How Inflammation, Diet, and Dysbiosis Drive Risk

In the past decade, research has shown that lack of dietary nutrients may be the driving force behind an increased risk of oral squamous cell carcinoma (OSCC).¹ A major factor for this conclusion is the pro-inflammatory nature of processed foods in the modern diet.^1,2 In addition, dysbiosis — the imbalance of the microbial environment’s composition, activities, and distribution — is bidirectional from the gut as it relates to the oral microbiome, the collective name for the complex environment of microorganisms that inhabit the mouth.^3,4 The resultant effect of inflammation and microbial dysbiosis impacts the epigenome (ie, how genes are reversibly or irreversibly expressed⁵ to direct cancer cells inhibition, formation, and progression).

Inflammation as the Source of Disease

Chronic systemic inflammation is associated with increased risk of developing diseases such as type 2 diabetes,⁶ neurodegenerative disease, cardiovascular disease,⁷ and all forms of cancer.² The pro-inflammatory nature of processed foods promotes mutagenic changes and increases the risk of OSCC.²

A Dietary Inflammatory Index (DII) was created to evaluate 45 food components to determine if a diet is high in inflammatory factors.^6,8 The DII score determines if there is an increase or decrease in pro-inflammatory biomarkers or anti-inflammatory biomarkers.^2,8 The lowest DII score represents a healthy anti-inflammatory diet that includes vegetables, fruits, nuts, seeds, green tea, and coffee. A high score indicates a pro-inflammatory diet, including whole fat products, refined cereals, alcohol, red meat, processed meats, and sugar.^8,9 A systematic review by Luo⁹ in 2022, determined that a high DII score with pro-inflammatory foods, such as red meat and sugar, increased oxidative stress and an elevated risk for oral cancers. For each incremental increase in the DII score, there is a 17% increased risk of developing OSCC.

Processed meats, preserved by smoking, curing, salting, or addition of chemical preservatives, have been associated with colorectal adenomas and esophageal, bladder, renal, and oral cancers.¹⁰ A 2014 meta-analysis by Xu et al¹⁰ showed a 91% increased risk of OSCC and oropharyngeal cancer among those consuming high quantities of processed meat. The high heme iron content and high saturated fat in red meat may create mutagens during the cooking process.

The thermal processing or browning of meat and other foods is called the Maillard reaction. This reaction may deplete the nutritional value of the food and may be responsible for the production of carcinogens such as acrylamide.¹¹ In addition, high cooking temperatures above 300° Fahrenheit or over an open flame may produce carcinogenic chemicals.¹²

The Oral Microbiome

Since the groundbreaking report, “Oral Health in America,” by the United States Surgeon General almost a quarter of a century ago,¹³ the significance of oral health has been emphasized as well as the importance of the oral-systemic connection. Technological developments in genomic testing and sequencing have provided insight into the human microbiome. Due to the oral microbiome’s contribution to host health, it is being studied extensively.¹⁴

A healthy oral microbiota environment has commensal, symbiotic, and pathogenic microorganisms of bacteria, fungi, viruses, and protozoans.^14,15 Alteration or disturbance of this delicate balance in the microbiome environments is known as dysbiosis. The oral cavity has diverse habitats and biologic niches where these microbiomes can colonize such as on the teeth, oral mucosa, gingival sulcus, tongue, tonsils, and hard and soft palate.¹⁴

The oral cavity is the gateway to the gastrointestinal system. The gut is the largest microbial environment in the human body, followed by the oral microbiome.⁴ The nutrients that feed the oral microbiome are the nutrients that feed the body. Food is consumed in the gut and digested by the gut microbiome.¹⁴ To maintain both oral and systemic health, a harmonious balance of the oral microbial environment must be maintained along with a constant 95 to 98.6° F temperature¹⁶ and stable salivary pH of 6.5 to 7.0.¹⁴

Research demonstrates a risk of interorgan transposition of microbes from the oral cavity to the gut and the gut to the oral cavity bidirectionally, with a resultant alteration of both habitats. This transposition of microbes may be implicated in inflammatory diseases, including diabetes and cardiovascular disease, in addition to cancers.^4,14

Lifestyle choices, including tobacco and alcohol consumption, hormones, stress, diet, antibiotics, and systemic disease, may negatively alter the oral ecosystem’s composition and microbial balance.¹⁴ Dysbiosis leads to an inflammatory cascade of localized and systemic disorders.¹⁷

A novel study reported that a disturbance of the gut microbiome was linked to the addition of food preservatives such as the lantibiotic, nisin. A chemical produced by bacteria, Nisin is designed to kill competing microbes. In the food industry, it is used to preserve items such as beer, sausage, and cheese. This “natural” preservative has been found to kill not only the pathogens in foods, but also essential commensal bacteria in the human gut, leading to dysbiosis, opportunistic microbial pathogens, and oral-systemic health concerns.¹⁸

A complex of oral microbial pathogens has been implicated in oral-systemic diseases. They are grouped into six categories called the Socransky complexes.¹⁹ The red and orange are high risk pathogens and yellow, green, blue, and purple complex organisms relate to healthy periodontium.¹⁷ Porphyromonas gingivalis, a red complex pathogen, and Fusobacterium nucleatum, an orange complex pathogen, are key in the development of dental caries and periodontal diseases.⁴

Even in limited quantities, the red complex pathogens, especially P. gingivalis, can alter the symbiotic balance of the oral microbiome into a dysbiosis, causing diseases ranging from periodontitis to oral cancer.^14,15 Orange complex oral pathogens not only are a risk for periodontal diseases,¹⁷ but are also associated with chronic systemic inflammatory diseases¹⁵ such as cardiovascular, diabetes, rheumatoid arthritis, chronic obstructive pulmonary disease, along with pancreatic²⁰ and colon cancers, and OSCC.^4,21,22

Point-of care technology for detecting and analyzing the intricate combination of these oral pathogens is within the dental office’s reach with salivary diagnostics.^14,15 The field of salivary testing, known as “salivaomics,” is for the early detection of biomarkers for oral cancers and systemic diseases.^15,23

Salivary diagnostics allow diagnostic identification of disease with detectable changes in proteins, messenger RNA, micro-RNA, metabolic compounds, and microbes.²³ Salivary testing, especially in pregnant women¹⁷ and patients with chronic disease,²² has shown relationships to the Socransky complex oral pathogens.

In pregnant patients, supragingival plaque niches test higher for red complex pathogens, resulting in pregnancy gingivitis and pregnancy tumors.¹⁴ Once these red, orange, or green complex oral pathogens are identified, a “precision dentistry” or individualized treatment plan can be developed.¹⁵ This plan focuses on goals to make periodontal care a top priority, to reduce pathogen thresholds, and to do salivary retesting to verify success of treatment.¹⁷ These precision treatment options are determined by the clinician and can include increased dental hygiene recare, laser therapy, localized antibiotic application, dietary counseling, and oral probiotics, to name but a few.

Oral microbial dysbiosis occurs as part of the body’s inflammatory immune response. Localized agents, such as antimicrobial and antibacterial mouthrinses and pastes, can cause dysbiosis. These oral care products may alter the oral microbiome by forming salivary nitrate compounds, which are metabolites found in both the oral cavity and the gut. A disbalance in nitric oxide results in blood pressure fluctuations.¹⁵ As healthcare providers, dental professionals should be aware of these oral-systemic concerns when advising patients on the long-term use of such products.

Epigenetic Diet and Dietary Suggestions

Epigenetics is the study of how environment and lifestyle choices cause changes that affect gene expression. These genetic changes have the potential to be passed down to multiple generations.⁵ Epigenetics is an important mediator of homeostasis in cells through four mechanisms: DNA methylation, covalent modification of histones, noncovalent modification of histones, and noncoding RNA-related modifications. All four mechanisms play a role in OSCC by influencing cancer cell formation, chromosomal instability, and less transcription of tumor suppressor genes.²⁴ Most important, in patients with OSCC, the oral microbiome shows epigenetic and mutagenic variations with greater dysbiosis compared to healthy patients.^4,14,25 Within the OSCC tumor cells, irregular gene-hypermethylation can occur, which promotes tumor growth by negatively affecting crucial functions of cellular cycle control, apoptosis, DNA repair, and cell-to-cell adhesion.⁵

Bioactive dietary factors play a major role in epigenetic management and anticarcinogenic effects. This new field is called nutrigenomics.²⁶ Dietary polyphenols, found in certain foods, can prevent, modulate initiation, and even regulate the progression of oncogenesis in oral, esophageal, breast, prostate, and other types of cancers.^26,27 Phenols and certain vitamins and minerals can directly influence the microbiome to activate or inactivate biotransformation of carcinogens.^1,3 These bioactive dietary factors act preventively by encouraging DNA repair and preventing methylation of cancer cells.²⁶

The epigenetic preventive diet is high in phytochemicals and polyphenols found in curcumin, resveratrol (RSV), folate, and vitamin C.²⁷ The epigenetic diet therefore consists of cruciferous vegetables such as broccoli, cauliflower, and cabbage, along with citrus, green tea, garlic, herbs, turmeric, eggs, fish, and dark grapes.^24,27

Green tea has high levels of polyphenolic compounds and its leaves are dried rather than fermented like those of black tea.²⁷ Among the polyphenol bioactive compounds in green tea, catechins are the most abundant with epigallocatechin gallate (EGCG) shown to be the most effective in exerting anticarcinogenic and anti-inflammatory effects. EGCG produces these effects by arresting the cellular cycle, initiating apoptosis, and regulating the signal transduction pathways. By doing so, this reduces cancer cell proliferation and may be directly corelated to prevention of oral, head and neck, eso­phageal, and gastric cancers.²⁷

Curcumin, a polyphenol component of turmeric spice, has been reported in Eastern medicine to have anti-inflammatory, antioxidant, antiangiogenic, and anticancer properties. It acts by inducing DNA hypomethylation to inactivate prometastatic and proto-oncogenes. Curcumin’s anti-cancer potential appears to be enhanced with the addition of bioactive compounds found in soy and egg yolks.²⁷

RSV is another type of dietary polyphenol found in peanuts, mulberries, cranberries, blueberries, blackberries, dark grapes, and red wine.²⁷ It is important in multiple cellular functions such as growth, division, migration, adhesion, apoptosis, and angiogenesis. RSV has also been shown to exhibit synergistic effects with cetuximab, a monoclonal antibody treatment. In cetuximab-resistant OSCC, RSV has been successfully used in combination with cetuximab, resulting in a reduction in cancer proliferation.²⁸

Also known as folic acid and vitamin B9, folate is found in vegetables, beans, cereals, pasta, plants, and animal products. Folate is essential for DNA methylation, DNA synthesis, and cell cycle repair.²⁴ Individuals who consume alcohol and tobacco regularly have reduced folate levels, therefore leading to a higher risk for OSCC.

Citrus fruits containing vitamin C act to reduce the development of primary cancers by promoting apoptosis and arresting the cellular cycle in OSCC. It can upregulate the expression of tumor suppressor genes, such as p53 and p21. In cancer therapy, the combination of vitamin C with cisplatin, a chemotherapy drug, is effective in reducing free radicals.²⁹

Importance of Oral Health Professionals

Dentists and dental hygienists routinely advise against the consumption of sugar to reduce caries risk. Due to the impact that a preventive epigenetic diet has on preventing oral cancer risks, oral health professionals should be prepared to offer additional nutritional counseling. With this knowledge, oral health professionals are able to work interprofessionally with physicians, dietitians, and oncologists for better patient outcomes.

Conclusion

The traditional view of tobacco and alcohol as the primary causative factors for oral cancer has dramatically expanded to include genetics, microbiome alterations, and epigenetics controlled by nutrition. The modern diet has a direct relationship to increased risk of oral cancers and other systemic cancers and diseases. The dental professional, as an integral part of oral-systemic healthcare, should have knowledge of the latest research in the field of nutrigenomics and precision dentistry for the prevention of oral cancer.

References

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From Decisions in Dentistry. January/February 2025;11(1):42-45.