Oral Probiotics: A Window to Novel Therapeutic Possibilities for Gum Disease

Host-associated bacteria exist on a continuum, from commensals with low virulence and beneficial properties to disease-causing pathogens whose colonization can be deadly.¹ As microbiomes evolve, their metabolites, interspecies interactions, and the host immune compartment can cause changes to the bacterial niche that facilitate the outgrowth of microorganisms associated with a dysbiotic state; this, in turn, can favor colonization with an infectious agent, stimulate the production of virulence factors, or exacerbate dysfunctional immune or metabolic states in the host to promote disease.² Commensal organisms provide protection from pathogenic species in several ways, including colonization resistance, stimulation of the host immune response, and interbacterial chemical warfare.^3,4

The human oral microbiome is a dynamic and diverse ecological niche which colonizes distinct microenvironments, including the hard surfaces of the teeth as well as epithelial surfaces of the mucosa.⁵ The ability of oral microbiota to self-assemble into site-specific biofilms mediates oral microbiome-host interactions and can produce different innate immune responses depending on the specific bacterial stimuli. For example, the overgrowth of subgingival bacteria, such as those associated with periodontitis, can induce dysbiosis and inflammation. The inflammation activates the systemic immune response through neutrophil priming in circulation.⁶ On the other hand, oral bacteria have been detected in distant body sites, including the intestine,⁷ lungs,⁸ heart,⁹ and brain.¹⁰ This necessitates the development of novel therapeutics to prevent the overgrowth of disease-associated bacteria in the oral cavity to limit the dissemination and initiation of distal diseases.

Examples of correlation between Oral bacteria and Systemic diseases

Oral microbes alone are not able to initiate systemic diseases, and this is evident from the fact that oral microbiota translocation (from the oral cavity into distal body sites) occurs even in healthy individuals. However, additional factors such as underlying genetic susceptibility or existing prosthetics or other tissue damage are needed to create an environment where translocated oral microbes can potentiate diseases at distal locations  Below are some examples of the correlation between oral bacteria and systemic diseases.

Alzheimer’s disease: P. gingivalis, the keystone pathogen in chronic periodontitis, and its toxic protease gingipain was identified in the brains of Alzheimer patients.¹¹

Ventilator-associated pneumonia (VAP): Dorsal surface of the tongue serves as a potential reservoir for bacterial species involved in VAP, including H. influenzae, S. pneumoniae.¹²

Infectious endocarditis: Fetal systemic infections can occur when oral bacteria enter the bloodstream and settle in the heart lining, a heart valve, or a blood vessel. This typically has occurred in the presence of dental infection and is associated with a dental procedure in patients with prosthetic heart valves or a history of previous endocarditis.¹³

Diabetes: There is a complex interaction between diabetes, inflammation, the oral microbiome, and periodontal disease. Diabetes causes a shift in oral bacterial composition, making it more pathogenic.¹⁴

Colon cancer: The oral microbe Fusobacterium nucleatum is implicated in triggering distal disease and is among the most prevalent bacterial species associated with colorectal cancer. F. nucleatum has been suggested to potentiate intestinal tumorigenesis and modulate the tumour-immune micro-environment.¹⁵

Complications of pregnancy: A growing body of evidence supports the link between the composition of the oral microbiome and adverse pregnancy outcomes such as preterm birth, preeclampsia, low birth weight and others.¹⁶

Rheumatoid arthritis (RA): P. gingivalis and Aggregatibacter actinomycetemcomitans (Aa) have been linked to RA pathogenesis through induction of changes in neutrophil function including hypercitrullination of host proteins.¹⁷

Fig. 1: Links between the oral microbiome and systemic diseases.

Periodontal Diseases: Periodontitis and Gingivitis

Periodontal Disease (PD) refers to a wide array of diseases of the gingiva and periodontium. Gingivitis is one such disease that starts in response to the bacteria found in dental plaque. Dental plaque is a biofilm of bacteria usually found on the enamel of the teeth and gums. Gingivitis results from localized inflammation in response to plaque-residing bacteria. If gingivitis is not diagnosed and treated, it can progress to chronic periodontitis. In this disease, inflammation chronically affects the host both locally and systemically. While causing alveolar bone loss and periodontal pocket development locally, the inflammation in periodontitis can also contribute to worsening systemic diseases such as diabetes, Alzheimer’s disease, and atherosclerosis.

There are numerous risk factors for the development of periodontal diseases. These risk factors can be grouped into modifiable and non-modifiable factors. For example, smoking cigarettes is a modifiable risk factor for periodontal diseases. However, genetic factors belong to the non-modifiable risk factor group.

Periodontal disease diagnoses usually occur through clinical methods such as clinical attachment level, bleeding on probing, probing depth and radiographic findings. However, these diagnostic methods factors such as bleeding on probing depend on the force applied and also rely on damage which has occurred during previous disease activity. Sczepanik et al. (2020) suggested that hyperactivated neutrophils are more prone to producing reactive oxygen species and proteases, leading to greater susceptibility in patients to developing periodontal disease.¹⁸ Reactive oxygen species are considered a “double-edged sword”. That is because they are beneficial for killing pathogenic bacteria by neutrophils, but their overproduction could be detrimental to the host itself through the damage they do to host proteins.

In order to develop more accurate and less intensive methods for diagnosing and screening periodontal diseases, researchers looked into oral neutrophil levels. Neutrophils, also known as Polymorphonuclear Neutrophils (PMNs), are the primary cells driving the inflammatory response observed in periodontal diseases. As cells of the innate immune system, the levels of these cells were suspected of changing upon disease development in the same way that blood levels of white blood cells are used to indicate a possible infection within the patient.
Our group and other researchers have been looking into whether quantifying the oral neutrophil levels would (a) correlate with periodontal disease stages and (b) be an accurate biomarker for painless screening for periodontal diseases and monitoring its progression.

To address the first concern, we counted the neutrophil levels in rinse samples collected from healthy subjects and patients suffering from gingivitis and chronic periodontitis, whose disease stages were assessed through periodontal examinations. Based on results, we found that oral neutrophil counts correlated with the severity of periodontal diseases.¹⁹ This showed that the oral neutrophil counts provided accurate measures of the oral inflammatory load and correlated with periodontal disease severity. Furthermore, it is shown in the literature that neutrophils could be excellent biomarkers of oral health. A substantial body of research supports the idea that oral neutrophil counts could be used as screening biomarkers for periodontal diseases.²⁰

Fig. 2: Development of gingivitis and periodontistis along with changes to the alveolar bone density and gingival pocket development.

Oral Probiotics

Bacteriotherapy refers to changing microbiomes towards a healthy composition to prevent and treat diseases. More precisely, bacteriotherapy would introduce beneficial bacteria, probiotics, to the targeted microbiome to overwhelm the pathogens.²¹ Probiotics by definition are “live microorganisms that, when administered in adequate amounts, confer a health benefit to the host”.²² Conventional probiotics are generally of intestinal origin, including species related to lactobacillus and Bifidobacterium genera, with the principal application to provide relief for disorders of the Gastrointestinal (GI) tract. Oral and upper respiratory tract diseases can not be prevented or treated with GI probiotics mainly since Lactobacilli and Bifidobacteria do not persist within the oral cavity. Hence, a more efficient strategy is to use oral microbes isolated from their natural oral habitat in healthy humans as oral probiotics.²³

Streptococcus salivarius as an oral probiotic

One of the earliest bacterial colonizers of the oral cavity is S. salivarius,²⁴ which secretes antimicrobial peptides (AMPs) called salivaricins to interfere with the growth of oral and upper-respiratory tract pathogens. In recently invited high-impact publications, our group provided expert opinions regarding the importance of salivaricins and other bacterial metabolites as novel compounds to fight antibiotic resistance and oral diseases.^2,25 Specific strains of S. salivarius that can recolonize the oral cavity and secrete anti-perio-pathogens metabolites would represent ideal candidates for oral probiotic development.

Additionally, while the produced salivaricins are expected to interfere with periodontal pathogens such as P. gingivalis, little is known about their other roles in the oral cavity, including re-shaping the dental biofilm and communicating with innate immunity. There are two examples of S. salivarius strains that are commercialized and available as oral probiotics; their produced salivaricins only target selected disease-associated bacteria mainly associated with halitosis^26,27 and bacterial strep throat.²⁸ There is no clear evidence that the available oral probiotics are adequate to prevent major oral diseases like dental caries²⁹ and periodontal disease since their in vitro interference with the growth of dental caries- and periodontitis-associated bacteria is not fully established.³⁰ This would require a continuous hunt for novel S. salivarius or other oral commensal strains that can interfere with multispecies pathogenic biofilms.

Oral probiotics for personalized dental care?

Developing oral commensals as specific oral probiotics will enable personalized dental bacteriotherapy, including different bacterial strains that secrete narrow spectrum AMPs that target specific oral pathogens without disturbing the indigenous composition of health-promoting microbes in the oral cavity. Next-generation sequencing enables dentists to identify their patients’ disease risk factors based on microbiome analysis data obtained from oral specimens, including dental plaque, saliva, and tongue swabs. Intervention with specific probiotics can help to repopulate the oral cavity with billions of beneficial bacteria that can suppress pathogens and promote a healthy and balanced oral microbiome. Our research group at the University of Toronto has identified a unique oral commensal bacterium, under development, as a future oral probiotic that can inhibit periodontal pathogens and communicate with innate immunity to reduce inflammation. More work is needed with close collaboration between clinicians, microbiologists, bioinformaticians and probiotics developers to make more beneficial oral probiotics available in the near future.

Oral Health welcomes this original article.

References

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About the Authors

Abdelahhad Barbour is a renowned molecular microbiologist in the field of oral probiotics development, antimicrobial peptides and host-microbe interactions. He is the co-founder and director of Ostia Sciences Inc, a biotech company focused on microbiomes and probiotics developments.

 

 

Abasom Kambakhsh has completed 3 years of undergraduate studies at UofT and has now joined the faculty of dentistry as a dental student.

 

 

 

Michael Glogauer is an internationally recognized clinician-scientist and leader in the fields of neutrophil biology, innate immunity, oral microbiome, and periodontology. He is Professor at UofT, Dentistry and head of dental oncology at University Health Network.