Periodontal Pathogens and Carcinogenesis by Dr Kishan Sheth

Is there any evidence to support a potential link? (Part 1)

by Dr Kishan Sheth

For years, dental professionals and their medical colleagues have paid attention to their own respective fields of discipline.

However, the gap between allopathic medicine and dentistry has begun to close at an alarmingly fast rate,²⁰ as we begin to appreciate how oral health is indicative of systemic health, and this holds true the other way around as well.

The events and activities in the tissues within the oral cavity can induce inflammatory processes in other areas of the body, and this is principally thought to be a result of the actions of periodontal pathogens residing in the tissues and on top of the tooth surfaces.²⁰

The purpose of this article is to introduce a new and potentially plausible disease connection between oral cavity and the rest of the human body, and its presence could see clinical implications for the way in which routine and actively employed dental care is carried out.

Introduction
Whilst some argument can be made that gingivitis is highly prevalent and almost universally present to some extent, periodontitis is a destructive, irreversible disease, which affects around 10% of the global population.²¹

The dysbiotic, chronic inflammatory condition destroys and compromises the integrity of gingival and periodontal ligament connective tissues, as well as leading to the loss of alveolar bone, and thus the apical migration of the junctional epithelium.¹

The disease is thought to be caused by gram-negative anaerobic or microaerophilic bacterial species that colonise the subgingival space, and examples include porphyromonas, gingivalis, aggregatibacter, actinomycetemcomitans and tannerella forsynthia.⁵ However, recent study findings demonstrate that an increased diversity of the microbiota is more likely to lead to disease than specific strains of bacteria.⁶ However, it may be true that the presence of certain strains is more likely to influence disease progression and severity. More research is required to confirm and validate this thought.

What is known is that the presence of bacteria represents the primary aetiological agent of the disease process, and the initiation, progression and severity of the disease depend on other factors such as medicinal drugs, smoking, immunosuppression, genetics and hormonal/immune factors. Diet may also have a role.¹²

Periodontitis has been linked with several disease forms, including type 2 diabetes mellitus,, cardiovascular disease,⁸ adverse pregnancy outcomes,⁹ respiratory disease,¹⁰ osteoporosis and rheumatoid arthritis.¹¹ The thought processes behind most of this is that the periodontal pathogens are able to secrete inflammatory mediators and proteins, which reduce the strength of the immune system and create an opportunity for opportunistic pathogens to create burden on the rest of the body.

The concept and understanding of the events taking place within the oral tissues, influencing the activity elsewhere within the body, is not a new concept. It has, however, undergone lots of changes in the level of understanding over the years.^2–4 During the earlier years, there was widespread debate and dispute regarding the existence of this, so-called, ‘oral-systemic link’; however, nowadays it is widely accepted.

Pathogenesis of human periodontitis
Page and Schroeder first placed the understanding of human periodontics pathology on an understandable and logical platform in 1976, and the concepts they proposed at the time are still acknowledged and accepted, despite our understanding continuing to remain as an incomplete picture because of the complex nature of the disease process.¹³

Global leaders in the field of periodontics agree that the disease is initiated by bacterial plaque, principally by the presence of gram-negative anaerobic or microaerophilic bacterial species that form residence within the subgingival pocket. Primary species believed to have an influential role in the disease process include porphyromonas, gingivalis, aggregatibacter, actinomycetemcomitans and Tanerella forsynthia; as this was concluded at the 1996 World Workshop on Clinical Periodontitis.¹⁴

We have now collected enough evidence to confidently establish that periodontitis is a collection of closely linked/related diseases which will vary in their onset, severity and treatment affectivity. It is no longer considered to be a single disease process.

The presence of bacterial plaque causes the capillary endothelial cells to separate, enabling fluid penetration into the extravascular tissue compartments. This is an important process because it allows immune cells to come into close contact with the bacterial cells, and also creates an opportunity to remove waste products from and transport nutrients to the immune cells. Many inflammatory mediators are present in the host tissues, including complement activation products, kinins and matrix metalloproteinases.¹⁵

Epidemiological studies
Attention will now be paid to two cohort studies that examine a possible periodontitis/cancer relationship at the population level.

Whilst many studies may well have demonstrated a relationship between these two variables, Ren et al. (2016)¹⁶ demonstrates that no relationship has been seen. The study looked at a total of around 1,063 patients with colorectal cancer, as well as 5,556 controls matched for age, sex, exercise, diet, alcohol and smoking levels.

All participants were interviewed and categorised by the number of teeth that they had lost – none; 1 to 5 missing teeth; 5 to 10 missing teeth; and more than 10 missing teeth. Smoking levels, red meat consumption, BMI and exercise levels were adjusted for using linear regression curves.

Two important considerations are that Fusobacterium nucleatum, a pathogen associated with chronic periodontitis, has been demonstrated to increase colorectal cell growth in mice. In addition, the human microbiome project has concluded that the microbial populations in the mouth and intestines are similar.

Some problems with this study are that oral health levels are self-reported and therefore may well be prone to recall errors, and we have a limited understanding of the oral microbiome composition and of the process of chronic inflammation. How can we even think of investigating the mechanisms at play when we lack the understanding about key molecules and substances that may be important in the process?

In addition, this study looks at periodontitis in the form of missing teeth, whereas missing teeth are a surrogate measure for periodontitis, and trauma and caries can also lead to missing teeth. It would be advantageous to use the 1999 Page and Eke AAP CDC case classification definition system, which takes into account levels of clinical attachment loss. Laprise et al. (2016)¹⁷ conducted a cohort study, which looked into the potential relationship between periodontitis and cancer, between the years 2008 and 2012 in Kerala, India. A life course questionnaire was used for information gathering, and periodontal disease levels were measured by gingival inflammation and recession. Generalised gingival recession (a measure of past disease) was strongly associated with an increased risk in the development of oral cancer.

A major challenge right from the beginning of this study was to appreciate that oral cancer and periodontitis share many mutual risk factors, such as smoking. Three hundred fifty patients participated in the study with 371 controls. The patients with histologically confirmed squamous cell carcinoma (by brush biopsy) were analysed via professional dentists under halogen light.

Inflammation was noted (mild, moderate, severe), as were recession levels and distribution. Generalised recession means more than one quadrant was involved. Generalised gingival recession was demonstrated to almost double the risk of oral cancer development.

Potential disadvantages of this study are that recession is an indication of past disease, whereas the use of clinical attachment loss would represent presenting disease levels.

In addition, oral health variables were not accounted for, particularly important because periodontal disease is a plaque-induced condition (in most cases).

Biological plausibility
Abnet et al. believe that the periodontal pathogens may be directly triggering the carcinogenesis process, and historical cases have seen bacterial species linked with malignancy, such as Helicobacter pylori linked with gastric cancers, Salmonella typhi with hepatic cancers and Streptococcus bovis with several tumour forms.¹⁸

Porphyromonas gingivalis has demonstrated an ability to speed up the action of nitrate-reducing microorganisms in the oral cavity, leading to an explosion in the level of carcinogenic nitrosamines. It has also demonstrated an ability to enter into epithelial cells and produce apoptosis silencing proteins and molecules.

Aggregatibacter actinomycetemcomitans has demonstrated an ability to release toxic compounds, which can increase the level of interleukin 1 and prostaglandin E2, as well as disrupt DNA and generate point mutations/gene deletions.

By increasing the level of prostaglandin E2, there is a knock on effect of accelerated osteoclast activity, furthering alveolar bone loss, and ultimately amplifying the signs and symptoms of periodontitis. It is clear from the points mentioned that this two-way relationship does have the backbone of biological plausibility.¹⁹

Conclusion
There has been limited research conducted within this potential relationship, but early epidemiological data demonstrates a potential relationship. It will be important to take this proposition into lab-based studies, particularly analysing the actions of Porphyromonas gingivalis and Aggregatibacter actinomycetemcomitans. Epidemiological studies can provide us with only potential trends, while lab-based studies will allow us to analyse the exact impacts of particular bacteria strains on cellular function.

Epidemiological research to date does generate clinical implications. It emphasises a need for thorough assessment, regular recall and maintenance, and expanding primary prevention initiatives at the population level.

Root surface debridement will be important in those suffering from periodontitis, because it will reduce bacterial loads in the pockets, reducing systemic inflammation and perhaps the potential for carcinogenesis.

Also, we can examine only clinical presentation, which doesn’t always correlate with levels of infection and inflammation. To measure those, we must detect vascular changes, oedema and tissue fragility via genetic testing and biochemical marker analysis and profiling techniques. It may be some time before we can employ these research methods.

ROOT CAUSE: Thoughts on the Netflix Documentary

I’m sure that I was not alone in being very surprised and concerned that Netflix, Vimeo, Amazon and Apple had allowed for the uploading of a documentary film entitled Root Cause which was spreading claims that were not evidence-based or scientifically acceptable.

The media plays a major role in increasing public awareness about a multitude of issues and topics, and we all are very much aware of the high degree of information that most our patients come armed with at their dental appointments. I’m sure that we also agree that freedom of speech should always be maintained, but if films wish to spread opinions and outdated research, they should be careful about how members of the public may perceive their footage.

The 72-minute film follows an Australian-born filmmaker, Frazer Bailey, as he tries to pinpoint the ‘root cause’ of his tiredness, anxiety and depressive episodes. He does attempt a range of treatment options such as antidepressants, balancing his chakras and even meditation; he also attempts to drink his own waste products. After several failed attempts, he comes to a final conclusion that an endodontic procedure he had performed when he was in his youth may have led to these signs and symptoms of aberrant function.

The film goes further to try and explain such a conclusion, attempting to argue that it is biologically plausible, through anaerobic bacteria being left behind inside the root system after endodontic therapy has been performed, and these bacteria can also apparently collect inside empty sockets after the extraction of wisdom teeth.

The bacteria can apparently collect and travel to other anatomical sites through “meridian lines,” a Chinese medical concept for energy-spreading pathways through the body.

The film also claims that there may be a possible connection between treated root canals and breast cancer cases, citing that ‘98% of women who have breast cancer have a root canal tooth on the same side as their offending breast cancer’. This is likely to be due to Dr. Josef Issel’s study of terminally ill cancer patients.

I believe that these leading digital platforms have to step up and be able to justify which films they allow to be distributed digitally on their platforms. The treatment of periapical periodontitis and pulpal pathology have good evidence-based track records, and our own annual appraisals and audits of success when we perform these techniques are a very good indicator that these procedures are here to stay.

Whilst there is growing evidence that some bacteria species can lead to inflammatory encouraging environments, far more research needs to be done before coming to such a radical conclusion. And should filmmakers make such films in the future, they should pay very careful attention to the terminology and language used.

There is no valid evidence base to support endodontically treated teeth with aberrant function elsewhere in other anatomical sites. The root canal is a widely used, safe and appropriate procedure to treat periapical pathology and pulpal irreversible pathology when these do arise. But we do have to agree that endodontic therapy is unlikely to be able to completely remove the bacterial species in the lateral canals; however, this is changing with the widespread introduction of 3D canal preparation and obturation techniques.

Endodontic therapy does go a huge way to reduce the bacterial count in the root system, with not only filing techniques but the use of antibacterial and bacteriostatic irrigants.

The elimination of clinical signs and symptoms after root fillings are placed are a testament to this effective procedure.