Vojnosanitetski pregled 2023 Volume 80, Issue 4, Pages: 289-301

https://doi.org/10.2298/VSP220625014N

Full text ( 3706 KB)

Oral microbiome, COVID-19 and probiotics

Nikolić-Jakoba Nataša (University of Belgrade, School of Dental Medicine, Department of Periodontology and Oral Medicine, Belgrade, Serbia) Manojlović Dragica (University of Belgrade, School of Dental Medicine, Department of Restorative Dentistry and Endodontics, Belgrade, Serbia)Jovanović-Medojević Milica (University of Belgrade, School of Dental Medicine, Department of Restorative Dentistry and Endodontics, Belgrade, Serbia), medojevic.milica@gmail.com

Keywords: gastrointestinal microbiome, microbiota, mouth, COVID-19, probiotics, virus diseases, immunity, symbiosis

Nataša Nikolić Jakoba*, Dragica Manojlović†, Milica Jovanović-Medojević†

University of Belgrade, Faculty of Dental Medicine, *Department of Periodontology and Oral Medicine, †Department of Restorative Dentistry and Endodontics, Belgrade, Serbia

Key words:

gastrointestinal microbiome; microbiota; mouth; COVID-19; probiotics; virus diseases; immunity; symbiosis.

Ključne reči:

mikrobiom, gastrointestinalni; mikrobiota; usta; COVID-19; probiotici; virusne bolesti; imunitet; simbioza.

Introduction

The COVID-19 pandemic is an ongoing global pandemic that seriously endangers human life and health. Clinical presentation of this disease varies from completely asymptomatic or mild infection to severe complications, post-COVID syndrome, and even lethal outcome 1.

The etiologic agent of COVID-19 disease is the SARS- CoV-2 virus, an RNA-positive single-stranded virus from the Coronaviridae family. Even though coronaviruses primarily cause zoonotic infections, there are currently seven strains that can cause an infection in humans 2. There are five different variants resulting from genetic evolution that have been identified since the onset of the pandemic: Alpha (B.1.1.7), Beta (B.1.351), Gamma (P.1), Delta (B.1.617.2),

and Omicron (B.1.1.529) 3.

The SARS-CoV-2 virus is one of many respiratory viruses where the oropharynx is the primary site of entry and replication 4. It binds to angiotensin-converting enzyme 2 (ACE-2) receptors via its glycoprotein extension (S protein) 4–6. These receptors are present on the tongue, oral and nasal mucosa, salivary glands, and nasopharynx 7–11. The study of Xu et al. 12 showed higher ACE-2 expression in small salivary glands than in lungs during COVID-19 disease, proving that salivary glands represent a significant virus reservoir 13.

Since the beginning of the COVID-19 pandemic, basic preventive measures have been applied to prevent the transmission of the virus (hand disinfection, wearing face masks, social distancing, and quarantine). Thirteen different official treatment protocols were introduced, though currently, there is no optimal treatment 1. Antiviral therapy, vaccines, and immunomodulating agents are widely used in

order to reduce disease severity, especially in patients with an increased risk of developing a severe clinical form of the disease 14. While searching for the most effective treatment against the COVID-19 infection, scientists and clinicians have also applied alternative possibilities for improving immunity 15. Recent research data have revealed the interaction of intestinal and respiratory systems in immunity induction, acting as local and systematic modulators of inflammation 16.

The human microbiome is important for blocking inflammation and immunity regulation. The impact of oral microbiome (OM) dysbiosis in patients with COVID-19, which can directly or indirectly favor the development of the infection and affect the pathogenesis of the disease, has been recognized. The human microbiome plays a significant role in the immune response of the host to respiratory viral infections. The modulation of local and systemic immune reactions by using probiotics is one of the most promising effects of probiotics on overall human health 15. The presence and registration of dominant microbial communities in an individual’s OM can enable personalized therapy that aims at restoring the microbiome and preventing the occurrence of many diseases in the future 17.

Many studies on COVID-19 published in the past three years have examined the exact mechanism of virus replication at the primary site of infection, as well as the role of OM on SARS-CoV-2 virus binding capacity and infection development 4, 5, 9, 18–25. The goal of this review was to evaluate the role of OM in the prevention of SARS-Cov-2 virus infection and its impact on the severity of COVID-19 clinical presentation. In addition, the aim of this literature review was to present possible preventive and therapeutic applications of probiotics which were used as one of the

Correspondence to: Milica Jovanović-Medojević, University of Belgrade, Faculty of Dental Medicine, Department of Restorative

remedies against SARS-Cov-2 virus infection. This review focuses on the analysis of oral microbiota during the COVID-19 infection and gives us new insights into the relationship between microbiota and probiotics.

Oral microbiome

The human OM is the genome of all microorganisms which inhabit the oral cavity. The term “microbiota” refers to a specific and unique composition of microbial population that affects health and varies from person to person. In many studies, these two terms are equated 26–28.

Oral flora is the second largest and one of the most di- verse microbiomes in the human body, right after the intes- tines, which weigh about 2 kg 29–32. The composition of oral flora is heterogeneous and contains over 1,000 different bac- terial species, viruses, fungi, helminths, protozoa, and ar- chaea that persist in mutual balance but also in symbiosis with the host 23, 33–35. Each person has a complex of microor- ganisms, and everyone carries an individual microbiome that develops over a lifetime. The composition and diversity of the OM can be influenced by the following: the duration of pregnancy, delivery method, breastfeeding, genetic factors (sibling microbiota profiles are more similar when compared to the profiles of persons who are not related), environmental conditions (oral hygiene, saliva quality, and quantity), habits (tobacco, alcohol, stress, etc.), diet, certain drugs (antibiotics, antacids, etc.), age (three stages of evolutionary develop- ment: childhood, adulthood, and old age), and individual general health 4, 36–42.

The most common species of bacteria in the OM are representatives of the genera Bacteroides, Synergistes, Ge- mella, Granulicatella, Streptococcus, Veillonella, the phyla Actinobacteria, Proteobacteria, Tenericutes, Firmicutes, and

Spirochaetes, while oral viruses are mainly composed of eu- karyotic viruses such as Herpesviridae, Papillomaviridae, and Anelloviridae [human papillomavirus (HPV), human cy- tomegalovirus (CMV), herpes simplex virus type-1 (HSV-1), and Epstein-Barr virus (EBV)] 32, 43. Myoviridae and Podo- viridae belong to lytic viruses (they rapidly degrade their bacterial hosts), while Siphoviridae are lysogenic viruses that are in balance with the host bacteria. Oral viruses represent a restricting factor for bacterial growth and can control bacte- rial oral populations 44, 45. Research by Peters et al. 46 de- scribed 154 species of commensal fungi and confirmed that the Candida genus was most commonly present in 70% of healthy patients. Recent studies revealed the commensal presence of different genera of protozoa, helminths, and ar- chaea. Nonetheless, their pathogenic potential in the devel- opment of oral diseases is still unexplored 47–49.

Importance of oral microbiome in oral and general health

The oropharyngeal microflora in a healthy host main- tains balanced symbiotic relationships defined as “microbial homeostasis” (eubiosis) 32. The OM is exposed to frequent daily fluctuations that can lead to microbial imbalance (dysbiosis) 50, 51. Microbial balance in the oral cavity is nec- essary because it enables equilibrium between beneficial and harmful microorganisms that interact with each other and can have an inhibitory, stimulating, or synergistic effect on each other 32, 50, 51. The OM contributes to the development of the local immune system. However, its imbalance, along with the complex interaction with the host resistance and various environmental factors, creates conditions for the develop- ment of various oral or systemic diseases (Figure 1) 17, 52, 53. During dysbiosis, the following three changes occur: loss of

Fig. 1 - Impact of microbiota dysbiosis on the overall health of humans 52.

microbial diversity, loss of beneficial microorganisms, and increase in pathogenic microorganisms that are not mutually exclusive and can occur simultaneously 54. As a result, poten- tiating cariogenic and inflammatory bacterial genomes 33, 55 make perfect conditions for the development of diseases such as caries 56–59, periodontal diseases 60–64, and malignant al- terations of oral tissues 65–67.

Many oral microorganisms enter the digestive tract through saliva, thus changing the intestinal microbiome, which plays an important role in digestion and absorption of nutrients, formation of a protective barrier against pathogens, development and regulation of the immune system, enzyme and vitamin production, control of inflammatory reactions, and neuro and psychological regulation 35. Consequently, the connection between the oropharyngeal and intestinal micro- biome sheds new light on inflammatory processes and their therapy. The link between oral and general health is well documented in the literature 35, 50, 52, 68–76. Chronic oral infec- tions lead to the release of proinflammatory mediators, i.e., cytokines that further propagate inflammatory processes and increase the risk of muscle and digestive problems 61, 72, bronchopulmonary diseases 37, 73, rheumatoid arthritis (RA) 53, 67, complications during pregnancy and child- birth 38, 41, 64, 71, 75, cardiovascular diseases 61, 67, 69, 70, 75, 76, obe-

sity 42, liver disease 67, oral cancer 65, pancreatic cancer 77

type 2 diabetes 67, 68, Parkinson’s disease 74, psychiatric dis- orders 78, and colorectal cancer 67. Each disease is character- ized by unique oral and intestinal microbial changes 79. Mi- crobiome rebalancing is closely related to the recovery from the primary disease, which proves the significant role of the microbiome in healing 72, 80.

Maintaining good oral hygiene is, therefore, important in controlling oral bacterial status, maintaining or restoring symbiotic homeostasis, as well as preventing the spread of oral pathogens to other parts of the body 81–83.

Disruption of the oral microbiome during and after SARS-CoV-2 virus infection

Human OM can have a great influence on the regulation of innate and acquired immunity to viral infections 4, which is especially important for viruses that enter the body through the oropharynx 5, 23, 84–86. Aerosol respiratory viruses encounter the OM of the upper respiratory tract and favor its dysbiosis and disease progression 87, 88 (e.g., the microbiome in patients with influenza is characterized by the abundance of genus Pseudomonas) 75. Oral dysbiosis promotes respira- tory infections directly by increasing pathogenic bacteria and aspirating oral pathogens into the respiratory organs. Indi- rectly, it alters the immune response of respiratory epitheli- um and promotes the adhesion of pathogens, cytokine secre- tion, and production of enzymes that interfere with pathogen clearance 23, 89. Even in the case of SARS-CoV-2 virus infec- tion, oral dysbiosis may favor the development of infection by these mechanisms 4. On the other hand, OM can also con- tribute to the regulation of immunity and inflammation blockade 13, 30, 84, 90. The study of Pfeiffer and Sonnenburg 91 showed that oral microbiota commensals could also produce

antiviral compounds (defensins) against several viral genera (Adenovirus, Herpesvirus, Papillomavirus, Orthomyxovirus, and Coronavirus).

The oropharyngeal and intestinal microbiota have the possibility of co-infection with microorganisms originating from the oral cavity. The correlation between the imbalance of OM and the increased number of dysbiotic species may serve as predictive factors for COVID-19 disease 5, 35, 79, 92–104. Ward et al. 24 showed that the severity of COVID-19 disease could be predicted according to the composition of the intes- tinal or OM. Two pathogens, Porphyromonas endodontalis in oral and Enterococcus faecalis in the intestinal microbi- ome, may serve as a predictor of the severity of SARS-CoV- 2 infection. The authors suggested that the key to prioritizing patients who need urgent treatment is the identification of biomarkers that can predict clinical outcomes of COVID-19 disease 24.

Haran et al. 23 described how the dysbiosis of the in- flammatory type of OM, characterized by the members of genera Prevotella and Veillonella, may play an important role in prolonging the duration of COVID-19 symptoms. The genus Veillonella are gram-negative anaerobic cocci that produce large amounts of lipopolysaccharides and may be an additional co-infectious agent (especially Veillonella dispar and Veillonella infantium) 98. The genus Prevotella is highly inflammatory and affects the promotion of SARS-CoV-2 in- fection, thus worsening the severity of the COVID-19 clini- cal presentation 105–107. Haran et al. 23 emphasized the im- portance of the presence of gram-negative bacteria with a liposaccharide component in the capsule (Leptotrichia and various species of genus Veillonella) which can have proin- flammatory effects and cause systemic damage and neuroin- flammation. Due to OM dysbiosis and the presence of patho- gens that promote chronic inflammation (Leptotrichia, Prevotella, and Fusobacterium), myalgic encephalomyelitis and symptoms of neurological diseases (confusion, disorien- tation, slow thinking, and poor concentration after six months) may occur in COVID-19 102–104. The present com- mensals (Prevotella and Neisseria) in OM can act as a local probiotic and counteract the SARS-CoV-2 virus 17. Likewise, the higher relative abundance of the Rothia genus in the pa- tient’s oral flora affects the occurrence of COVID-19 com- plications 108.

Ren et al. 79 identified specific microbial markers of oral microbiota in patients with COVID-19 but also in re- covered patients. The results of this study showed composi- tional and functional changes in OM of COVID-19 pa- tients. During infection, there is an overall decrease in the diversity of oral microorganisms. The number of bacteria that produce lipopolysaccharides was increased, while the number of bacteria that produce butyric acid was de- creased. Thus, by secreting lipids into the bloodstream, mi- crobiome dysbiosis may affect the progression of COVID-

1. Ren et al. also noticed a better prognosis in patients with severe COVID-19 who had an OM enriched with Streptococcus (S. parasanguinis). Oral dysbiosis persisted even after the recovery from COVID-19 infection when a constant increase in Porphyromonas and Haemophilus gen-

79

era and a decrease in Leptotrichia, Megasphaera, and Sele- nomonas (Megasphaera is a cariogenic bacterium) 106 gene- ra was detected.

Furthermore, an imbalance in the relative numbers of different bacterial strains and the genera Enterococcus and Enterobacter were present only in patients with COVID-

19 (not observed in the control group of healthy pa- tients) 5. Ward et al. 24 showed that higher quantities of Porphyromonas endodontalis are correlated with an in- crease in severe stages of COVID-19, while higher quanti- ties of Muribaculum intestinale are linked with moderate cases. Cox et al. 95 also highlighted the impact of coinfec- tions on the clinical presentation and mortality of patients with COVID-19. They indicated an association between cariogenic and oral pathogenic bacteria and complications of COVID-19. According to the earlier literature evidence, these bacteria are involved in the pathogenesis of respira- tory and chronic inflammatory systemic diseases (type 2 diabetes mellitus, hypertension, cardiovascular disease), which are also the most common comorbidities associated with the risk of severe complications and death from COVID-19 97, 109, 110. Marouf et al. 101 also observed an abundance of periodontopathogenic bacteria in COVID-19 patients and demonstrated that the presence of periodonti- tis was associated with a 3.5-fold higher risk of admission to intensive care units, a 4.5-fold higher risk of assisted ventilation, and an 8.81-fold higher risk of mortality inde- pendent of other concomitant risk factors. On the other hand, numerous studies reported that interventions aimed at boosting oral hygiene in patients with pneumonia have significantly improved the clinical picture and reduced mortality 23, 35, 105, 107.

The exact genome of oral flora in patients with COVID-

19 is still the focus of scientific interest. Iebba et al. 20 were among the first who had described the bacterial component of OM in patients with COVID-19, pointing to the im- portance of fungi and viruses in defining individual sensitivi- ty. By examining an oropharyngeal swab, Ai et al. 93 found that more than half of COVID-19 patients had co-infection with another virus, such as influenza A or B, rhinoviruses, enteroviruses, or respiratory syncytial virus. Soffritti et al. 5 investigated an association between OM profile and severity of COVID-19 clinical presentation and observed a signifi- cant increase in Herpesviridae viruses, EBV, and HSV-1. EBV infection in patients with COVID-19 has been associat- ed with an increased risk of severe COVID-19 symptoms as well as a fatal outcome 96, 99.

Changes have also been observed in the fungal part of the microbiome, with the appearance of Aspergillus, Nak- aseomices, and Malassezia spp., Candida albicans, Saccha- romyces cerevisiae, Aspergillus fumigatus, and Malassezia restricta (OM of healthy patients consists only of Candida and Candida cerevisiae, Aspergillus fumigatus, and Malas- sezia restricta) 5. According to Jasinski-Bergner et al. 109, these changes in COVID-19 patients could be an inducing factor influencing the onset of SARS-CoV-2 virus infection because dysbiosis facilitates the activation or reactivation of oral pathogens, which can further impair proper immune

control and lead to deterioration of immune response effec- tiveness.

Ward et al. 24 found that the composition of OM has a high accuracy of COVID-19 severity prediction (84% accu- racy of predicting fatal outcome).

Application of probiotics

With the emergence of increasing antibiotic resistance, new concepts for the prevention and therapy of multidrug- resistant infections are proposed by causing the microbiolog- ical shift of the endogenous microbiota. For this reason, re- search into bactericidal action and antiviral factors of probi- otics became the focus of modern interest 107, 111–113.

Positive effects of probiotics are primarily observed in the treatment of gastrointestinal infections but also in the prevention of various pathological conditions in the field of gastroenterology, allergology, internal medicine, oncology, oral medicine, pediatrics, infectiology, and psychiatry 104–107, 109–114.

Modern therapeutic procedures have introduced chang- es in treatment protocols with a tendency to establish a healthy environment to prevent the development of oppor- tunistic infections and recover the OM. Probiotics are living microorganisms (so-called “good” bacteria) that, if applied in an adequate amount, could establish and maintain the eco- logical balance of microflora. They are safe, non-pathogenic, non-invasive, and non-carcinogenic strains that can perform recolonization and restore symbiosis between the host and the disturbed microbiota 115. Several bacterial genera are most often used as probiotics: Bifidobacterium, Lactobacil- lus, Bacillus, and Pediococcus. The strains used most often are Bifidobacterium bifidum, Bifidobacterium breve, Bifidobacterium infantis, Bifidobacterium longum, Lactoba- cillus acidophilus, Lactobacillus casei, Lactobacillus planta- rum, Lactobacillus reuteri, Lactobacillus rhamnosus. In ad- dition, fungi can be used as probiotics 112–115.

Probiotics act in complex multifactorial ways. Probiotic bacteria can interfere with the absorption process by directly binding to the virus or inhibiting the entry into the epithelial cells by blocking the host receptor 25. Probiotics can also compete with nutrient pathogens, produce antimicrobial agents, strengthen the intestinal epithelial barrier, and modu- late the immune system of the host 116–118. The performance of probiotics can be twofold – immunostimulatory and im- munoregulatory. A group of immunostimulatory probiotics affects the proliferation of T helper (Th) 1 cells and stimu- lates the production of interleukin (IL)-12, which induces the production of interferon-gamma (IFN-γ) in natural killer cells. Immunoregulatory probiotics stimulate regulatory T cells but also suppress proinflammatory responses by induc- ing IL-10 117. Experimental animal models showed that bal- ancing cellular and humoral immune responses mitigates the effects of a “cytokine storm” 25, 119.

The significant role of probiotics in maintaining home- ostasis of the upper respiratory tract microbiome was proven in multiple studies. In addition, it was revealed that oropha- ryngeal probiotics are very effective in maintaining immune

system stability and protecting against viral infections 120–122. Direct and indirect efficiency of various probiotic strains (e.g., Lactococcus lactis JCM 5805 and Bacteroides breve IIT4064) has been proven against influenza virus 123. Probi- otic bacteria release various substances, such as bacteriocins, biosurfactants, lactic acid, hydrogen peroxide, nitric oxide, and organic acids, which can inhibit virus proliferation 25. Lactobacillus genus produces lactic acid as an antiviral in- hibitory metabolite, thus preventing secondary infections 124. Furthermore, like the genus Bifidobacterium, Lactobacillus genus can capture the virus and interfere with the binding of the virus to the receptors of the host cell 125, 126. Nisin and peptide P18 are bacteriocins with antiviral effects against in- fluenza A virus 127. Apart from bacteriocin production, the antiviral ability of oropharyngeal probiotics is also maintained by the stimulatory effect on the innate immune response, which is manifested by an increase in the IFN-γ levels in human saliva ten hours after oral administration of Streptococcus salivarius (strain K12) lozenge 128. Probiotic strains of genera Lactobacillus and Bifidobacterium (such as Lactobacillus reuteri ATCC 55730, Lactobacillus paracasei, Lactobacillus casei 431, Lactobacillus fermentum PCC, and Bifidobacterium infantis 35624) are significant factors in generating immunomodulatory responses during various in- fections 25, 129. In addition, probiotic bacteria have antioxidant potential in neutralizing free radicals. The strains Lactobacil- lus rhamnosus GG, Lactobacillus plantarum CAI6, Clostrid- ium butyricum MIIAIRI 588, and strains in VSL#3® increase total antioxidant capacity 130. Moreover, by participating in the formation of redox homeostasis, probiotics can inhibit the progression of COVID-19 disease 25.

Probiotics and COVID-19

The proven effectiveness of probiotics both in the treatment and prevention of viral infections was the ra- tionale behind their use in patients with SARS-Cov-2 virus infection 25, 28, 131–135.

In the last three years, studies dealing with the importance and benefits of probiotics in the prevention and treatment of COVID-19 have been conducted (Table 1) 21, 135-143. The use of probiotics, along with other therapies, led to a shorter and easier clinical presentation, with reduced severity of gastro- intestinal and respiratory symptoms, a lower percentage of smell and taste disorders, and less frequent symptoms of post-COVID syndrome 125–143. However, in patients on corti- costeroid therapy, probiotic supplemental therapy is contra- indicated due to their primary disease 135.

The first study that proved the positive effects of probi- otics in the treatment of COVID-19 infection was the 2020 Wuhan study 21. The use of the probiotic strain ENT-K12 (Streptococcus thermophilus) among medical workers in in- stitutions for COVID-19 treatment has reduced the possibil- ity of respiratory infection and lethal outcomes by 80%. This probiotic strain locally releases two antibiotics (salivaricin A2 and B) and reduces the possibility of colonization of β- hemolytic group A streptococci, including Streptococcus py- ogenes (a bacterial pathogen that causes coinfection during

viral infection). The use of probiotics has also reduced the use of antibiotics among the respondents by more than 90% 21.

Block 144 suggested the concomitant use of probiotics in patients with COVID-19, treated with azithromycin, to re- duce the risk of hypercolonization of Candida albicans strains. Nutritional support with probiotic strains of Lactoba- cillus acidophilus, Bifidobacterium, and Saccharomyces bou- lardii, along with minerals and vitamins, has reduced the complications of massive antibiotic therapy 145–147.

D’Ettorre et al. 135 compared the incidence of respirato- ry failure and control of symptoms, after probiotic therapy, with different Streptococcus, Lactobacillus, and Bifidobacte- rium strains. The use of probiotics was associated with a lower risk of respiratory failure and faster control of COVID-19 symptoms (especially diarrhea). In patients with a severe clinical picture, the immunomodulatory effects of probiotics may be relevant for the prevention of acute respir- atory distress syndrome and multiple organ failure as a com- plication of cytokine storm 135.

Ceccarelli et al. 147 observed a lower mortality rate after the use of probiotic strains of genera Streptococcus, Bifidobacterium, and Lactobacillus during COVID-19, but with longer hospital stays. However, research by Bozkurt and Bilen 142 showed that in patients with moderate and se- vere COVID-19 symptoms, an additional therapeutic dose of the probiotic strain Bifidobacterium animalis resulted in a shorter hospital stay and lower mortality rates.

Probiotics mechanism of action in COVID-19

The mechanism of probiotic protection against SARS- CoV-2 infections is based on general effective principles, such as inhibition of pathogen adhesion and antimicrobial and immunomodulatory specific properties of different pro- biotic strains 118, 145, 148. These mechanisms can enhance the elimination of the SARS-Cov-2 virus but also act preventive- ly by suppressing bacterial coinfections that correlate with COVID-19 (Figure 2) 118, 148, 149.

During fermentation, probiotic strains produce specific bioactive peptides that block ACE-2 enzyme receptors, thus preventing the SARS-CoV-2 virus from binding to these ac- tive sites 4, 150, 151. The remnants of dead probiotic cells can act as ACE-2 inhibitors as well. These bioactive peptides may modulate blood pressure due to the inhibition of the conversion of angiotensin-I to angiotensin-II. The possible effect of these peptides on reducing the progression of COVID-19 is still being examined 152. The concept of using ACE-2 receptor-blocking drugs as a treatment modality for COVID-19 was first proposed by Fernandez-Fernandez 151. Imai et al. 152 reported that the usage of ACE blockers had a positive effect on the reduction of respiratory distress syn- drome. The study by Singh and Rao 25 confirmed that by binding mucosal cell receptor and ACE-2, probiotic strains interfere with coronavirus and block its binding, while an in- crease of innate immunity is stimulated by releasing intesti- nal mucins from mucosal cells and producing secretory anti- bodies (IgA). The authors stated that the key role in combati-

Fig. 2 - Antiviral mechanisms of probiotics against SARS-CoV-2 infection.

ng coronavirus proliferation is played by modulation of im- mune responses and balance of acquired immunity, produc- tion of inflammatory cytokines, the proliferation of B cells that produce specific antibodies, and activation of cytotoxic T lymphocytes that participate in the adaptive immune re- sponse 27. Baindara et al. 126 also showed that some probiotics improved the regulatory activity of T cells and reduced the production of proinflammatory cytokines. In addition, the antiviral effect of probiotics may be achieved by a large number of secreted specific metabolites and bacteriocins 153.

Strengthening the immune response during incubation and the initial phase of COVID-19 disease is crucial in elim- inating the virus and preventing the progression of the dis- ease. The use of certain strains of Bifidobacterium or Lacto- bacillus has a great influence on the elimination of the SARS-CoV-2 virus from respiratory organs 154. The use of probiotics, along with adequate treatment for COVID-19, can significantly reduce the occurrence and duration of vari- ous systemic diseases 154, 155.

The limitations of this comprehensive literature review arise due to the high heterogeneity of studies that investigat- ed the change and impact of oral microbiota during COVID- 19 without knowing the previous status of patients’ OM and because patients with different immune statuses used differ- ent probiotic strains.

It should be emphasized that introducing targeted drugs and beneficial bacteria was of great importance in restoring

the damaged microbiome. Further research should be di- rected to discovering the most effective probiotic strains, doses, and formulations, as well as the interaction of probiot- ics and microbiomes. In addition, the influence of environ- mental factors on the oropharyngeal microbiome, as well as possible coinfection, should be further investigated.

Conclusion

After an extensive review of the literature, it was con- cluded that numerous clinical studies showed that OM might influence resistance to primary infection and be a predictor for disease severity and complications during COVID-19. The use of probiotic strains can inhibit the ad- hesion of pathogens, improve the barrier function of the in- testine and strengthen the immune response. Through these mechanisms, probiotics can reduce the progression and the development of more severe forms of the disease, shorten the hospital stay and reduce the frequency of post-COVID syndrome.

Acknowledgement

The authors would like to thank Ph.D., MLIS Jelena Jaćimović and MLIS Ružica Petrović, academic librarians at the Faculty of Dental Medicine, University of Belgrade, Ser- bia, for their help in literature access and management.

R E F E R E N C E S

1. World health organization (WHO). WHO coronavirus (COVID-19) dashboard. [Internet] 2022. Available from: https://covid19.who.int/ [Accessed on 22 Apr 2022].
2. Ye ZW, Yuan S, Yuen KS, Fung SY, Chan CP, Jin DY. Zoonotic origins of human coronaviruses. Int J Biol Sci 2020; 16(10): 1686–97.
3. Łoniewski I, Skonieczna-Żydecka K, Sołek-Pastuszka J, Marlicz W. Probiotics in the management of mental and gastrointestinal post-COVID J Clin Med 2022; 11(17): 5155.
4. Baghbani T, Nikzad H, Azadbakht J, Izadpanah F, Haddad Kashani H. Dual and mutual interaction between microbiota and viral infections: a possible treat for COVID-19. Microb Cell Fact 2020; 19(1): 217.
5. Soffritti I, D'Accolti M, Fabbri C, Passaro A, Manfredini R, Zuliani G, et Oral mycrobiome dysbiosis is associated with symp- toms severity and local immune/inflammatory response in COVID-19 patients: a cross-sectional study. Front Microbiol 2021; 12: 687513.
6. Bohórquez-Ávila S, Bernal-Cepeda L, Reina-Marin M, Navarro-Saiz L, Castellanos J. The mouth, oral health, and infection with SARS-CoV-2: an underestimated Infectio 2022; 26 (1):

78–82.

1. To KK, Tsang OT, Yip CC, Chan KH, Wu TC, Chan JM, et Consistent detection of 2019 novel coronavirus in saliva. Clin Infect Dis 2020; 71(15): 841–3.
2. Amorim Dos Santos J, Normando AGC, Carvalho da Silva RL, De Paula RM, Cembranel AC, Santos-Silva AR, et Oral mucosal lesions in a COVID-19 patient: new signs or secondary mani- festations? Int J Infect Dis 2020; 97: 326–8.
3. Bao L, Zhang C, Dong J, Zhao L, Li Y, Sun J. Oral mycrobiome and SARS-CoV-2: beware of lung co-infection. Front Micro- biol 2020; 11: 1840.
4. Silva A, Azevedo M, Sampaio-Maia B, Sousa-Pinto B. The effect of mouthrinses on severe acute respiratory syndrome coronavirus 2 viral load: a systematic J Am Dent Assoc 2022: 635–
5. [Epub ahead of print].
6. Paradowska-Stolarz AM. Oral manifestations of COVID-19: brief Dent Med Probl 2021; 58(1): 123–6.
7. Xu J, Li Y, Gan F, Du Y, Yao Y. Salivary glands: Potential res- ervoirs for COVID-19 asymptomatic infection. J Dent Res 2020; 99(8): 989.
8. Mohapatra RK, Dhama K, Mishra S, Sarangi AK, Kandi V, Tiwari R, et The microbiota-related coinfections in COVID-19 pa- tients: a real challenge. Beni Suef Univ J Basic Appl Sci 2021;10 (1): 47.
9. Rocchi G, Giovanetti M, Benedetti F, Borsetti A, Ceccarelli G, Zella D, et al. Gut microbiota and COVID-19: potential implica- tions for disease Pathogens 2022; 11(9): 1050.
10. Amrouche T, Chikindas ML. Probiotics for immunomodulation in prevention against respiratory viral infections with special emphasis on COVID-19. AIMS Microbiol 2022; 8(3): 338–56.
11. Cyprian F, Sohail MU, Abdelhafez I, Salman S, Attique Z, Kamareddine L, et al. SARS-CoV-2 and immune-microbiome in- teractions: lessons from respiratory viral Int J Infect Dis 2021; 105: 540–50.
12. Rafiqul Islam SM, Foysal MJ, Hoque MN, Mehedi HMH, Rob MA, Salauddin A, et al. Dysbiosis of oral and gut microbiomes in SARS-CoV-2 infected patients in Bangladesh: elucidating the role of opportunistic gut microbes. Front Med (Lausanne) 2022; 9: 821777.
13. Herrera D, Serrano J, Roldán S, Sanz M. Is the oral cavity relevant in SARS-CoV-2 pandemic? Clin Oral Investig 2020; 24(8): 2925–30.
14. Zhao H, Chen S, Yang F, Wu H, Ba Y, Cui L, et Alternation of nasopharyngeal microbiota in healthy youth is associated

with environmental factors: implication for respiratory diseas- es. Int J Environ Health Res 2022; 32(5): 952–62.

1. Iebba V, Zanotta N, Campisciano G, Zerbato V, Di Bella S, Cason C, et Profiling of oral microbiota and cytokines in COVID- 19 patients. Front Microbiol 2021; 12: 671813.
2. 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): 1061–9.
3. Barros MIOS, Firmino GLO, Vieira T da S, Araujo A de A, Souza L de LB, Reis BS, et al. Oral manifestations associated with COVID-19 infection. RSD [Internet] 2021; [accessed on 19 Mar 2023] 10(16): e555101624107. Available from: https://rsdjournal.org/index.php/rsd/article/view/24107
4. Haran JP, Bradley E, Zeamer AL, Cincotta L, Salive MC, Dutta P, et Inflammation-type dysbiosis of the oral mycrobiome as- sociates with the duration of COVID-19 symptoms and long COVID. JCI Insight 2021; 6(20): e152346.
5. Ward DV, Bhattarai S, Rojas-Correa M, Purkayastha A, Holler D, Qu MD, et The intestinal and oral microbiomes are robust predictors of COVID-19 severity the main predictor of COVID-19-related fatality [preprint]. 2021; medRxiv: 2021.01.05.20249061. Available from: https://doi.org/doi:10.1101/2021.01.05.20249061
6. Singh K, Rao A. Probiotics: a potential immunomodulator in COVID-19 infection Nutr Res 2021; 87: 1–12.
7. Ursell LK, Metcalf JL, Parfrey LW, Knight R. Defining the human Nutr Rev 2012; 70 (Suppl 1): S38–44.
8. Santacroce L, Charitos IA, Ballini A, Inchingolo F, Luperto P, De Nitto E, et The human respiratory system and its microbi- ome at a glimpse. Biology (Basel) 2020; 9(10): 318.
9. Santacroce L, Sardaro N, Topi S, Pettini F, Bottalico L, Cantore S, et The pivotal role of oral microbiota in health and disease. J Biol Regul Homeost Agents 2020; 34(2): 733–7.
10. Gomez PAM. Use of probiotics in Dent Oral Crani- ofac Res 2017; 4(1): 1–4.
11. Lamont RJ, Koo H, Hajishengallis G. The oral microbiota: dy- namic communities and host Nat Rev Microbiol 2018; 16(12): 745–59.
12. Caselli E, Fabbri C, D'Accolti M, Soffritti I, Bassi C, Mazzacane S, et al. Defining the oral mycrobiome by whole-genome se- quencing and resistome analysis: the complexity of the healthy BMC Microbiol 2020; 20(1): 120.
13. Radaic A, Kapila YL. The oralome and its dysbiosis: new in- sights into oral microbiome-host Comput Struct Biotechnol J 2021; 19: 1335–60.
14. Wade WG. The oral mycrobiome in health and Phar- macol Res 2013; 69(1): 137–43.
15. Rowan-Nash AD, Korry BJ, Mylonakis E, Belenky P. Cross- domain and viral interactions in the microbiome. Microbiol Mol Biol Rev 2019; 83(1): e00044–18.
16. Yamamoto S, Saito M, Tamura A, Prawisuda D, Mizutani T, Yotsuyanagi H. The human microbiome and COVID-19: a sys- tematic PLoS One 2021; 16(6): e0253293.
17. Biagi E, Candela M, Fairweather-Tait S, Franceschi C, Brigidi P. Ag- ing of the human metaorganism: the microbial counterpart. Age (Dordr) 2012; 34(1): 247–67.
18. Park SH, Kim KA, Ahn YT, Jeong JJ, Huh CS, Kim DH. Com- parative analysis of gut microbiota in elderly people of urban- ized towns and longevity BMC Microbiol 2015; 15: 49.
19. Arweiler NB, Netuschil The oral microbiota. Adv Exp Med Biol 2016; 902: 45–60.
20. Brooks AW, Priya S, Blekhman R, Bordenstein SR. Gut microbiota diversity across ethnicities in the United States. PLoS Biol 2018; 16(12): e2006842.
21. Rinninella E, Raoul P, Cintoni M, Franceschi F, Miggiano GAD, Gasbarrini A, et What is the healthy gut microbiota compo- sition? A changing ecosystem across age, environment, diet, and diseases. Microorganisms 2019; 7(1): 14.
22. Liu J, Lahousse L, Nivard MG, Bot M, Chen L, van Klinken JB, et Integration of epidemiologic, pharmacologic, genetic and gut microbiome data in a drug-metabolite atlas. Nat Med 2020; 26(1): 110–7.
23. Boyajian JL, Ghebretatios M, Schaly S, Islam P, Prakash Micro- biome and human aging: probiotic and prebiotic potentials in longevity, skin health and cellular senescence. Nutrients 2021; 13(12): 4550.
24. Pérez-Brocal V, Moya A. The analysis of the oral DNA virome reveals which viruses are widespread and rare among healthy young adults in Valencia (Spain). PLoS One 2018; 13(2):
25. Baker JL, Bor B, Agnello M, Shi W, He X. Ecology of the oral microbiome: beyond Trends Microbiol 2017; 25(5): 362–74.
26. de la Cruz Peña MJ, Martinez-Hernandez F, Garcia-Heredia I, Lluesma Gomez M, Fornas Ò, Martinez-Garcia Decipher- ing the human virome with single-virus genomics and meta- genomics. Viruses 2018; 10(3): 113.
27. Peters BA, Wu J, Hayes RB, Ahn The oral fungal mycobiome: characteristics and relation to periodontitis in a pilot study. BMC Microbiol 2017; 17(1): 157.
28. Mosaddad SA, Tahmasebi E, Yazdanian A, Rezvani MB, Seifalian A, Yazdanian M, et Oral microbial biofilms: an update. Eur J Clin Microbiol Infect Dis 2019; 38(11): 2005–19.
29. Dubar M, Zaffino ML, Remen T, Thilly N, Cunat L, Machouart MC, et Protozoans in subgingival biofilm: clinical and bac- terial associated factors and impact of scaling and root planing treatment. J Oral Microbiol 2019; 12(1): 1693222.
30. Belmok A, de Cena JA, Kyaw CM, Damé-Teixeira N. The oral ar- chaeome: a scoping J Dent Res 2020; 99(6): 630–43.
31. Lu M, Xuan S, Wang Oral microbiota: A new view of body health. Food Sci Hum Wellness 2019; 8(1): 8–15.
32. Stubbendieck RM, May DS, Chevrette MG, Temkin MI, Wendt- Pienkowski E, Cagnazzo J, et Competition among nasal bacte- ria suggests a role for siderophore-mediated interactions in shaping the human nasal microbiota. Appl Environ Microbiol 2019; 85(10): e02406–18.
33. Gebrayel P, Nicco C, Al Khodor S, Bilinski J, Caselli E, Comelli EM, et al. Microbiota medicine: towards clinical revolution. J Transl Med 2022; 20(1): 111.
34. Edwards V, Smith DL, Meylan F, Tiffany L, Poncet S, Wu WW, et Analyzing the role of gut microbiota on the onset of auto- immune diseases using TNFΔARE murine model. Microorgan- isms 2021; 10(1): 73.
35. Petersen C, Round Defining dysbiosis and its influence on host immunity and disease. Cell Microbiol 2014; 16(7): 1024–

33.

1. Nikolić-Jakoba N, Vojnović S, Pavić A, Janković S, Leković V, Va- siljević Polymerase chain reaction in the identification of per- iodontopathogens: a reliable and satisfactory method? Arch Biol Sci 2012; 64(4): 1413–23.
2. Tandelilin RT, Widita E, Agustina D, Saini R. The effect of oral probiotic consumption on the caries risk factors among high- risk caries J Int Oral Health 2018; 10(3): 132–7.
3. Zaura E, Twetman Critical appraisal of oral pre- and probiot- ics for caries prevention and care. Caries Res 2019; 53(5): 514–
4. https://doi.org/10.1159/000499037. PMid: 30947169
5. Ayala LDO, Zambrano JFB, Vire JMY, Gavilanes MPP, Coyago M de LR. Modulation of oral biofilm and immune response asso- ciated to mucosa with probiotic bacteria as a potential ap- proach in the prevention of dental caries: a systematic Dent Oral Biol Craniofac Res 2020; 3(5): 1–7.
6. Talaat D. Effect of probiotic chewable tablets on oral health and white spot lesions in pre-school children: a randomized clinical Egypt Dent J 2021; 67(3): 1797–807.
7. Milićević R, Brajović G, Nikolić-Jakoba N, Popović B, Pavlica D, Leković V, et Identification of periodontopathogen micro- organisms by PCR technique. Srp Arh Celok Lek 2008; 136(9– 10): 476–80. (Serbian)
8. Kumar PS. From focal sepsis to periodontal medicine: a century of exploring the role of the oral mycrobiome in systemic dis- ease. J Physiol 2017; 595(2): 465–76.
9. Allaker RP, Stephen AS. Use of probiotics and oral Curr Oral Health Rep 2017; 4(4): 309–18.
10. Radović N, Nikolić-Jakoba N, Petrović N, Milosavljević A, Brković B, Roganović J. MicroRNA-146a and microRNA-155 as novel crevicular fluid biomarkers for periodontitis in nondiabetic and type 2 diabetic J Clin Periodontol 2018; 45(6): 663–

71.

1. Ratna Sudha M, Neelamraju J, Surendra Reddy M, Kumar Eval- uation of the effect of probiotic Bacillus coagulans unique IS2 on mutans Streptococci and Lactobacilli levels in saliva and plaque: a double-blind, randomized, placebo-controlled study in children. Int J Dent 2020; 2020: 8891708.
2. Wang L, Ganly The oral mycrobiome and oral cancer. Clin Lab Med 2014; 34(4): 711–9.
3. Li Y, He J, He Z, Zhou Y, Yuan M, Xu X, et al. Phylogenetic and functional gene structure shifts of the oral microbiomes in periodontitis ISME J 2014; 8(9): 1879–91.
4. Abusleme L, Morandini AC, Hashizume-Takizawa T, Sahingur SE. Editorial: Oral mycrobiome and inflammation connection to systemic Front Cell Infect Microbiol 2021; 11: 780182.
5. Qin J, Li Y, Cai Z, Li S, Zhu J, Zhang F, et A metagenome- wide association study of gut microbiota in type 2 diabetes. Nature 2012; 490(7418): 55–60.
6. Marchi-Alves LM, Freitas D, de Andrade D, de Godoy S, Toneti AN, Mendes IAC. Characterization of oral microbiota in re- movable dental prosthesis users: influence of arterial hyperten- Biomed Res Int 2017; 2017: 3838640.
7. Bryan NS, Tribble G, Angelov N. Oral mycrobiome and nitric oxide: the missing link in the management of blood Curr Hypertens Rep 2017; 19(4): 33.
8. Cobb CM, Kelly PJ, Williams KB, Babbar S, Angolkar M, Derman RJ. The oral mycrobiome and adverse pregnancy outcomes. Int J Womens Health 2017; 9: 551–9.
9. Chen C, Hemme C, Beleno J, Shi ZJ, Ning D, Qin Y, et Oral microbiota of periodontal health and disease and their changes after nonsurgical periodontal therapy. ISME J 2018; 12(5): 1210–24.
10. Kaul D, Rathnasinghe R, Ferres M, Tan GS, Barrera A, Pickett BE, et Microbiome disturbance and resilience dynamics of the upper respiratory tract during influenza A virus infection. Nat Commun 2020; 11(1): 2537.
11. Lee HS, Lobbestael E, Vermeire S, Sabino J, Cleynen I. Inflamma- tory bowel disease and Parkinson's disease: common patho- physiological Gut 2021; 70(2): 408–17.
12. Willmott T, McBain AJ, Humphreys GJ, Myers J, Cottrell E. Does the oral mycrobiome play a role in hypertensive pregnancies? Front Cell Infect Microbiol 2020; 10:
13. Sohail MU, Hedin L, Al-Asmakh M. Dysbiosis of the salivary microbiome is associated with hypertension and correlated with metabolic syndrome Diabetes Metab Syndr Obes 2021; 14: 4641–53.
14. Milasin J, Nikolić-Jakoba N, Stefanović D, Sopta J, Pucar A, Leković V, et Periodontal inflammation as risk factor for pancreatic diseases. In: Nagal A, editor. Inflammatory diseases - a modern perspective. London: IntechOpen; 2011.
15. Đorđević V, Jovanović M, Stefanović V, Nikolić Jakoba N, Đokić G,

Stašević Karličić I, et al. Assessment of periodontal health among

the inpatients with schizophrenia. Vojnosanit Pregl 2019; 76(11): 1139–46.

1. Ren Z, Wang H, Cui G, Lu H, Wang L, Luo H, et Alterations in the human oral and gut microbiomes and lipidomics in COVID-19. Gut 2021; 70(7): 1253–65.
2. Zhang X, Zhang D, Jia H, Feng Q, Wang D, Liang D, et The oral and gut microbiomes are perturbed in rheumatoid arthritis and partly normalized after treatment. Nat Med 2015; 21(8): 895–905.
3. Kurt BS, Ilhan B, Sevki BI, Kurt AF, Orhan Periodontal man- agement during COVID-19 pandemic: mini review. Balk J Dent Med 2021; 25(3): 135–8.
4. Rakić M, Nikolić-Jakoba N, Struillout X, Petković-Ćurčin A, Stama- tović N, Matić S, et Receptor activator of nuclear factor kap- pa B (RANK) as a determinant of peri-implantitis. Vojnosanit Pregl 2013; 70(4): 346–51.
5. Kilian M, Chapple IL, Hannig M, Marsh PD, Meuric V, Pedersen AM, et al. The oral mycrobiome - an update for oral healthcare Br Dent J 2016; 221(10): 657–66.
6. Belkaid Y, Hand TW. Role of the microbiota in immunity and inflammation. Cell 2014; 157(1): 121–41.
7. Trompette A, Gollwitzer ES, Pattaroni C, Lopez-Mejia IC, Riva E, Pernot J, et Dietary fiber confers protection against flu by shaping Ly6c- patrolling monocyte hematopoiesis and CD8+ T cell metabolism. Immunity 2018; 48(5): 992–1005. e8.
8. Willis JR, Gabaldón The human oral mycrobiome in health and disease: from sequences to ecosystems. Microorganisms 2020; 8(2): 308.
9. Lynch SV. Viruses and microbiome alterations. Ann Am Thorac Soc 2014; 11(Suppl 1): S57–60.
10. Li N, Ma WT, Pang M, Fan QL, Hua JL. The commensal mi- crobiota and viral infection: a comprehensive review. Front Immunol 2019; 10: 1551.
11. Scannapieco FA. Role of oral bacteria in respiratory infection. J Periodontol 1999; 70(7): 793–802.
12. Khan R, Petersen FC, Shekhar S. Commensal Bacteria: An emerging player in defense against respiratory pathogens. Front Immunol 2019; 10: 1203.
13. Pfeiffer JK, Sonnenburg JL. The intestinal microbiota and viral Front Microbiol 2011; 2: 92.
14. Hanada S, Pirzadeh M, Carver KY, Deng JC. Respiratory viral in- fection-induced microbiome alterations and secondary bacteri- al pneumonia. Front Immunol 2018; 9: 2640.
15. Ai JW, Zhang HC, Xu T, Wu J, Zhu M, Yu YQ, et Optimiz- ing diagnostic strategy for novel coronavirus pneumonia, a multi-center study in Eastern China [preprint]. 2020; medRxiv: 2020.02.13.20022673. Available from: https://www.medrxiv.org/content/10.1101/2020.02.13.20022 673v1
16. Xu K, Cai H, Shen Y, Ni Q, Chen Y, Hu S, et Management of COVID-19: the Zhejiang experience. Zhejiang Da Xue Xue Bao Yi Xue Ban 2020; 49(2): 147–57. (Chinese)
17. Cox MJ, Loman N, Bogaert D, O'Grady J. Co-infections: poten- tially lethal and unexplored in COVID-19. Lancet Microbe 2020; 1(1): e11.
18. Roncati L, Lusenti B, Nasillo V, Manenti A. Fatal SARS-CoV-2 coinfection in course of EBV-associated lymphoproliferative disease. Ann Hematol 2020; 99(8):1945–6.
19. Chakraborty S. Metagenome of SARS-Cov-2 patients in Shen- zhen with travel to Wuhan shows a wide range of species - Lautropia, Cutibacterium, Haemophilus being most abundant - and Campylobacter explaining diarrhea [preprint]. OSF Pre- prints 2020; doi: 10.31219/osf.io/jegwq.
20. Wu F, Zhao S, Yu B, Chen YM, Wang W, Song ZG, et A new coronavirus associated with human respiratory disease in Chi-
21. Nature 2020; 579(7798): 265–9. Erratum in: Nature 2020;

580(7803): E7.

1. Chen T, Song J, Liu H, Zheng H, Chen C. Positive Epstein-Barr virus detection in coronavirus disease 2019 (COVID-19) pa- tients. Sci Rep 2021; 11(1):

• Yeoh YK, Zuo T, Lui GC, Zhang F, Liu Q, Li AY, et al. Gut microbiota composition reflects disease severity and dysfunc- tional immune responses in patients with COVID-19. Gut 2021; 70(4): 698–706.
• Marouf N, Cai W, Said KN, Daas H, Diab H, Chinta VR, et Association between periodontitis and severity of COVID-19 infection: a case-control study. J Clin Periodontol 2021; 48(4): 483–91.
• Song WJ, Hui CKM, Hull JH, Birring SS, McGarvey L, Mazzone SB, et al. Confronting COVID-19-associated cough and the post-COVID syndrome: role of viral neurotropism, neuroin- flammation, and neuroimmune Lancet Respir Med 2021; 9(5): 533–44.
• Oronsky B, Larson C, Hammond TC, Oronsky A, Kesari S, Lybeck M, et al. A review of persistent post-COVID syndrome (PPCS). Clin Rev Allergy Immunol 2023; 64(1): 66–74; Epub

2021; 20: 1–9.

• France K, Glick M. Long COVID and oral health care consid- J Am Dent Assoc 2022; 153(2): 167–74.
• Larsen JM. The immune response to Prevotella bacteria in chronic inflammatory disease. Immunology 2017; 151(4): 363–

74.

• Xu L, Chen X, Wang Y, Jiang W, Wang S, Ling Z, et Dynam- ic alterations in salivary microbiota related to dental caries and age in preschool children with deciduous dentition: a 2-year follow-up study. Front Physiol 2018; 9: 342.
• Khan AA, Khan Z. COVID-2019-associated overexpressed Prevotella proteins mediated host-pathogen interactions and their role in coronavirus outbreak. Bioinformatics 2020; 36(13): 4065–9.
• Wu Y, Cheng X, Jiang G, Tang H, Ming S, Tang L, et Author correction: Altered oral and gut microbiota and its association with SARS-CoV-2 viral load in patients with COVID-19 dur- ing hospitalization. NPJ Biofilms Microbiomes 2021; 7(1): 90.

Erratum for: NPJ Biofilms Microbiomes 2021; 7(1): 61.

• Jasinski-Bergner S, Mandelboim O, Seliger B. Molecular mecha- nisms of human herpes viruses inferring with host immune surveillance. J Immunother Cancer 2020; 8(2):
• Azarpazhooh A, Leake JL. Systematic review of the association between respiratory diseases and oral health. J Periodontol 2006; 77(9): 1465–82.
• Hols P, Ledesma-García L, Gabant P, Mignolet J. Mobilization of microbiota commensals and their bacteriocins for Trends Microbiol 2019; 27(8): 690–702.
• Barbour A, Wescombe P, Smith L. Evolution of Lantibiotic Sali- varicins: New weapons to fight infectious Trends Mi- crobiol 2020; 28(7): 578–93.
• Hadžić Z, Pašić E, Gojkov-Vukelić M, Hadžić Effects of Lac- tobacillus reuteri lozenges (Prodentis) as adjunctive therapeutic agent in non-surgical therapy of periodontitis. Balk J Dent Med 2021; 25(1): 41–5.
• Bottari B, Castellone V, Neviani E. Probiotics and Covid-19. Int J Food Sci Nutr 2021; 72(3): 293–9.
• Mikulicic A, Bakarcic D, Ivancic Jokic N, Hrvatin S, Culav T. The use of probiotics in dental medicine. Madridge J Dent Oral Surg 2017; 2(1): 44–6.
• Bermudez-Brito M, Plaza-Díaz J, Muñoz-Quezada S, Gómez- Llorente C, Gil Probiotic mechanisms of action. Ann Nutr Metab 2012; 61(2): 160–74.
• Eguchi K, Fujitani N, Nakagawa H, Miyazaki T. Prevention of respiratory syncytial virus infection with probiotic lactic acid

bacterium Lactobacillus gasseri SBT2055. Sci Rep 2019; 9(1): 4812.

• Moravvej H, Memariani H, Memariani M. Therapeutic and pre- ventive potential of probiotics against COVID-19. Res Bull Med Sci 2020; 25(1): e18.
• Azad MAK, Sarker M, Wan D. Immunomodulatory effects of probiotics on cytokine profiles. Biomed Res Int 2018; 2018:
• Hardy H, Harris J, Lyon E, Beal J, Foey AD. Probiotics, prebiot- ics and immunomodulation of gut mucosal defences: homeo- stasis and immunopathology. Nutrients 2013; 5(6): 1869–912.
• Al Kassaa I. The antiviral activity of probiotic In: Al Kassaa I. New insights on antiviral probiotics. Springer, Cham: 2017; 83–97.
• Xia Y, Cao J, Wang M, Lu M, Chen G, Gao F, et Effects of Lactococcus lactis subsp. lactis JCM5805 on colonization dy- namics of gut microbiota and regulation of immunity in early ontogenetic stages of tilapia. Fish Shellfish Immunol 2019; 86: 53–63.
• Hung YP, Lee CC, Lee JC, Tsai PJ, Ko WC. Gut dysbiosis dur- ing COVID-19 and potential effect of Microorgan- isms 2021; 9(8): 1605.
• Al Kassaa I, Hober D, Hamze M, Chihib NE, Drider D. Antiviral potential of lactic acid bacteria and their Probiot- ics Antimicrob Proteins 2014; 6(3–4): 177–85.
• Mahooti M, Abdolalipour E, Salehzadeh A, Mohebbi SR, Gorji A, Ghaemi A. Immunomodulatory and prophylactic effects of Bifidobacterium bifidum probiotic strain on influenza infec- tion in World J Microbiol Biotechnol 2019; 35(6): 91.
• Baindara P, Chakraborty R, Holliday ZM, Mandal SM, Schrum AG. Oral probiotics in coronavirus disease 2019: connecting the gut-lung axis to viral pathogenesis, inflammation, second- ary infection and clinical trials. New Microbes New Infect 2021; 40: 100837.
• Małaczewska J, Kaczorek-Łukowska E, Wójcik R, Siwicki AK. Antiviral effects of nisin, lysozyme, lactoferrin and their mix- tures against bovine viral diarrhoea BMC Vet Res 2019; 15(1): 318.
• Di Pierro F. A possible probiotic (S. salivarius K12) approach to improve oral and lung microbiotas and raise defenses against SARS-CoV-2. Minerva Med 2020; 111(3): 281–3.
• Zhang H, Yeh C, Jin Z, Ding L, Liu BY, Zhang L, et Prospec- tive study of probiotic supplementation results in immune stimulation and improvement of upper respiratory infection rate. Synth Syst Biotechnol 2018; 3(2): 113–20.
• Seminario-Amez M, López-López J, Estrugo-Devesa A, Ayuso- Montero R, Jané-Salas E. Probiotics and oral health: a system- atic review. Med Oral Patol Oral Cir Bucal 2017; 22(3): e282–8.
• Conte L, Toraldo DM. Targeting the gut-lung microbiota axis by means of a high-fibre diet and probiotics may have anti- inflammatory effects in COVID-19 Ther Adv Respir Dis 2020; 14: 1753466620937170.
• Olaimat AN, Aolymat I, Al-Holy M, Ayyash M, Abu Ghoush M, Al-Nabulsi AA, et al. The potential application of probiotics and prebiotics for the prevention and treatment of COVID-

1. NPJ Sci Food 2020; 4: 17.

• Stavropoulou E, Bezirtzoglou E. Probiotics in medicine: a long Front Immunol 2020; 11: 2192.
• Xavier-Santos D, Padilha M, Fabiano GA, Vinderola G, Gomes Cruz A, Sivieri K, et Evidences and perspectives of the use of probiotics, prebiotics, synbiotics, and postbiotics as adju- vants for prevention and treatment of COVID-19: a biblio- metric analysis and systematic review. Trends Food Sci Tech- nol 2022; 120: 174–92. Erratum in: Trends Food Sci Technol 2022; 121: 156–160.
• d'Ettorre G, Ceccarelli G, Marazzato M, Campagna G, Pinacchio C, Alessandri F, et Challenges in the management of SARS- CoV2 infection: the role of oral bacteriotherapy as comple- mentary therapeutic strategy to avoid the progression of COVID-19. Front Med (Lausanne) 2020; 7: 389.
• Tang H, Bohannon L, Lew M, Jensen D, Jung SH, Zhao A, et Randomised, double-blind, placebo-controlled trial of probiot- ics to eliminate COVID-19 transmission in exposed household contacts (PROTECT-EHC): a clinical trial protocol. BMJ Open 2021; 11(5): e047069.
• Endam LM, Tremblay C, Filali A, Desrosiers MY. Intranasal ap- plication of Lactococcus lactis W136 bacteria early in SARS-CoV- 2 infection may have a beneficial immunomodulatory effect: A proof-of-concept study [preprint]. 2021; medRxiv: 01.05.20249061. Available from: https://www.medrxiv

.org/content/10.1101/2021.04.18.21255699v1.full

• Gutierrez-Castrellon P, Gandara-Martí T, Abreu AT, Nieto-Rufino CD, Lopez- Orduna E, Jimenez-Escobar I, et al. Efficacy and safe- ty of novel probiotic formulation in adult Covid19 outpatients: a randomized, placebo-controlled clinical trial [preprint]. 2021; medRxiv: 2021.05.20.21256954. Available from: https://medrxiv.org/content/10.1101/2021.05.20.21256 954v1.full.pdf+html
• Mozota M, Castro I, Gomez-Torres N, Arroyo R, Lailla Y, Somada M, et Administration of Ligilactobacillus salivarius MP101 in an elderly nursing home during the COVID-19 pandemic: immunological and nutritional impact. Foods 2021; 10(9): 2149.
• Wang Q, Lin X, Xiang X, Liu W, Fang Y, Chen H, et Oro- pharyngeal probiotic ENT-K12 prevents respiratory tract in- fections among frontline medical staff fighting against COVID-19: a pilot study. Front Bioeng Biotechnol 2021; 9: 646184.
• Li M, He Z, Yang J, Guo Q, Weng H, Luo J, et Clinical char- acteristics, outcomes, and risk factors of disease severity in pa- tients with COVID-19 and with a history of cerebrovascular disease in Wuhan, China: A Retrospective Study. Front Neurol 2022; 12: 706478.
• Bozkurt HS, Bilen Ö. Oral booster probiotic bifidobacteria in SARS-COV-2 Int J Immunopathol Pharmacol 2021; 35: 20587384211059677.
• Wischmeyer PE, Tang H, Ren Y, Bohannon L, Ramirez ZE, Andermann TM, et Daily lactobacillus probiotic versus pla- cebo in COVID-19-exposed household contacts (PROTECT- EHC): a randomized clinical trial [preprint]. 2022; medRxiv: 2022.01.04.21268275. Available from: https://www.medrxiv

.org/content/10.1101/2022.01.04.21268275v1

• Block J. High risk COVID-19: potential intervention at multi- ple points in the COVID-19 disease process via prophylactic treatment with azithromycin or bee derived products. J Bio- med Res Rev 2020; 3(1): 26–31.
• Horowitz RI, Freeman PR, Bruzzese Efficacy of glutathione therapy in relieving dyspnea associated with COVID-19 pneumonia: a report of 2 cases. Respir Med Case Rep 2020; 30: 101063.
• Pourhossein M, Moravejolahkami Probiotics in viral infec- tions, with a focus on COVID-19: a systematic review [pre- print]. Authorea 2020; doi: 10.22541/au.158999387.76467979.
• Ceccarelli G, Borrazzo C, Pinacchio C, Santinelli L, Innocenti GP, Cavallari EN, et al. Oral bacteriotherapy in patients with COVID-19: a retrospective cohort Front Nutr 2021; 7: 613928.
• Patra S, Saxena S, Sahu N, Pradhan B, Roychowdhury A. System- atic network and meta-analysis on the antiviral mechanisms of probiotics: a preventive and treatment strategy to mitigate SARS-CoV-2 infection. Probiotics Antimicrob Proteins 2021;13(4): 1138–56.
• Ayyash M, Olaimat A, Al-Nabulsi A, Liu SQ. Bioactive proper- ties of novel probiotic Lactococcus lactis fermented camel sausag- es: cytotoxicity, angiotensin converting enzyme inhibition, an- tioxidant capacity, and antidiabetic activity. Food Sci Anim Re- sour 2020; 40(2): 155–71.
• Nayebi A, Navashenaq JG, Soleimani D, Nachvak Probiotic supplementation: a prospective approach in the treatment of COVID-19. Nutr Health 2022; 28(2): 163–75.
• Fernández-Fernández COVID-19, hypertension and angio- tensin receptor-blocking drugs. J Hypertens 2020; 38(6): 1191.
• Imai Y, Kuba K, Rao S, Huan Y, Guo F, Guan B, et Angio- tensin-converting enzyme 2 protects from severe acute lung failure. Nature 2005; 436(7047): 112–6.
• Spagnolello O, Pinacchio C, Santinelli L, Vassalini P, Innocenti GP, De Girolamo G, et Targeting microbiome: an alternative

strategy for fighting SARS-CoV-2 infection. Chemotherapy 2021; 66(1–2): 24–32.

• Infusino F, Marazzato M, Mancone M, Fedele F, Mastroianni CM, Severino P, et al. Diet supplementation, probiotics, and nutraceuticals in SARS-CoV-2 infection: a scoping review. Nu- trients 2020; 12(6): 1718.
• Santos TGFTD, Brito DHS, Santos NMVD, Paiva MC, Lyra MCA, Heimer MV, et al. Viral symptoms in children and SARS-COV-2: information for pediatric dentists for the con- trol of Braz Oral Res 2022; 36: e029.

Received on June 25, 2022

Revised on February 20, 2023

Accepted on March 3, 2023 Online First March 2023