The human oral bacteriome is the second largest bacterial community in the human body, after that of the gut, and it includes around 700 recognized species [61,62]. The oral bacteriome has been regarded as an important player in the establishment of infection caused by viruses that enter the body via the oropharynx [63]. In the oral cavity, respiratory viruses encounter bacterial residents and are modulated in their ability to establish infection [64]. Moreover, viruses can alter the balance of the oral microbiota, thus promoting dysbiosis. A dysbiotic oral bacteriome is often associated with periodontal inflammation, which could lead to local and systemic disease conditions, including those sustained by viral infections [65].

As noted, before, numerous bacterial spp. make up the oral bacteriome; thus, the oral cavity may be regarded as an ecological community of bacterial commensals, symbionts, and potential pathogens [66]. The primary bacterial genera residing in the oral bacteriome include Capnocytophaga, Corynebacterium, Fusobacterium, Leptotrichia, Neisseria, Prevotella, Streptococcus, and Veillonella [44]. Oral bacteria have been related to respiratory infections in several ways: (i) oral pathogens can be aspirated into the lungs, (ii) enzymes secreted by periodontal pathogens can modify mucosal surfaces, resulting in increased colonization and adhesion by respiratory pathogens, and (iii) cytokines secreted in response to periodontal pathogens can alter respiratory epithelia, thus promoting the colonization of pathogens [67,68].

Metagenomic analysis of the oral bacteriome of patients suffering from COVID-19 have revealed the abundance of cariogenic (tooth decay) and periodontopathic (periodontitis) bacteria [69]. This indicates that changes in the diversity of the oral bacteriome can lead to COVID-19 complications. Periodontopathic bacteria have been associated with respiratory infections and other chronic inflammatory pathologies including diabetes, hypertension, and cardiovascular diseases [45]. These diseases have also been reported to exhibit co-morbidities associated with complications and mortalities due to COVID-19. The well-known putative periodontopathic organisms include Actinobacillus actinomycetemcomitans, Eikenella corrodens, Bacteroides forsythus, Bacteroides gingivalis, Bacteroides intermedius, and Wolinella recta [70,71]. Analyses of the oral bacteriomes of COVID-19 patients can give information about indicator species that increase in number during infections. If these species have pathogenic potential, they may cause complications associated with the disease.

A study by Ward and co-workers identified indicator species of the oral bacteriome as predictors of COVID-19 severity in patients [46]. Three bacterial spp. that appear to be associated with disease severity include Porphyromonas endodontalis, Veillonella tobetsuensis, and Bifidobacterium breve. However, as this research was based on disease modeling, further clinical research is imperative in order to confirm the association of these bacterial species with disease progression. Interestingly, P. endodontalis was observed to be the most important discriminator of COVID-19 severity. Conversely, the abundance of Muribaculum intestinale in patients was indicative of more moderate COVID-19 infections. In a recent study by Miller et al., minimal differences were observed between the oral bacteriomes of newly admitted COVID-19 patients and non-COVID-19 patients [72]. Sequencing of the 16S rRNA gene was performed to make a comparative analyses of the bacterial diversity between the positive and the control patients. The authors observed increased abundance of Prevotella pallens in the positive patients, while Rothia mucilaginosa, and Streptococcus spp. were abundant in the control patients. Species abundant in the saliva samples of the control patients included Prevotella denticola, Prevotella oris, Saccharibacteria strain HMT356, and Streptococcus peroris. The high and low viral loads in the saliva of patients corresponded to the distribution of the different bacterial spp. These included Prevotella pallens, Stomatobaculum spp., Streptococcus infantis, Streptococcus parasanguinis clade 411, Streptococcus sanguinis, and Treponema spp. The authors also hypothesized that the relationship between the bacteriome and viral saliva load in the patients could be affected by the receipt of supplemental oxygen.

A comparison of the oral bacteriomes of healthy people and COVID-19 patients along with immunological analyses of their cytokine levels could provide valuable information about beneficial bacterial residents of the oral cavity, allowing discrimination of cytokine levels raised during SARS-CoV-2 infection. In this regard, a study by Iebba et al. analyzed 16S rRNA sequencing for samples taken from the oral cavity [73]. These investigators identified various bacterial species as potential biomarkers for COVID-19 severity. These included Prevotella jejuni, Prevotella salivae, Soonwooa purpurea, and Veillonella infantium. Bacterial spp. that predominated the oral bacteriome were Gemella taiwanensis, Granulicatella elegans, Kallipyga gabonensis, Neisseria perflava, Porphyromonas pasteri, Rothia mucilaginosa, and Streptococcus oralis. Results of the in silico analyses also predicted the above aforementioned bacterial spp. as probiotics, which could assist in controlling COVID-19 severity and the associated cytokine storm. The authors also identified six COVID-19-related discriminant cytokines including Interleukins (IL)-2, 5, 6, Granulocyte colony-stimulating factor (GCSF), Tumor necrosis factor-α (TNF- α), and Interferon-γ (IFN- γ), but only IL-12 for controls. Both IL-6 and -12 were the most discriminant cytokines for positive and control patients. Past literature suggested that during viral immune responses, IL-6 can be overexpressed, thus leading to impaired functionality of T-helper cells [74]. Due to this constant antigen stimulation (as in the case of SARS-CoV-2), cluster of differentiation 8 (CD8) T-cells do not respond to the antigenic stimuli as they normally would and as a consequence memory CD8 T-cells do not form—a situation that limits viral clearance [75]. As reported by Iebba et al., the predicted probiotic bacterial spp. had a negative correlation with IL-6. This could indicate that these organisms may help lower the pro-inflammatory environment of the oral cavity, and potentially help in countering the cytokine storm associated with COVID-19.

Another recent metagenomic analysis identified enrichments in opportunistic oral pathogens, Megasphaera and Veillonella in COVID-19 patients. However, no significant changes in alpha-diversity were observed during the comparison of the non-critically ill patients to healthy controls [76]. Findings from various studies highlight the necessity for further comprehensive studies on the oral bacteriome in COVID-19 patients. It is also pivotal to establish a clear picture of how a dysbiotic oral bacteriome may be an important player in disease severity. It is the need of the hour to identify key probiotic strains that may aid in the recovery from this disease.

Studies on the relationships between respiratory viruses and the oral bacteriome indicated that the virus–bacterium interaction could enhance disease severity [77]. For instance, the interaction between neuraminidase-producing streptococci and influenza virus has been shown to increase the viral load [78]. Similar trans-kingdom interactions are expected for SARS-CoV-2 and the oral bacteriome of humans, as similar interactions have been reported in other bacteriomes of the human body [72]. Martino and co-workers analyzed the oral bacteriome of COVID-19 patients and observed changes in the normal bacterial communities in comparison to controls [79]. There was an abundance of bacterial species capable of modifying heparan sulfate, a component that is essential for the binding of SARS-CoV-2 to ACE2. Similar interactions have been reported for the gut bacteriome (discussed in later sections), as gut residents may influence the synthesis of various cofactors that are needed for viral binding to ACE2. In addition, inflammation-causing bacterial species (Streptococcus mutans and Prevotella nigrescens) have been associated with a dysbiotic oral bacteriome [80]. It is possible that COVID-19-mediated inflammation may cause a change in the normal oral bacteriome and increase the number of pathogens, which may cause further inflammation. At this point, it is imperative to further analyze the interplay of the immune system with the normal and/or dysbiotic oral bacteriome during COVID-19 infection.

Past studies showed that oral hygiene improves the symptoms of patients suffering from pneumonia while reducing the mortality rate. Sjogren et al. suggested that good oral hygiene could prevent one in ten deaths of older patients (65 years and older) suffering from pneumonia [81]. Mori et al. observed that hygienic oral practices can prevent the incidence of ventilator-associated pneumonia in intensive care units [82]. As of now, the search continues for the establishment of a defined relationship between the oral bacteriome and COVID-19 severity. However, oral dysbiosis could be a modifiable risk factor for COVID-19, as hygienic oral practices may circumvent dysbiosis. It seems that these practices should be adopted for public health promotion during the COVID-19 pandemic and even during future COVID-19 endemics.