduced in IG compared to CG. (Berggren, Ahrén et al. 2011) 222 healthy elderly participants / ≥70 years Influenza vaccination L. casei (Actimel® DN-114 001), S. thermophiles, L. bulgaricus IG: Actimel® 100 g /bottle CG: a control dairy product that is not fermented 100 g per bottle 200 g each day from two bottles for 13 weeks.
-Following vaccination, there was a rise in the titers of influenza-specific antibodies, which were higher in IG than CG.
-Five months following immunization, the intended to treat analysis revealed significant variations in seroconversion between the groups. -The IG had an increase in NK cells, whereas the CG did not (2 weeks after vaccination).
-Following IG vaccination, there was a considerable rise in blood levels of total and specific anti-influenza IgM.
-Five months after immunization, the incidence of an influenza-like illness was reduced in IG. (Olivares, Díaz-Ropero et al. 2007 faecalis at a concentration of 4.5×10 9 /0.25 g and 0.5×10 9 /0.25 g, respectively, three times per day by nasogastric feeding tube along with conventional prophylactic measures for a period of 14 days. CG: standard preventive strategies alone -In the IG, the incidence of VAP was substantially lower than in the CG. -In the IG compared to the CG, the mean time to develop VAP was substantially longer.
-In comparison to the CG, the IG had a smaller percentage of patients who had acquired stomach colonization of PPMOs.
-Probiotic therapy had no positive impact on the frequency of clinically suspected VAP, consumption of antibiotics, time spent on mechanical ventilation, death, or length of hospital stay. (Zeng, Wang et al. 2016 -There was no discernible difference in the flu's incidence rate. -Although the intervention had a considerable impact on serum IFNproduction, it had no influence on -NK cell activity. (Kinoshita, Maruyama et al. 2019) 152 volunteers Experimental rhinovirus challenge (RV-A39) B. animalis ssp. lactis Bl-04 IG: received a sachet every day for 28 days that included a minimum of 2 10 9 cfu of Bl-04 combined with 1 g of sucrose as a carrier. CG: daily received a sachet containing 1 g of sucrose for 28 days.
-The IG dramatically reduced the CXCL8 response to rhinovirus infection in nasal lavage.

THE POSSIBLE SIDE EFFECT OF PROBIOTIC
Since the COVID-19 global pandemic has an unexpected spread globally, it is hard to place a safe drug/product as fast as the virus is distributing. The possible potential of probiotics as non-pharmacological substances considering their advantages, availability, and posing negligible side effects have been successfully applied in the current phenomenon. However, some reported side effects that experienced in different clinical approaches should be taken into account. Mainly reported side effects were nausea, taste disturbance, and diarrhea ( The FDA also states that the probiotic is a generally recognizad as safe (GRAS) for humans organism (Pourhossein and Moravejolahkami 2020). Therefore, it is estimated the low risk associated with probiotic administration. However, an overall control should be done regarding the strain and dose.

CONCLUSION
This research clarified the function of probiotics as a safe strategy for alleviating the SARS-COV-2 infection. Probiotics possessed notable effects on immune responses in the host and could promote the reaction toward infection. Besides, clinical studies indicated that probiotics in COVID-19 treatment could decrease the risk of other infections in patients with COVID-19. Also, probiotics were capable of interrupting the synthesis of RNA and DNA in such viral infections. Since the control of cytokine storm may have benefits in COVID-19 treatment, probiotics and other modalities can be noticed regarding their immunomodulatory effects. In addition, probiotics have an inhibitory impact on the ACE enzymes and can block the active sites. It is proved that some strains of probiotic microorganisms produce anti-inflammatory interleukins and anti-body in versus the viruses. According to current knowledge, it is emerging needed to apply practical methods for preventing the COVID-19 infection. Considering how effective probiotics are at preventing viral infections, they can use as an alternative and adjuvant nutritional therapy for the treatment of new coronavirus. More clinical research is required for a comprehensive evaluation of the effects of determining strains of probiotics on COVID-19 infection.