Introduction
Recently, it has been revealed that oral microbiota exert several effects on the general health in humans [1]. Investigations demonstrated a bunch of microbial complexes that possess systemic impact on the host via interfering with the immune host response and up-regulating host gene expression [2]. Different diseases such as Diabetes Mellitus (DM), Cardiovascular Diseases (CVD), obesity and periodontal diseases have been linked to alterations of the oral microbial ecosystems [3]. To date, researchers are still exploring the incidence of a variety of diseases and linking them to oral microbial dysbiosis in an attempt to seek for crucial therapeutic modalities [4]. It was reported that abnormalities of Nitric Oxide (NO) signaling pathways were coupled with higher risk to hypertension, CVD, reduced insulin sensitivity and obesity [1]. Recently, reduction of oral commensal flora by antiseptic mouthrinses was found to prevent endogenously generated nitrates from being converted to nitrite by their bactericidal effects [5]. As a result, the decreased nitrites due to bacterial unbalance can possess a direct lowering effect on the blood pressure [6]. Accordingly, it was suggested that excessive use of oral antiseptic mouthrinses might lead to cardiovascular events particularly in patients with high risk to cardiovascular diseases [7].
The ingested nitrates from dietary sources generate nitrite molecules by the action of microbial enzymes. Nitrites have been considered as a secondary source of NO as well as other forms of nitrogen oxides [8]. It was exhibited that nitrite metabolism plays a crucial role in maintaining the basal vascular tone and endothelial integrity, thus preserving normal blood pressure and preventing vasculitis during inflammatory stress conditions [9]. The NO metabolic pathway in addition to generated nitrites depends on the reduction of inorganic nitrate via specific bacteria which synthesise nitrate reductases (Naturally, are not present in humans) [10]. Dietary nitrates are readily absorbed after ingestion in the gastrointestinal tract via the nitrate-nitrite-NO pathway [Table/Fig-1] [11]. With regards to the total amount of dietary nitrate, about 25% of plasma nitrate is concentrated into the salivary glands to be secreted with whole salivary flow (It is 20-fold higher than in plasma concentration) [12]. It was previously reported that NO synthase and O2-independent enzymatic reductions convert salivary nitrates into nitrites in the oral cavity [13]. Then, nitrites are ingested and subjected to a series of successive reactions to produce NO and NO-donating molecules after protonation to HNO2 and a group of secondary nitrosating and nitrating molecules in the presence of low pH in the stomach [14], or reduction by intestinal bacterial nitrite reductase enzymes [15] thus, resulting in the formation of nitro-fatty acid signaling molecules such as NO2-conjugated linoleic acid and derivatives of S-nitrosothiol that could be detected at elevated plasma concentrations after oral nitrate ingestion [16]. These reactions can effectively regulate the cardiovascular functions and will cease after killing of the oral microbiota [17]. Based on the nitrate-nitrite-NO pathway, signal transduction leading to the generation of NO and bioactive nitrogen oxides will not progress to cGMP-dependent signaling and NO synthesis [18]. Thus, a wide spectrum of redox-derived nitrogen oxides induced post-translational modification of proteins with alterations in their function and gene expression profiles [19].
Diagrammatic illustration of nitrate-nitrite-nitric oxide pathway.
Vascular Health and Blood Pressure
The impaired nitrate-nitrite-NO pathway decreases the conversion of nitrate to nitrite and NO, which might lead to systemic complications, mainly in inflammatory and metabolic disorders [20]. A large body of evidence substantiates that bacterial activation of nitrate might play a major role in preventing and treating cardiovascular diseases [21]. Strong evidence has confirmed appreciated lowering blood pressure and improved vascular changes of nitrate and nitrite dietary supplementation [21]. Previous studies showed that using of chlorhexidine antiseptic mouthrinse resulted in reduction of oral bacterial nitrate reductases and thus reduction of 90% of concentrations of oral nitrite in humans associated with decrease in plasma levels significantly by 25% and increase in blood pressure by 2-3.5 mmHg [5]. Another study in hypertensive patients showed statistically significant blood pressure reduction with different nitrate supplementations [22]. Furthermore, the use of antimicrobial mouthwash reduced this valuable crucial effect [5]. It was reported that endothelial dysfunction has been linked to decreased plasma concentrations of nitrite [7]. It was proven that dietary supplementation with either nitrates or nitrites elevate systemic plasma nitrite levels and ameliorate the endothelial health in a dose-dependent pattern in a mouse model and obese individuals [23]. The same actions have been demonstrated in subjects with peripheral vascular disease and elevated plasma total cholesterol levels [21]. Furthermore, dietary nitrate and nitrite supplements showed significant inhibition of vascular intimal hyperplasia in mice [24], whereas nitrate supplementation reduced ischemia-reperfusion injury and endothelial dysfunction in different animal models and humans [25].
Complexity of the Oral Microbiome
It was previously reported that several billions of bacteria resides in the oral cavity; comprised of almost 700 different bacterial species [26]. A remarkable variability was found in the different sites in the oral cavity, such as gingiva, hard and soft palate, on dorsum of the tongue as well as the tooth surface [27]. It was established that specific types of bacterial flora have been associated with systemic and oral diseases [28]. For instance, bacterial species such as Streptococci and Lactobacilli were found to be involved in the dental carious lesions, whereas anaerobic gram negative bacteria such as species of Porphyromonas and Prevotella have been linked to periodontal diseases [29]. Recently, Porphyromonas gingivalis was revealed to be linked with atherosclerotic lesions, and certain types of cancer [30]. However, individual isolated bacterial strains do not exhibit any activity in a vacuum, they show virulence activity when present in microbial communities; they may have several oral and systemic health affections [31].
Periodontal Disease and Salivary Gland Dysfunction
Chronic periodontitis is a local chronic inflammation of the tooth supporting apparatus initiated by specific microorganisms including Porphyromonas gingivalis, Tannerella forsythia, and Treponema denticola, which are collectively known as the “red complex” [29]. It was revealed that periodontal tissue damage begins as inflammatory neutrophil mediated reaction followed by chronic infiltration of monocytes [32]. Previous investigations have reported that most of periodontal tissue destruction is directly caused by the host immune response to the aforementioned specific periodontopathogenic bacteria [33]. Nevertheless, Hajishengalis G and Lamont RJ have established a new model for periodontal disease pathogenesis exhibiting that periodontal disease is initiated by synergistic and dysbiotic periodontopathogens. In this polymicrobial synergy, different members in the microbial community perform specific roles to become a disease provoking microbiota. For a potentially pathogenic community to evolve, certain species, known as ‘keystone pathogens’, are able to modulate the host response by impairing the immune surveillance and tip the balance from symbiosis to dysbiosis [34].
Previous reports have revealed an association between cardiovascular diseases and periodontal disease which has been linked to direct vascular entry of the nitrate-reducing oral pathogenic bacteria, systemic inflammation, and endothelial dysfunction [35]. Conventional periodontal treatment by Scaling and Root Planing (SRP) in conjunction with or without chlorhexidine mouthwash has improved systemic inflammation [36]. Moreover, the levels of salivary nitrate and nitrite and gingival expression of NO have been found to be elevated in periodontal diseases, which increased with disease severity and improves after effective periodontal therapy [37]. It was shown that growth and survival of the nitrate-reducing bacteria inhabiting periodontal pockets and furcation areas can lead to pronounced imbalance of the oral micobiome [38]. Beside the aforementioned periodontal effects on bacterial communities, antimicrobial effects may also be exerted elsewhere in the buccal cavity and gastrointestinal tract as a result of high concentrations of salivary nitrite, possibly disrupting community composition or function of biologically beneficial communities of nitrate-reducing bacteria [39]. Based on the association between periodontal disease and other systemic diseases such as diabetes mellitus and obesity [40] the possibility of dysbiosis and systemic inflammation as a result of periodontal disease and general oral health might affect or reverse the valuable impacts on physiological salivary nitrate metabolism [39]. An additional association also was found between polymicrobial dysbiosis and salivary glands dysfunction which leads to xerostomia [41]. In salivary gland diseases, there is a reduction in salivary nitrate concentration and increase in urinary excretion, consequently diminishing the overall concentration of circulating nitrate [42]. Most importantly, several diseases which share increased pH and enhanced rates of vascular disease, including systemic sclerosis and Sjogren’s syndrome [43], HIV [44], and mucoviscidosis [45] also show dysregulated salivary flow and altered oral microbiota [46].
Conclusion
Some studies have reported that high blood pressure was associated with a reduced production and/or bioavailability of NO by oral microbiota. It was noticed that the dysreguation of the nitrate-nitrite-NO pathway through the use of antibacterial mouthrinses in treated hypertensive individuals was associated with a moderate elevation of systolic blood pressure. In fact, the clear mechanism is still to be identified. More future studies are warranted to explore whether different antibacterial agents present in mouthwashes have the same effect on blood pressure especially in patients with cardiovascular events.
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