Oral Cavity is the Gateway to the Body: Role of Oral Health Professionals: A Narrative Review

ABSTRACT

Background

The oral cavity is the most important link between the human body and the external environment and is well-equipped to protect the body against invading pathogens. Emerging data on the bidirectional relationship between oral health and the severity of COVID-19 symptoms has prompted us to reexamine our role as the guardians of the oral cavity - the true gateway to the body. Recent studies have shown that the oral microbiome is a complex ecological system and the interactions between its residents and the host cells influence human health and disease. This narrative review elaborates on the oral-systemic connection from an oral microbiome standpoint and discusses the future role of oral health professionals.

Methods

A PubMed literature search using the keywords “Oral Microbiome and Diseases” and “Oral microbiome and Health” for a range of ten years between 2012-2022 was completed. Meta-Analyses, Reviews, Randomized Control Trials, Clinical Trials, and books were included in the search.

Results

“Oral microbiome and Diseases” yielded 6392 results and “Oral microbiome and Health” yielded 4287 results.

Conclusion

Oral health professionals need to be trained on the oral-systemic connection periodically to appreciate the recent advances in this field.

Practical Implications

A deeper understanding of the impact of existing treatment modalities on the oral microbiome could expand the role of oral health professionals in preventing and maintaining patients' overall health. Implementing point-of-care salivary diagnostics to detect salivary biomarkers for oral and non-oral diseases and conditions may be a significant leap toward this goal.

KEYWORDS:

• Oral microbiome
• salivary diagnostics
• point-of-care salivary diagnostics
• oral systemic connection
• cytokines
• oral-gut-lung-brain axes

Introduction

The oral microbiota has 700 species of different taxa of microorganisms in various sites of the oral cavity including bacteria, fungi and viruses, whereas the oral microbiome is the collective entity that includes the microorganisms, the extracellular matrix, protein signals, molecular communications, enzymatic byproducts and other interactions with the host cell.¹ With the recent advances in culture independent, next-generation sequencing (NGS) techniques, polymerase chain reaction (PCR), gel-based techniques and DNA microarrays, it is possible to analyze the genomes and their activity in the oral microbiome.² The healthy oral microbiome provides colonization resistance to pathogenic invaders of the mucosal barrier in the mouth. The commensal bacterium of the oral microbiome is predominantly comprised of the phyla Actinobacteria, Proteobacteria, Firmicutes, Bacteroidetes and Fusobacter with a smaller number of Spirochetes. The fungal members of the oral microbiome include Candida, Cladosporium, Aureobasidium, Saccharomyces, Aspergillus, Fusarium and Cryptococcus. The saprophytic protozoa include Entamoeba gingivalis and Trichomonas tenax.³ The salivary microbiome has 17.5% of Streptococcus, 15.5% Prevotella, 15.3% Veillonella, 12.7% Neisseria and 10% Haemophilus.⁴ The viruses found in the oral microbiome are bacteriophages and are very different from the viruses inhabiting other parts of the body.⁵ These bacteriophages function by releasing lytic enzymes that can wipe out bacterial communities and change the composition of the oral microbiome.⁶ Other viruses include 66% herpesviruses, 24% retroviruses and 1.2% papilloma viruses. The oral virome and its function are poorly understood, and researchers believe that they may act as hubs for gene function resulting in infections.⁷ Now, with the COVID-19 pandemic, the salivary glands may serve as a reservoir of SARS-CoV-2 viruses, even in asymptomatic carriers.⁸

Several mechanisms in the oral cavity protect the symbiotic relationship between the microbiome and the host cells to maintain homeostasis. The microbial interactions could be between different species such as bacteria interacting with fungi and protozoa in the microbiome. The results of these interactions could be positive, negative or neutral. Secondary metabolites are important for such communications. An example of such a system is quorum sensing activated by small molecules, such as the peptides, to help bacteria adapt to the host environment and adhere to a biofilm.⁹ Direct interspecies electron transfer is another communication channel in anaerobic systems.¹⁰ Saliva has antimicrobial components, secretory immunoglobulin A and the buffering capacity to alkalinize the pH of the oral cavity. The glycoproteins in the saliva influence the attachment apparatus of microbes entering the mouth and contribute to the immune response.¹¹ Salivary glands produce copious amounts of nitrite into the saliva that converts it into nitric oxide, adding to the antimicrobial properties.

When there is a disruption to the composition, activity and function of the oral microbiome, it causes dysbiosis. The major categories influencing the microbiome are age, host, environment, habitat and biofilm maturation. The subcategories include age-related physiological changes, habits, transfer of microbes from the external environment, genetics, lifestyle, immune responses, medications, hormonal changes, living environment, nutrition, oral hygiene, pH and salivary rate and volume, molecular biochemistry in the oral biofilm, probiotic, the extracellular matrix, etc.¹² Dysbiosis of the oral microbiome in turn causes pro-inflammatory reactions orally and elsewhere in the body, causing oral and non-oral diseases. The main pathways are through the bloodstream via a bacteremia, endotoxins from oral pathogens circulating and causing damage and immune responses to oral pathogens and endotoxins initiating a cascade of reactions, causing further damage.¹³

A literature review of the past 10 years (2012–2022) was performed in PubMed using the keywords “oral microbiome and diseases” and yielded 6,392 results (Figure 1).

Figure 1. PubMed Results.

Non-Oral Diseases

Table 1 is a concise summary of articles and results with clinical relevance.

Table 1. Oral microbiome and its influence on non-oral diseases.

Article information	Non-Oral Disease	Significant Results	Clinical relevance
Abdelbary et al., Kitamoto et al., Atarashi et al., Qi et al., Zhao et al.^Citation14–18	Gastrointestinal diseases	Five genera, Veillonella, Prevotella, Megasphaera, Atopobium and Rothia, were highly abundant. Depletion of Proteobacteria, Fusobacteria and Patescibacteria in patients with inflammatory bowel disease (IBD) compared to the healthy subjects.	Antimicrobial stewardship to prevent oral and gut dysbiosis; improper use of antibiotics could potentiate oral and gut dysbiosis; innovative therapy could include isolated commensals from healthy individuals and introducing into IBD patients (Koch’s commensal postulates).
		P. gingivalis and F. nucleatum were enriched in colonic mucosa of IBD patients.
Kuraji et al., Yoneda et al., Abe et al., Rao et al., Bajaj et al.^Citation19–23	Liver disease	The frequency and virulence of P. gingivalis (Type II) are significant predictors in the development and progression of non-alcoholic fatty liver disease.	Periodontal therapy reduces oral and systemic inflammation in cirrhotic patients, especially with hepatic encephalopathy; improves the model for end-stage liver disease (MELD) score and restores the ALT/AST levels in patients with NAFLD; improves quality of life for cirrhotic patients. Oral biomarkers could be an early and noninvasive diagnostic tool for autoimmune hepatic diseases.
Xiao et al., Matsha et al., Negrini et al., Isola et al.^Citation24–27	Diabetes	Receptors for advanced glycation end products(RAGE) levels are raised in diabetics and could be used as a biomarker for potential complications from diabetes. NOD-Like receptor pryin domain 3 protein is an inflammasome that is highly elevated in patients with periodontitis and diabetes.	Bidirectional relationship between diabetes and periodontitis warrants a careful monitoring of both diseases when present in the same patient. Diabetes increases the pathogenicity of oral pathogens, resulting in increased periodontal bone loss and inflammation.
Coker et al., Keller et al., Li et al., Yang et al.^Citation28–31	Obesity	Bifidobacterium and Lactobacillus species were associated with decreased obesity, lower BMI. Longitudinal studies found a positive correlation between obesity at baseline and development of periodontitis	Obese patients may be at high risk for periodontal disease. Nonsurgical periodontal treatment may not be effective in obese patients. Oral microbiome analysis may help intervene in patients with weight gain and prevent obesity.
Giordano-Kelhoffer et al., Bartova et al, Zhang et al., Blekkenhorst et al., Koch et al., Hezel et al., Kapil et al., Pussinen et al.^Citation32–39	Cardiovascular diseases	High levels of Prevotella and Veillonella indicate a high risk for cardiovascular events. High levels of Rothia and Neisseria are important for nitric oxide metabolism that is essential for heart health. P. gingivalis-Several mechanisms facilitate the formation of atherosclerotic plaques and progression of disease	Patients with periodontitis have a 25% to 50% higher chance of cardiovascular disease compared to patients in periodontal health. Pulmonary hypertension, atherosclerosis, cardiovascular events, and obesity are related to the levels of nitric oxide that has a tremendous influence on the vascular response to oxidative stress. Lipopolysaccharides are endotoxins. These are byproducts of gram-negative periodontal bacteria, and they cause endotoxemia when they travel in the bloodstream and cause severe chronic inflammation in distant sites, leading to cardiometabolic syndromes. Chlorhexidine mouth rinses reduced the oral nitrite in the mouth by 90% and the plasma concentrations of nitrite by 25% leading to an increase of 2–3.5 mmHg in systolic and diastolic BP within one day of the seven-day treatment.
Kumar et al., Pathak et al., Mammen et al., Willis et al., Bassis et al., Didilescu et al.^Citation40–45	Respiratory diseases	Oral microbiome in smokers showed unstable, increasingly diverse pathogens that were gained early and colonized the oral biofilm. Various hypotheses were developed for mechanisms involving the oral microbiome being transferred to the lungs as in aspiration.	By educating other healthcare providers and caregivers on the importance of the oral systemic connection, it is possible to improve pulmonary health. Low salivary pH and abundance of C. albicans in the oral cavity of patients with cystic fibrosis leads to high caries rate and frequent oral infections. Frequent antibiotics for these oral infections could further contribute to oral dysbiosis.
Fleury et al., Fan et al., Liu et al.^Citation46–48	Neurodegenerative diseases	Oral phos-alpha synuclein in submandibular glands may result in reduction of salivary production and dysphagia. High levels of P. gingivalis in the oral cavity and brain of patients with Alzheimer’s disease (AD) showed that oral dysbiosis was moderately associated with risk for development of AD.	High levels of pro-inflammatory cytokines in the saliva and increases in caries and periodontitis pathogens in the oral cavity in the absence of active disease is an indication for progression of Parkinson’s disease. Dysphagia and reduction in volume of saliva could be early indication of Parkinson’s disease. Amyloid beta 1–42 may be a noninvasive salivary biomarker for Alzheimer’s disease.
Li et al., Simpson et al., Wingfield et al., Ahrens et al.^Citation49–52	Psychiatric disorders	Oral microbiome specifically on the dorsum of tongue were associated with symptoms of anxiety and depression in a large study in the U.K. Salivary cortisol levels and circulating C-reactive protein may play an important role in initiating mood-related disorders in adolescents. Increased levels of Neisseria spp and Prevotella nigrescans were observed in DSM-IV category young adults with depression.	These studies systematically explored the relationship between the oral microbiome and anxiety and depression, which could help improve our understanding of disease pathogenesis and propose new diagnostic targets and early intervention strategies. Periodontitis could be a risk factor for development of depression at a later stage.
Yuan et al., Fang et al., Alwithanani et al., Liu et al.^Citation53–56	Genitourinary diseases	F. nucleatum and P. gingivalis influence the cell signaling to escape cell death and promote cancer cell growth through intracellular and intercellular pathways. Pseudomonas had an inverse relationship to the presence of immunoglobulin G in patients with chronic kidney disease.	Periodontal therapy improved prostate function score in patients with periodontal and prostate diseases. Oral pathogens may spread via the bloodstream directly or indirectly via proinflammatory cytokines that may potentiate chronic inflammation of the prostate. A reduction in prostate-specific antigen was observed after periodontal therapy in patients with prostate disease. Compliance of patients with prostate and periodontal disease could be the key to positive outcomes. Measuring Pseudomonas could be a biomarker in chronic kidney disease and saliva transplants could be therapeutic.
Lee et al., Meurman et al., Nacler et al., Peters et al., Castellarin et al., Gaba et al.^Citation57–62	Cancer	P. gingivalis has special mechanisms that help evade immune recognition and apoptosis of infected gingival epithelial cells. Viridans streptococci and Candida in the oral cavity utilize enzyme alcohol dehydrogenase to metabolize alcohol to acetaldehyde which is a carcinogen. Acetaldehyde in the saliva of patients with poor oral hygiene is considerably higher than those with good oral hygiene. This may explain the association of oral microbiota to oral cancer. Human cytomegalovirus (HCMV) was detected in the tumor tissue in a wide variety of cancers including breast, colon, prostate. HCMV targeted tumor cells and promoted carcinogenesis by complex interactions that evaded immune responses and apoptosis and increased tumor angiogenesis. T. forsythia was associated with a high risk for esophageal adenocarcinoma (EAC) and P. gingivalis was associated with high risk for esophageal squamous cell carcinoma (ESCC). F. nucleatum, a keystone periodontal pathogen, has been isolated in tumor cells of colorectal cancer patients and with metastasis to lymph nodes. F. nucleatum has been isolated in breast tissue of female breast cancer patients.	There is potential for early detection of HCMV in saliva for prevention and improving prognosis in cancer patients. Microbial networks and interactions with commensals would be the key to understanding the possibility of early detection of EAC and ESCC. Directing more attention to the F. nucleatum species during different stages of breast cancer would help develop precision therapy for women who are at high risk for breast cancer.
Cobb et al., Balan et al., Ye et al., Wang et al.^Citation63–66	Adverse pregnancy outcomes	Adverse outcomes in pregnancy could be due to intrauterine infections or intraamniotic infections F. nucleatum, a keystone pathogen, is responsible for intrauterine infections. Keystone pathogens Prevotella intermedia and P. gingivalis are responsible for pregnancy gingivitis. Culture-independent methods concluded that Bergeyella and F. nucleatum-caused intraamniotic infections and sepsis in newborn infants. Study showed evidence that low levels of commensal Neisseria were responsible for preterm low-birth-weight babies.	Periodontal therapy interventions must be directed to both parents and before conception as well as every three months during pregnancy to prevent adverse outcomes.
Cheng et al., Correa et al., Hajishengalis et al., Tseng et al.^Citation67–70	Autoimmune diseases Systemic lupus erythematosus (SLE) Rheumatoid arthritis (RA) Sjogren’s syndrome	Lowered diversity and increased abundance of periodontal pathogens were found in the oral cavity of patients with SLE, independent of presence of periodontitis. This confirms the pathogenicity of periodontal pathogens in causing systemic diseases. Anticyclic citrullinated peptide (anti-CCP) in subgingival microbiomes of patients who were at risk for arthritis proved that increase in P. gingivalis and anti-CCP may be triggers for RA. P. gingivalis promotes the production of IL-6 which in turn activates osteoclastic progenitor activity leading to bone loss, such as in RA.	Salivary gland epithelial cells are the center of activation of the autoimmune response resulting in Sjogren’s syndrome. H. parainfluenzae may be a key microbe in this immune modulation.

Interesting mechanisms of oral microbiome and its interactions with the host in causing systemic diseases are described below.

Gastrointestinal Disease ^14–18

The pathophysiology of oral microbiota invading the gut is investigated in a study by Kitamoto et al. who proposed that gut dysbiosis could be a requirement for colonization by oral microbiota. Though the gastric acid may be a successful barrier for most pathogens, oral microbiota-like P. gingivalis is acid resistant and crosses the stomach barrier. The researchers examined the role of oral microbes such as Fusobacterium nucleatum, Fusobacterium varium and P. gingivalis in the gut and their mechanisms of damage in the gut. It is highly possible that an overgrowth of oral microbes leads to migration to the gut to colonize it and cause diseases. Fusobacterium nucleatum utilizes matrix metalloproteinases (MMPs) and lipopolysaccharides to invade the gut and promote tumor cell proliferation, chemotherapy resistance and immune evasion. Fusobacterium varium potentiated adhesion and invasion of gut cells. P. gingivalis acted as an antiapoptotic and promoted cell proliferation. The fact that MMPs play an important role in the progression of gut tumors, and oral microbiota residing in tumors of the colon could be responsible for metastasis. The oral bacteria Klebsiella may be the connection between oral and gut microbiome in colonizing and inducing certain types of irritable bowel syndrome.

Liver Disease ^19–23

Primary biliary cholangitis (PBC) and autoimmune hepatitis (AIH) are both autoimmune conditions affecting the liver. Studies have shown the connection between dysbiosis in the oral-gut axis causing inflammation in the liver. Veillonella dispar is a lipopolysaccharide-producing bacterium found in abundance in the saliva of patients with AIH, and it is unclear if the liver disease caused this change in the oral microbiome or vice versa. Both Veillonella and Eubacterium are increased in patients with PBC, with a decrease in the frequency of Fusobacterium, compared to healthy subjects. P. gingivalis, a periopathogen, has an adverse effect on nonalcoholic fatty liver disease and may even hasten the progression to carcinoma of the liver. This highlights the need for further research on the oral-liver axis of the microbiome.

Diabetes

Oral microbiome dysbiosis has been found to be responsible for the initiation and progression of diabetes mellitus. Patients with diabetes mellitus had an abundance of Fusobacteria and Actinobacteria and a decrease in Proteobacteria compared to healthy patients.^24–27

Obesity

Coker et al.²⁸ examined the variation in oral microbiome in 3- and 4-year-old preschool children and gathered data on the diversity of the oral microbiome, body mass index and overweight status. They identified that phylum Firmicutes, Actinobacteria and Bacteroidetes were associated with weight gain in the first 2 years of life. The diversity of the oral microbiome was found to be decreased as the BMI increased. The conclusion was that the changes in body composition impacted the diversity of the oral microbiome, leading to increased risk factors for developing diseases in adult life. This process has immune modulating effects because of gut and oral microbiome dysbiosis. This is an important interaction in the oral-gut axis.^29–31

Cardiovascular Disease

Giordano-Kelhoffer et al.³² did a systematic review on articles published between January 2003 and April 2022 on the oral microbiome and its impact on systemic diseases. Evidence showed that individuals with periodontal disease had a 25% to 50% higher chance of developing an adverse cardiovascular event than individuals without periodontal disease.³³ The bacterial products released into the blood activate pro-inflammatory processes and facilitate the progression of cardiovascular disease. Additionally, the immune system is also triggered to react to this resulting in further damage to the circulatory system. Blekkenhorst et al.³⁴ examined the role of oral microbiome in nitrate metabolism that directly affects cardiovascular health. Koch et al.³⁵ studied the connection between nitrate metabolism and cardiac and pulmonary health. According to this study, the pathophysiology of pulmonary hypertension, obesity, hypertension and cardiovascular disease are all the result of poor nitrate metabolism by oral microbiome. Hezel et al.³⁶ traced the uptake of nitrate into the parotid salivary glands (25%) from food such as leafy green vegetables, recirculation into saliva and conversion to nitric oxide after commensal bacteria act on it. Rothia mucilaginosa and Neisseria flavescens in the oral microbiome were responsible for the nitrate-to-nitrite metabolism.³⁷ Chronic endotoxemia due to lipopolysaccharide producing gram-negative bacteria from periodontitis, may be responsible for local and systemic inflammation that is responsible for many of the cardiometabolic conditions.³⁸

Increased numbers of P. gingivalis, increased Firmicutes/Bacteroidetes ratio in the oral microbiome may be an indication for an upregulation in the inflammatory response, mediated by cytokines. Metabolites such as lipopolysaccharides from bacterial infections of P. gingivalis, Helicobacter pylori, Chlamydia pneumoniae, Prevotella intermedia and A. actinomycetemcomitans may be responsible for the development of atherosclerosis.³⁹

Respiratory Diseases

Smokers have a diverse, unstable, early colonizations of oral biofilms with periodontal pathogens such as Fusobacterium, Cardiobacterium, Synergistes and Selenomonas genera and respiratory pathogens belonging to the genera Haemophilus and Pseudomonas compared to nonsmokers.⁴⁰

The oral cavity is anatomically positioned to translocate microorganisms to the lungs either by aspiration or through the bloodstream. Studies on the composition of the lung microbiome have a great overlap between oral microbiomes.^41,42 One very old theory posits that dysbiosis from the oral cavity results in migration of pathogens and their metabolites to other parts of the body causing diseases.⁴³ Many studies have shown that there is a continuity of the microbiome from the nasal passages and oral cavity to the upper respiratory tract and lungs as well as the gut.⁴⁴ Overall, the oral-lung axis may exchange components of their microbiome in health and disease, as confirmed by a study that found respiratory pathogens in the teeth of patients in intensive care units.⁴⁵ In chronic obstructive pulmonary disease (COPD), researchers have found that the “vicious circle hypothesis” results in smoke-related injury to the lungs and dysbiosis of the lung microbiome causing poor immune responses, which leads to complications.⁴⁶ In cystic fibrosis, studies found less diversity in the oral and lung microbiome, with an abundance of candida in the mouth and lungs, along with an increased number of oral and respiratory pathogens.⁴⁷

Neurodegenerative Diseases

Alzheimer’s disease is a chronic inflammatory disease of the brain resulting in tissue destruction. The presence of proinflammatory cytokines and lipopolysaccharides from T. denticola, T. forsythia and P. gingivalis suggests that oral microbiota plays an important role in disease progression of Alzheimer’s disease. Inversely, disease processes in the brain have affected the oral microbiota as well. Because gram-negative bacteria are implicated in oral dysbiosis and amyloid production in the brain, interventions aimed at this process could be a focus in the future research.^48–50

Psychiatric Disorders

Many studies examined the diversity of the oral microbiome and dysbiosis and found correlations between increased levels of Neisseria spp. and Prevotella nigrescens and depression in young adults.^51–53 Ahrens et al.⁵⁴ performed an interesting study to show the correlation between salivary microbiome and suicidal tendencies in college students. Along with the salivary microbiome, major histocompatibility complexes (MHC) were also compared between 47 students with a history of suicidal thoughts and 325 control subjects. The absence of four specific types of MHC in the students with suicidal tendencies was a stark contrast to others. They were also missing Alloprevotella rava, which produces an organic acid for brain homeostasis. The study concluded that depression was in fact an inflammatory disease and warranted further research on human leukocyte antigen (HLA) complexes and their role in depression.

Genitourinary Diseases

P. gingivalis and F. nucleatum may potentiate chronic inflammation of the prostate. Periodontal therapy reduced the levels of prostate-specific antigen in older patients. Levels of Pseudomonas could be measured as a biomarker for patients at risk for chronic kidney diseases.^55–58

Cancer

Several studies in the last two decades have provided an association between colonization of specific bacteria in the oral microbiome and types of cancer.^59–64 The mechanism of involvement of the oral microbiome could be manifold. Chronic inflammatory mediators from periopathogens help with unregulated cell growth, mutagenesis and oncogene activation. P. gingivalis is suggested to be antiapoptotic due to the metabolism of nucleoside-diphosphate-kinase homolog, which is an enzyme in bacteria. S. gordonii, S. mitis, S. oralis, S. salivarius, S. sanguinis and Candida produce carcinogenic substances such as acetaldehyde from ethanol and other sulfuric compounds that promote gene mutations resulting in oral cancer. Cytomegalovirus has been associated with oral cancer due to its immunosuppressive and antiapoptotic properties. Esophageal cancer is associated with increased numbers of T. forsythia and P. gingivalis. P. gingivalis and A. actinomycetemcomitans have been implicated in pancreatic cancer. Fusobacterium nucleatum, a commensal in the oral cavity, has been identified in 30% of patients, with colorectal cancer revealing the role in progression to cancer.

Adverse Pregnancy Outcomes

Recent studies on periodontal therapy interventions during the second trimester did not see strong evidence on reduction of adverse pregnancy outcomes. This may be due to migration of oral pathogens before conception. Pregnancy gingivitis is associated with an increase in P. intermedia in the oral biofilm. Chronic periodontal infections cause pro-inflammatory cytokines to be released into the body, causing a systemic response. Though not abundant, the pathogens involved in periodontitis, Prevotella intermedia and P. gingivalis, are involved in adverse outcomes in pregnancy such as preterm delivery and low birth weight.^65–68

Autoimmune Diseases

Research shows that autoimmune diseases like rheumatoid arthritis could have keystone pathogens as triggers. The autoimmune response initiation for Sjogren’s syndrome is in the salivary gland tissues.^69–72

Age-Related Changes

The oral microbiome is affected by age-related changes. In a study comparing the oral and gut microbiomes of healthy aging individuals versus nonhealthy aging individuals (those with one or more chronic diseases) aged 70 t0 82, the salivary microbiome had more alpha diversity in the healthy aging individuals. Akkermansia muciniphilia and Erysipelotrichaceae UCG-003 were abundant in healthy aging, while Streptococcus was decreased in number. It is believed that these microbes are abundant because they function as probiotics.⁷³

Effect of Medications on Oral Microbiome

Amoxicillin is the most prescribed antibiotic for oral infections. One study investigated the effect of this antibiotic on the oral microbiome and found imbalances in 35 taxa of microorganisms that reduced the richness and the diversity of the oral microbiome considerably, and the recovery was incomplete even after 3 weeks.⁷⁴

Oral Diseases

An in-depth study by Socransky and Haffajee in 1998 published certain criteria to be classified as key perio pathogens. Aggregatibacter actinomycetemcomitans and Porphyromonas gingivalis fulfill these criteria. They classified all the bacteria involved in periodontitis into six colored complexes that were indicated in health and disease⁷⁵ (Table 2).

Table 2. Bacterial Complexes in Six Colored Groups.

Health (H) or Disease (D)	Bacterial Complexes	Color
H	Actinomyces	Purple
	Veillonella
H	Streptococcus: gordonii, intermedius, mitis, sanguis	Yellow
H	Capnocytophaga	Green
	E. corrodens
D	Campylobacter rectus	Orange
	Fusobacterium nucleatum
	P. micros
	P. intermedia
D	T. forsythia	Red
	T. denticola
	P. gingivalis
D	A. actinomycetemcomitans	Not grouped
	Selenomonas

A meta-analysis reviewed the studies that utilized saliva samples and subgingival plaque samples to detect red complex bacteria in more than 60% of the patients with periodontitis. Recent research has highlighted the importance of the interaction between the oral microbiome with the host cell under specific circumstances resulting in a “personalized pathology” of periodontitis.^76–78

Peri-implant microbiota has been shown to be less diverse and less variable with a healthy peri-implant environment with mostly Streptococcus (45% to 86%) in the supragingival and subgingival sites. In peri-implantitis, 12 species were enriched, with the red complex bacteria colonizing the most followed by P. endodontalis, F. fastidiosum, Prevotella intermedia and F. nucleatum. Of these, F. nucleatum was closely associated with peri-implant mucositis.⁷⁹

Caries is a multifactorial oral disease and has been researched extensively.⁸⁰ It is manifested as a cavitation due to the presence of three factors: aciduric bacteria, carbohydrates from diet and host factors. The process starts with the biofilm in the oral cavity and factors resulting in dysbiosis. Once dysbiosis occurs, certain cariogenic bacteria like Bifidobacterium dentium, Bifidobacterium longum and S. mutans, S. salivarius and A. viscosus and Firmicutes strains are increased in numbers compared to Bacteroidetes.⁸¹ Cariogenic microorganisms produce acid that reduces the pH of the oral environment, causing demineralization of the enamel and further loss of tooth structure. Streptococcus mutans, non-mutans Streptococci, Lactobacillus and Actinomyces are involved in this process. Another study reported the beneficial role of the oral biofilm in replenishing nutrients to increase the protective factors of saliva.⁸² New techniques in genomic analysis have revealed the presence of extracellular polymeric substances (EPS) in the biofilm that is related to virulence factors of pathogenic bacteria like mutans streptococci in early childhood caries.⁸³

Role of Salivaomics in Early Detection of Oral and Systemic Diseases

Salivaomics is the study of the various components of saliva and the genomics, proteomics, transcriptomics, metabolomics and microbiomics.⁸⁴ Emerging technology that detects specific biomarkers in saliva could be revolutionary in terms of personalized and precision medicine.⁸⁵ This biomarker technology can be used in all branches of health care to facilitate prevention, diagnosis, prognosis and management of diseases and conditions. Saliva could be easily utilized in point-of-care applications at medical and dental offices because of convenient collecting and testing. The FDA-NIH defines biomarkers as “defined characteristics that (are) measured as indicator(s) of normal biological processes, pathogenic processes or response to an exposure or intervention, including therapeutic interventions.”⁸⁶ Biomarkers in the biofluids could be classified into susceptibility biomarkers; screening and diagnostic biomarkers; prognostic biomarkers; predictive biomarkers; response or safety biomarkers; and monitoring biomarkers.

The identification of biomarkers in biofluids especially saliva is an inexpensive, noninvasive method for prevention, early diagnosis and therapeutic interventions for many oral and systemic diseases. Human whole mouth saliva (WMS) contains DNA, RNA, microRNA, messenger RNA, proteins, peptides, cytokines, profilin, transferrin and many more biomarkers that indicate premalignant lesions and cancer in the oral cavity.⁸⁷ MicroRNA as a biomarker could be significant for certain types of cancer and inflammatory and autoimmune conditions.⁸⁸ Salivary cortisol levels have been used as a biomarker for oral lichen planus.⁸⁹ Measuring levels of uric acid could be a diagnostic for metabolic syndromes, cancer, neurological conditions, HIV, psychiatric conditions and gout.⁹⁰ Patients with Crohn’s disease had decreased activity of antioxidants and increased lipid peroxidation. Salivary diagnostics show that malondialdehyde is a good biomarker for Crohn’s disease along with overexpression of certain types of microRNA.⁹¹ Salivary diagnostics in a patient with Sjogren’s syndrome has detected twice the amount of lipids and elevated level of IgA, IgG, IL-6, prostaglandins and antibodies compared to healthy individuals. Some salivary biomarkers for Sjogren’s syndrome are profilin, anhydrase-I, IL-4 and IL-5. C-reactive proteins, cardiac troponin and creatinine phosphokinase are whole-mouth salivary biomarkers for cardiovascular diseases.⁹² A recent study found differences in salivary versus serum in levels of glucose, amylase, calcium and phosphorus in diabetic versus nondiabetic patients.⁹³

One study utilized nuclear magnetic resonance (NMR) metabolomics⁹⁴ to understand the biomarkers responsible for the diagnosis and prognosis and monitoring of several types of oral and systemic cancers.⁹⁵ The data collected from this study may be used to design targeted therapy and interventions for patients.

The biggest limitation has been difficulty in finding specific biomarkers for oral and systemic diseases. Most of the biomarkers already discovered from various research are generic biomarkers of inflammation or infection. Moreover, the presence of biomarkers in the saliva is influenced by many factors such as the circadian cycle, diet and so on. The challenges of implementing point-of-care salivary diagnostics are understanding the collection guidelines, storage and processing protocols and the need for improvement in the standardization. Further studies on the specificity and the sensitivity of these salivary diagnostics are required for accuracy. In summary, point-of-care salivary diagnostics could be the answer to understanding the oral systemic connection and dysbiosis in the oral-gut-brain-liver-lung axes and addressing the needs of our patients with complex medical needs.⁹⁶

If implemented into clinical practice, salivary diagnostics could lead to a paradigm shift in treatment of oral and systemic diseases with a focus on the reversal of dysbiosis⁹⁷ and targeted interventions aimed at the microbial interactions in the microbiome including phage therapy, probiotics and prebiotic supplements,⁹⁸ photodynamic therapy, quorum-quenching therapy, antibiotics bound to nanoparticles (NP) or oral microbiome transplants.

Conclusion

Although there have been multiple studies on the oral dysbiosis and its effects on systemic diseases; this is just the tip of the iceberg with regard to understanding the complexity of the relationship between the host cells and the oral microbiome. Further research on the unculturable oral microbiota may be essential to map out the key players that initiate, facilitate and advance oral and non-oral diseases. The first step is to periodically educate and train oral health-care professionals on this crucial topic. The next step is to implement salivary diagnostics as part of screening at routine dental visits to assess risk factors. Educating other health-care providers and forming alliances with them to coordinate care would elevate the quality of care and improve outcomes. Longitudinal studies on dysbiosis and treatment outcomes aided by salivary diagnostics may be the future. Translational research on designing precision medicine that is directed toward prevention is the goal.

Additional information

Notes on contributors

Parvati Iyer

Parvati Iyer is a tenure-track Assistant Professor in the Department of Diagnostic Sciences at the University of the Pacific, School of Dentistry. After graduating from the University of Michigan, School of Dentistry, and completing a residency in Hospital Dentistry at the University of California San Francisco, she practiced cosmetic dentistry in Scottsdale, AZ. She has been an academic since 2011 and has developed an identity as an educational researcher. Parvati is the recipient of the Omicron Kappa Upsilon Charles Craig Award for Teaching Innovation in 2020 and is passionate about promoting critical thinking, utilizing technology to teach, and increasing student engagement in an integrated curriculum. She is a Fellow of Pierre Fauchard Academy, ADA, CDA, and the San Francisco Dental Society.