1. Oral Microbiota and Diabetes
Some medical conditions are caused by an increase in inflammation in the body
[1][29]. Some authors have pointed out that among these pathologies, the most frequent are periodontal disease, diabetes, systemic lupus erythematosus (SLE), and rheumatoid arthritis (RA).
People with increased susceptibility to inflammation have an increased risk of developing periodontitis and have higher blood sugar levels, meaning a greater risk of developing SLE and RA.
The increase in inflammation in these diseases influences the oral microbiota, causing substantial changes.
Systemic diseases have a significant impact on periodontal health, and diabetes mellitus is one of the most correlated factors.
Diabetes is a metabolic disorder and can be divided into two main types: type 1 and type 2 (T1DM and T2DM)
[2][30]. At the basis of this metabolic disorder, there is an inflammatory response; in fact, the introduction of the same bacteria into the connective tissues of diabetic animals causes a more intense inflammatory response than in controls with normal blood glucose levels
[3][31]. Diabetes can influence several factors that contribute to increased inflammation, and this is very often found at the level of the oral microbiome and especially in the periodontal tissues. These include elevated glucose levels, the increased formation of advanced glycation end products, and the increased expression of cytokines, such as tumor necrosis factor (TNF)
[2][30]. In diabetic patients, neutrophils and monocytes/macrophages show elevated cytokine expression in response to stimuli and are less effective at fighting bacteria
[4][32]. Elevated blood glucose levels also affect host mesenchymal cells, such as periodontal ligament cells, osteoblasts, and osteocytes, which increase RANKL expression, resulting in a reduction in bone formation and hence loss of tooth support tissue
[2][30].
Cause-and-effect relationships have been established, demonstrating that blocking the formation of advanced glycation end products (AGEs) reduces levels of inflammatory cytokines (including TNF), matrix metalloproteinase expression, and bone loss in the gums
[5][33]. The various forms of diabetes, in particular T1DM, are associated with complications related to the increase in the degree of inflammation, as in the case of cardiovascular diseases, neuropathies, nephropathies, and periodontal diseases. Both types of diabetes increase the inflammatory response to the presence of bacteria
[3][31]. This must, therefore, be considered during dental maneuvers that could induce bacterial spread, such as extractions, endodontic treatments, and alveolar curettage
[6][34].
The increased inflammation of the gums observed in T1DM and T2DM could be attributable to the damage caused by bacteria colonizing the tooth surface.
According to a consensus report by the European Federation of Periodontology and the American Academy of Periodontics, there is no direct evidence that diabetes directly affects the oral microbiota. In fact, it is still not clear whether the destruction of the periodontium in diabetic patients is caused exclusively by an impairment of the host immune response or if there is a change in the pathogenicity of the bacteria that leads to an increase in inflammation and damage
[7][35].
As a result, there are still no clear conclusions from human studies examining the impact of diabetes on the oral microbiome. However, some studies have instead shown alterations in the oral microbiome in association with high blood sugar levels. For example, increases in
Capnocytophaga levels have been observed in patients with diabetes mellitus
[8][36], as well as increases in
P. gingivalis and
T. forsythia [9][10][37,38], and in
Capnocytophaga,
Pseudomonas,
Bergeyella,
Sphingomonas,
Corynebacterium,
Propionibacterium, and
Neisseria in hyperglycemic subjects
[11][39]. However, these results contradict other studies which showed that some bacterial species such as
Porphyromonas,
Filifactor,
Eubacterium,
Synergistetes,
Tannerella, and
Treponema decreased in diabetic patients
[12][40].
Thus, current studies have shown conflicting results on the influence of diabetes on the oral microbiome.
Furthermore, it has been suggested that differences in the oral microbiome may be more pronounced between normoglycemic and diabetic individuals than between healthy and diseased sites within the same location
[11][39].
The lack of a general consensus could be attributable to several reasons, such as statistical reasons based on a large number of oral microorganisms that could generate false positives, insufficient samples that could lead to false negatives, confounding factors such as the degree of hyperglycemia, duration of illness, and medication intake, technical limitations such as the lack of unbiased approaches for identifying oral bacteria, and a limited number of longitudinal studies.
2. Oral Microbiota and Rheumatoid Arthritis (RA)
RA is a systemic condition of an autoimmune nature characterized by long-lasting inflammation
[13][41]. Some pathogenetic mechanisms underlying periodontal disease share common features with those leading to the development and progression of rheumatoid arthritis. The main mechanism is the dysregulation of the inflammatory process, resulting in the destruction of bone tissue. It has also been shown that periodontitis can trigger RA through the production of enzymes that generate compounds such as malondialdehyde-acetaldehyde, citrullinated adducts, and carbamylates, which increase self-antigenicity and trigger an autoimmune response
[13][41]. Animal studies have also been conducted, showing that, in rodents in which an inflammatory process was induced at the joint level, bone loss was observed at the level of the alveolar processes
[14][15][42,43]. The use of oral antiseptics, used with the aim of lowering the amount of bacterial load in the oral cavity, has been correlated with less bone destruction related to the inflammatory processes of rheumatoid arthritis, indicating that the oral microbiome plays a role
[16][44]. These data suggested a model involving two factors: the first represents the oral microbiota, and the second concerns the impact of systemic disease on local inflammation. RA can modify, by upregulation, the inflammatory response at the periodontal level, which in turn induces a change in the microbiota
[17][45]. Synergistically, the chronic systemic inflammation present due to the pathogenetic mechanisms of rheumatoid arthritis may influence the levels of inflammatory cytokines in oral tissues, inducing greater disease progression
[18][46]. In fact, it was observed that, in the oral cavity of rodents with RA, there was an increased concentration of pro-inflammatory cytokines such as TNF-α, IL-1, IL-6, and IL-17
[16][44]. RA patients also show increased concentrations of IL-17, TNF-α, and IL-33 in saliva, very similar to what is observed in the case of SLE
[14][42]. IL-17 has been associated, in several studies, with other diseases that have shown a correlation with alterations in the microbiota, as in the case of LAD-1 (leukocyte adhesion deficiency 1) and oral lichen planus
[19][47]. There is, in rodents with rheumatoid arthritis, a change in both the qualitative and quantitative composition of the oral microbiome. In fact, higher levels of
P. micra,
Selenomonas noxia, and
Veionella parvula are found in mice with RA than in the control group
[14][42]. In the case of humans, the microbiome associated with RA shows significant differences from that of healthy subjects. Increasing in the oral microbiota of RA patients are anaerobic bacterial species, such as
Lactobacillus salivarius,
Atopobium,
Leptotrichia,
Prevotella, and
Cryptobacterium curtum, while a decrease in oral health-associated species such as
Corynebacterium and
Streptococcus was observed
[20][48].
In patients with RA who do not have periodontitis, an increase in periodontitis-related bacterial species such as
Prevotella (e.g.,
P. melaninogenenica,
P. denticola,
P. histicola,
P. nigrescens,
P. oulorum, and
P. maculosa) and other pathogenic species (
S. noxia,
S. sputigena, and
Anaeroglobus geminatus) can be observed. In addition, subjects with rheumatoid arthritis show a significant decrease in species associated with good health (such as
Streptococcus,
Rothia aeria,
Kingella oralis,
Haemophilus, and
Actinomyces). A number of studies have analyzed the composition of the gut microbiome in the onset stages of rheumatic disease and observed differences from the control group of healthy patients; in particular, there is a decrease in
Bifidobacterium and
Bacteroides and an increase in
Prevotella [21][49]. Similarly,
Prevotella species show an increase in both saliva
[22][50] and subgingival microbiota of patients with RAL. Interestingly,
Prevotella copri shows a strong ability to induce Th17-related cytokine production, just as
Prevotella spp. is associated with Th17-mediated mucosal inflammation
[23][51]. Increased inflammatory mediators in the periodontal tissues of individuals with rheumatoid arthritis and other diseases may create favorable conditions for pathogenic bacterial species and promote the onset and progression of periodontitis
[24][25][52,53]. Local inflammation, amplified by systemic disease, may influence microbial composition toward an environment conducive to inflammation. The increased inflammation caused by RA, together with alterations in the microbiota, may amplify periodontal inflammation and explain the increased susceptibility to periodontitis observed by several researchers in these patients
[13][41]. Systemic and local inflammatory changes may thus alter the microbial balance and, consequently, increase bacterial pathogenicity and susceptibility to periodontal disease. In contrast, the treatment of RA improves gum status and affects the oral microbiome
[22][50]. Disease-modifying antirheumatic drugs reduce inflammation and RA severity by modifying the gut and oral microbiota
[22][50].
3. Oral Microbiota and Systemic Lupus Erythematosus (SLE)
SLE is an autoimmune condition characterized by persistent inflammation that causes tissue damage in various organs, including the kidneys, lungs, joints, heart muscle, and brain. Pathogenic causes leading to the onset of SLE include genetic and environmental factors and occur due to an imbalance in microbial composition
[14][26][42,54]. Regarding the oral cavity, symptoms of SLE are manifested by the occurrence of nonspecific oral ulcers
[27][55], dry mouth, a reduction in saliva production
[27][55], and an increased chance of developing forms of periodontal disease
[28][29][56,57]. A meta-analysis in the literature showed that there is a 1.76-fold increased risk of developing periodontal disease in SLE patients
[30][58]. This increased risk is associated with changes in the upregulation of both local and systemic inflammatory processes, as indicated by the elevated levels of cytokines (e.g., IL-6, IL-17, and IL-33) present in the saliva of patients with SLE
[31][59]. This dysregulation of inflammatory processes has been associated with an imbalance of the biofilm present at the subgingival level in patients with SLE. These observations have been documented in human studies. However, there are currently no focused studies in the literature that are able to establish a specific link between oral microbiota disturbances, inflammatory processes, and periodontal damage in SLE patients, as is demonstrated in patients with diabetes
[32][60]. Studies have shown that SLE patients have a higher bacterial load than healthy subjects
[14][42], which is associated with altered bacterial composition. High levels of
lactobacilli and
Candida albicans have been found in the oral cavity of SLE patients, which are present in lower amounts in healthy control patients
[27][55]. Subjects with SLE show a reduced microbial diversity and a greater presence of potentially pathogenic bacteria
[14][42]. Bacteria associated with periodontal disease, such as
Prevotella oulorum,
P.
nigrescens,
P. oris,
S noxia,
Leptotrichia, and
Lachnospiraceae, occur in higher percentages in SLE patients, even in periodontally healthy areas
[14][42]. On the other hand, bacteria commonly associated with periodontal health, such as
Capnocytophaga,
Rothia,
Haemophilus parainfluenzae, and
Streptococcus, are in a lower concentration in SLE patients who also have periodontitis. In addition, the presence of pathogenic bacteria correlates with the level of systemic inflammation, as analyzed and measured by the parameter and concentration from serum C-reactive protein
[14][42]. Overall, the onset and development of periodontal conditions correlates with systemic inflammation
[14][42]. Consistent with these findings, periodontal treatment appears to improve response to conventional therapy in patients with SLE by reducing disease activity and progression
[33][61]. Increased inflammation may be a source of nutrients formed as a result of tissue breakdown processes and may alter the environment by promoting the growth of bacteria, particularly anaerobic species
[34][62]. In turn, alterations in the microbiota could contribute to amplifying local inflammation and periodontal tissue damage, worsening the impact of systemic disease on periodontal health. Overall, these data highlight the link between microbiota and SLE, suggesting that a reduction in systemic inflammation due to SLE promotes the formation of a less pathogenic oral microbial profile. It has also been reported that changes in the gut microbiome of patients with SLE occur with greater diversity than in healthy individuals
[26][54]. In mice with lupus, a decrease in
Lactobacilli and an increase in
Clostridial species (
Lachnospiraceae) were observed, associated with an overall increase in bacterial diversity
[22][50].
4. Oral Microbiota and Cancer
The oral cavity is a unique environment within the digestive tract as it is openly exposed to the external environment. This characteristic differentiates it from other regions of the digestive tract and represents a challenge for the microbiota present in the area, as it must prevent colonization by external pathogenic microorganisms
[35][36][63,64].
Dysbiosis, an imbalance of the oral microbiome, has been associated with several oral pathologies according to recent studies
[36][37][64,65]. The most common and expensive chronic oral pathologies are caries and periodontitis. In addition, a link between the presence of oral dysbiosis and oral cancer has been established
[38][39][66,67]. Several studies showed an association between periodontal disease and an increased risk of cancer affecting distant organs
[40][68].
In addition, specific models of dysbiosis of the oral microbiome have been related to different types of cancer. For example, the increased colonization of
T. forsythia and
P. gingivalis in the oral microbiome has been associated with esophageal cancer
[41][69], while
P. gingivalis and
A. actinomycetemcomitans have been linked to pancreatic cancer
[42][70]. The genera
Fusobacterium and
Porphyromonas have been implicated in colorectal cancer
[43][44][71,72].
5. Oral Microbiota and Alzheimer’s Disease (AD)
AD is the major cause of dementia worldwide and the fifth leading cause of death in people older than 65 years
[45][46][47][48][49][50][51][73,74,75,76,77,78,79]. One hypothesis that has emerged is that there may be a contribution from bacteria with neuroinflammation and senile plaque formation
[52][80]. Soluble amyloid beta peptide (Aβ) is normally produced and degraded through enzymatic mechanisms
[53][54][81,82]. In AD patients, however, the brain performs insufficient degradation, leading to an accumulation of Aβ fragments
[52][80]. Moreover, the presence of these peptides impairs the degradation mechanisms of brain cells
[52][80]. An important role of Aβ peptides in the brain is the antimicrobial function in the case of brain infections. However, the prolonged presence of Aβ peptides, either due to recurrent infections or due to ineffectiveness in degrading them once they are no longer needed, can lead to the destruction of neighboring tissues
[55][83]. A study by Kato et al. showed that the presence of
P. gingivalis in mice, one of the red complex bacteria described by Socranski, increases intestinal permeability, whereby it facilitates the transfer of LPS across the intestinal barrier, fueling systemic inflammation
[56][84]. A study by Ilievski et al. showed that the pro-inflammatory mechanism caused by the repeated application of
P. gingivalis in mice also occurs at the brain level, causing neurodegeneration. Oral pathogens, such as the bacterium
P. gingivalis, have been studied using human postmortem brain tissue
[55][83]. Similarly, studies have been conducted on animal models, such as ApoE/mice and BALB/c mice that were free of pathogens, as well as on different spirochetes, which have been reported to co-localize with amyloid-beta (Aβ) plaques
[52][55][56][80,83,84]. In addition, the dysbiosis of oral and intestinal microbiota might play a role in promoting and accelerating the formation of Aβ plaques and neurofibrillary tangles
[57][85]. As explained above, periodontitis is a dysbiotic immunoinflammatory disease that can directly cause neuroinflammation
[58][59][60][86,87,88]. Several studies support that chronic inflammation associated with periodontitis can induce changes in the gut microbiota, increasing individual inflammatory responses
[61][89]. In addition, periodontitis has been observed to be associated with an increased risk of dementia, including AD, through mechanisms of systemic inflammation
[62][63][90,91]. Another study argues that the oral microbiota may influence AD risk through systemic access to the brain of the imbalanced strains of oral microbiota and hypothesizes a possible relationship between AD neuropathology and periodontitis through this mechanism
[64][92]. The first study considers the fact that chronic periodontitis is significantly related to an increased risk of developing AD and other age-related dementias
[65][93]. AD patients have also been shown to have a lower diversity of microorganisms in the oral microbiota than healthy subjects, indicating a specific oral dysbiosis associated with AD. In addition, oral pathogens such as
P. gingivalis may cause an alteration of the gut microbiota, which leads to intestinal inflammation and may be related to the onset and maintenance of neuroinflammation through the translocation of toxic bacterial proteases from the oral/intestinal environment to the brain
[64][66][67][92,94,95]. The significant consumption of fish rich in docosahexaenoic acid (DHA) has been reported to significantly reduce the likelihood of developing Alzheimer disease (AD). In addition, a daily intake of 900 mg of DHA may provide neuroprotection during the onset of cognitive deficits associated with early stage dementia
[68][69][96,97]. DHA is associated with several neuroprotective abilities, such as the inhibition of the signaling cascade between Toll-like receptors and cytokines. It has been found that lipid components of the diet can influence TLR receptor activation and associated immune and inflammatory responses. Recently, evidence has emerged linking TLR receptors to neurodegenerative conditions
[70][98]. A recent study by Ribeiro-Vidal et al. showed that both DHA and eicosapentaenoic acid (EPA) had a significant effect on reducing harmful bacterial strains, including
P. gingivalis,
A. actinomycetemcomitans,
F. nucleatum, and
Veillonella parvula, among others
[64][92]. In addition, several studies have been conducted on the effect of anthocyanins, a type of polyphenols, on preventing and improving specific clinical manifestations of progressive AD. A review of the literature concluded that the gut microbiota has a significant impact on the pathogenesis of AD, and that anthocyanin administration could clinically delay its development
[65][66][67][68][93,94,95,96]. A study conducted in 2020 showed the neuroprotective ability of cyanidin-3-glucoside (C3G) in a mouse model of AD
[68][96]. It is known that oral health status can influence overall health. Therefore, the prevention of oral disease and inhibition of proteases produced by bacteria such as
P. gingivalis and other bacteria associated with periodontitis and AD may help reduce the neurodegenerative disease
[69][70][97,98]. Several studies showed that the oral microbiota can easily reach the gut or lungs in people with compromised immune systems, causing systemic health problems and inflammation
[70][71][72][8,11,98].
6. Oral Microbiota and Cardiovascular Diseases
It has been observed that certain bacteria, including
P. gingivalis, can potentially increase the risk of developing cardiovascular disease by acting on autoimmunity and in metabolic syndromes, causing alterations in the metabolism of amino acid chains and in the host immune feedback
[71][8]. The cytokine-mediated pro-inflammatory response may undergo upregulation by the increased
Firmicutes/Bacteroidetes ratio; this increased response may contribute to the development and progression of cardiovascular disease
[67][95]. Epidemiological studies reported in the literature indicate that various types of bacterial infections, such as
Helicobacter pylori,
C. pneumoniae,
P. gingivalis,
F. nucleatum,
A. actinomycetemcomitans, and
P. intermedia, and the presence in serum of metabolites from these products, such as lipopolysaccharides, are implicated in the development of atherosclerosis. It has also been observed that inflammatory risk factors associated with myocardial infarction have a similar profile to those involved in periodontitis, suggesting a common pathway of atherogenesis related to systemic inflammation. In addition to oral immunity, the oral microbiome also regulates and modulates the gut microbiome, which can go into dysbiosis, resulting in the disruption of the gut barrier and subsequent systemic inflammation. Studies conducted on nitrates, which are present in large amounts in food products such as meat, vegetables, particularly beets, lettuce, and spinach, and in drinking water, have led to findings showing prebiotic potential for the oral microbiota
[70][73][74][10,98,99]. These data were derived from a study examining the cardiovascular benefits of nitrates in foods. In this study, the profiles of the bacteria that make up the oral microbiome were measured, and it was observed that in 65 hypercholesterolemic subjects who had randomly received 250 mL of nitrate-rich beet juice or a placebo juice for 6 weeks, the percentage of two nitrate-reducing bacterial species (
Rothia mucilaginosa and
Neisseria flavenscens) was significantly increased. These strains are themselves associated with periodontal and dental disorders. In another study, the microbiome on the tongue of subjects who were subjected to a diet of beet juice enriched in inorganic nitrate for 10 days was analyzed, and then bacterial 16S ribosomal RNA genes were sequenced. It has been observed that nitrate is converted to nitrous oxide, which induces a lowering of blood pressure
[70][98]. Emerging data showed that an increased presence of the oral bacteria
Prevotella and
Veillonella is detrimental, while the bacterial strains
Rothia and
Neisseria play a beneficial role in the homeostatic maintenance of nitric oxide and for associated rates of cardiovascular disease, as well as improved blood pressure
[70][74][75][76][98,99,100,101].