Influence of oral microbiome, gut microbiome and pulmonaire microbiome with COVID-19: review

3.1. Intestinal microbiome and the immune system

The effect of viral infection has been present in the intestinal microbiome [13], which leads to the possibility of the pulmonary and intestinal microbiome having an influence on each other, determining how the body will react towards a pathogen [14]. Nevertheless, when some of those microbiomes find themselves out of balance, the result is the dysbiosis of the digestive system and bacterial aspiration into the respiratory system, making it harder for the immune reaction. This intestinal dysbiosis (prior to a viral infection, as in COVID-19) can also be related to a superinfection, which is associated with chronic diseases, chronic characteristics of inflammation, abnormal metabolism, including cardiovascular problems, diabetes and even periodontitis [14], [15].

The relation between intestinal, pulmonary and oral microbiome can be the answer to COVID-19 complications as it is known that intestinal microbiome is responsible for the system’s immune response, which means, a lack of equilibrium can affect the response of oral and pulmonary microbiome. [15] The intestinal microbiome is essential for the first immune response against viral infection, which is composed by actinobacteria and bacteroidetes, being responsible for the regulation of many physiological functions of the host, including dietary digestion and ensuring protective immunity against pathogens [15], [16].

Thus, the intestinal mucosa is exposed to a wide variety of antigens coming from food, resident bacteria and invading microorganisms, and those need to be limited by the mucosal barrier that provides immune defence to harmful antigens. The intestine commensal microorganisms induce the maintenance of important cells for the mucosal immunity. The immune system identifies the intestine commensal microorganisms and causes the immune response [14].

In some studies made by F. Sommer and F. Bäckhed, it was found that commensal microorganisms developed in germ free mice all over the immune system structure. The villi in germ free mice were distended and narrow, the depth of crypts smaller and less developed vascularisation. The intestine mucosa showed less B cells, T cells and dendritic cells, as well as premature mesenteric lymph nodes and immature and small Peyer’s patches. During the colonisation with commensal microorganisms, it was observed in those animals a development of conformation linked to the immune system [17].

In addition, it is known that the bacterial colonisation in the upper respiratory tract is normally the first part of a bacterial infection [18] and also that periodontal microorganisms such as Prevotella - gram-negative bacteria, obligate anaerobes, Veillonella and Streck Opus 20 have the ability to colonise the upper respiratory tract [19]. That way, it is noted that an individual who has periodontitis has a disequilibrium between the intestinal and oral microbiome, which means the individual is more susceptible to the aggravation of other infections (such as viral infections) [20]. It was observed in a study with mice lacking microbiome an underdevelopment of tissue-associated lymphocytes, a decreased number and size of Peyer’s patches, mesenteric lymph nodes and defect in antibiotic production. This has led to an increased susceptibility of numerous infections including viruses, bacteria and fungi [19].

The dysbiosis or imbalance in the composition of the microbiome is associated with several chronic diseases, characteristics of chronic inflammation and abnormal metabolism, including cardiovascular disease, diabetes and periodontitis itself, since studies performed on patients with periodontitis the ingestion of high concentration of pathogens results in dysbiosis of the intestinal microbiome, favouring a microbiome with inflammatory profile [21].

In a study by Talita Gomes Beata Lourenço, the composition of oral and intestinal microbiome of patients with different periodontitis conditions were evaluated. The data demonstrated that the diversity of intestinal microbiomes is reduced in individuals with periodontitis. Furthermore, due to the sequencing of the 16S rRNA bacterial gene, there is a high prevalence and increased levels of oral pathogens in the intestinal microbiome in those patients [22].

Therefore, it is possible that periodontal pathogens could manage to resist the gastrointestinal system and reach the intestinal microbiome in order to cause a dysbiosis characterised by a reduction in the diversity of this microbiome [22]. A hypothesis is raised that patients with periodontitis in the group of risk causing COVID-19 complications (which could progress to pneumonia and even ARDS).

It is known that SARS-COV-2 has the ability to replicate throughout the whole organism. This is because, as well as affecting the respiratory tract, it can replicate in the enterocytes [23]. Thus, if the microbiome is in dysbiosis caused by other microorganisms (such as periodontal pathogens), the local immune response to a viral attack would be less efficient, which would also affect the entire immune’s system response [24].

A meta-analysis of 60 studies, with a total of 4,243 patients showed that 17,6 % of the individuals who had COVID-19 showed gastrointestinal symptoms such as diarrhoea, nausea, vomiting, loss of appetite and abdominal pain. This would be the reaction of the intestine against a viral infection, the dysbiosis of the intestinal microbiome which is related to the reduction of diversity, due to inflammatory products and autoimmune diseases. [25] Periodontitis is related to this response, considering a study carried out by Bao J, who compared the presence of bacteria in the saliva of patients with periodontitis, which found that 52,38 % of these bacteria were found in the intestinal microbiome. This percentage was lower in healthy patients, showing evidence of the capacity of periodontal pathogens that lead to dysbiosis [6].

A dysbiosis of the intestinal microbiome can be harmful to the organism's immune response towards an infection, which means, in case this occurs there is a worsening of the response against COVID-19. Studies have shown an important role for the commensal microbiome in antiviral responses in the lung, modelling the immune response in homeostatic conditions and during a viral infection [26].

3.2. Relation of the viral infection with a secondary bacterial infection

Studies have shown that a viral infection can cause a secondary bacterial infection. This hypothesis can be raised due to the detection of a bacterial co-infection, as occurred in 30 % of H1N1 cases in 2009 [19] and also in the 1918 pandemic where most deaths were caused by a bacterial superinfection, and not the virus itself [1].

Co-infection is discussed by several authors, linking microbiome imbalance with the emergence of an opportunistic infection. This mechanism of viruses and bacteria are complex, since they present multi-factors such as the interaction of the virus, bacteria colonisation and the immune system [27]. An example of this is that after contracting influenza, the mucosa/epithelium is damaged by the virus, which increases the colonisation of bacteria in the respiratory tract, leading to the deregulation of immune responses, providing higher susceptibility to secondary bacterial infection [1]. A possibility of aggravating the condition of viral infection comes from the oral microbiome, as demonstrated, it mentions that this microbiome is the main source for the formation of microbiome in the lungs and the development of lung disease such as pneumonia, chronic lung obstruction, fibrous cyst, asthma and even lung tumours might be associated with pathological bacteria present in the oral cavity [28].

With functions similar to the intestine microbiome or oral cavity, bacterial communities which colonise the lungs aim to preserve the tissue, immunity and homeostasis of the organ. Lower respiratory tract infection is initiated by the epithelium contamination in the lower airways by inhalation of microorganisms in droplets aerosols or by aspiration of secretion associated with oral diseases (P. Gingivalis, F. Nucleatum, P. Intermedia) [29]. Having periodontitis more frequently, cytokines (IL-1 AND TNF) from periodontitis can contaminate saliva through gingival crevicular fluid and if aspirated can cause lung inflammation [30]. 49,400 patients with chronic periodontitis were treated with periodontal therapy for 11 years, Kaplan-Meier demonstrated in a study that the incidence of pneumonia dropped drastically [29], [30].

Epithelial sensitivity and hematogenous dissemination of pro-inflammatory mediators such as cytokines (produced in periodontal disease tissue) can increase systemic inflammation and decrease airflow. This can be exacerbated by stimulating the liver to produce acute phase proteins, such as interleukin-6, which potentiate the inflammatory response in the lungs and the rest of the body [19]. Similarly, patients with severe COVID-19 infections also express systemic inflammation and significantly higher levels of interleukin-6, interleukin-2, interleukin-10, TNF and C-reactive protein. [20] In an ecological disorder or facing an oral disease, the microorganisms present in the oral cavity can migrate into the bloodstream or digestive system [31], [32].

This pathogenic microorganisms in the oral microbiome have the ability to enter the respiratory system with aid of the human body through: an accidental inhalation of oral saliva into the trachea, the act of sneezing taking the mucus from the respiratory tract into the mouth and also mutual exchange of substances in the oral cavity and respiratory tract. This would cause bacterial colonisation of oral bacteria, mainly Porphyromonas gingivalis, responsible for periodontitis. The result is a fragile system which when in contact with a more virulent pathogen could aggravate the situation [33].

In that way, it is observed that an individual with periodontitis has a high virulent capacity pathogen. When it is infected by SARS-COV-19, there is a favourable environment for its replication. The spread of periodontal bacteria to lung tissues can cause the induction of lipopolysaccharide senescence, which would facilitate SARS-COV-2 adhesion, therefore facilitating its replication. Altogether, pre-existing gram-negative bacterial infection and the associated presence of LPS can exacerbate local lung inflammation as result of SARS-COV-2 protein binding, increasing the activation of NF-KB [34].