Nontobacco-related oral cancers: Is gut microbiome the missing link?

Head-and-neck cancer represents the 6th-most common malignancy worldwide and the annual incidence of oral cancer exceeds 3,000,000 new cases. Oral cancer is historically linked to well-known behavioral risk factors such as tobacco, smoking, and alcohol consumption.[1] In addition, several dietary factors, nutrition deficiencies, viruses, sexually transmitted infections, chronic irritation, and possibly genetic predisposition have also been associated with oral cancer.[2] Furthermore, several premalignant lesions and conditions such as leukoplakia, erythroplakia, oral submucous fibrosis, and lichen planus carry an increased risk for malignant transformation.[3] Additional risk factors such as chronic oral candidiasis, human papillomavirus, altered oral flora, chronic trauma, and infections also play an important role in disease progression.[4–9] In individuals with significantly lower risk factors and the absence of tobacco exposure, the role of Helicobacter pylori has been explored extensively in the literature. H. pylori is a known causative agent in gastric cancers, however, the exact correlation in oral squamous cell carcinoma (SCC) is still debatable. H. pylori produces a potent cytotoxin vacuolating cytotoxin A that causes progressive vacuolization and gastric injury by disruption of endosomal and lysosomal activity in the host cells. These along with environmental and host genetic factors regulate chronic gastric injury and inflammation leading to gastric carcinogenesis.[10] However, it has been hypothesized that H. pylori causes cell damage and initiates the release of pro-inflammatory mediators that in turn stimulate the host immune system to release cytokines and oxygen radicals, facilitating carcinogenesis. Previous research has found a positive association between premalignant oral diseases and H. pylori infection.[11–14] In one study, 26.4% of observed cases were seropositive for H. pylori, with greater additive risk seen in those exposed to tobacco or alcohol in conjunction with H. pylori.[11] The presence of this bacterium is believed to alter the oral microbiome. The role of H. pylori as a risk factor for oral cancers has been supported by multiple other studies in the literature.[11–13] However, some studies like Meng et al.[14] have demonstrated a negative correlation, requiring further research to conclusively determine the relationship. The diagnosis of inflammatory bowel disease (IBD) including ulcerative colitis and Crohn’s disease is based on a combination of clinical, biochemical, stool examination, endoscopic, cross-sectional imaging, and histological investigations.[15] Besides the gastrointestinal tract, they are also characterized by various extraintestinal manifestations (EIMs), with at least one EIM affecting up to 63.4% of patients, including aphthous stomatitis in 21.6% of patients.[16] Oral lesions are more common in Crohn’s disease as compared to ulcerative colitis.[17] Although the exact pathogenesis of the oral and dental manifestations of IBD is unknown, they are mostly related to the alteration of inflammatory mediators at the cytokine levels.[18] Another common hypothesis that has been put forward is that of immune system dysregulation where a cross-reaction of common antigens occurs in the bowel and oral mucosa.[18] EIMs in patients with active IBD may result from altered cytokine activity in the gastrointestinal tract including the oral cavity.[19] Several studies investigating saliva in patients with IBD found elevated levels of pro-inflammatory cytokines when compared to controls. Said et al.[20] investigated salivary cytokine profiles in patients with ulcerative colitis and Crohn’s disease. They found that saliva levels of interleukin-1β (IL-1β) were elevated in both patient groups compared to controls. However, levels of IL-6, IL-8, and monocyte chemoattractant protein-1 were selectively elevated in ulcerative colitis patients, while tumor necrosis factor-alpha (TNF-α) levels were increased only in Crohn’s disease patients compared to controls. These findings suggest differential salivary cytokine profiles may help distinguish ulcerative colitis from Crohn’s disease. Szczeklik et al.[21] found higher salivary levels of IL-1β, IL-6, and TNF-α in patients with active Crohn’s disease compared to inactive disease and controls.[21] A correlation was observed between elevated levels of pro-inflammatory cytokines IL-6 and TNF-α in saliva and specific oral lesions, such as oral lichen planus.[21] In addition, a strong correlation was seen between lysozyme and IL-1β levels and the relative salivary abundance of different bacteria.[20] The available evidence suggests that oral manifestations of inflammatory bowel disease (IBD), which can be categorized as extraintestinal manifestations (EIMs), may be associated with upregulated pro-inflammatory cytokine levels in the oral cavity of IBD patients. This upregulation appears to be secondary to the systemic immune dysregulation that characterizes IBD. Current evidence confirms that the gut microbiota alterations associated with IBD can lead to dysbiosis of the oral microbiota. This oral dysbiosis subsequently causes localized inflammation that manifests as oral complications of the disease. While oral squamous cell carcinoma remains rare in inflammatory bowel disease patients, the increasing incidence in young individuals with no known risk factors warrants further research into this association. Although oral cancer prevalence in inflammatory bowel disease is low (1.08-1.78%),[22] mandatory oral examinations by experts and a multidisciplinary approach involving gastroenterologists and dermatologists when needed is a rational way to ensure high-quality patient care. Additional studies are warranted to further elucidate the pathogenesis underlying oral manifestations of inflammatory bowel disease, characterize the relationship between gut and oral microbiota and their associations with intestinal disease activity, and optimize management strategies for these manifestations. The true prevalence and incidence of oral cancers in inflammatory bowel disease patients may be obscured by classification with upper digestive tract tumors, along with lack of routine oral screening in this population. These factors highlight the importance of a coordinated multidisciplinary approach involving routine oral assessment and close collaboration between gastroenterology, dermatology, and dental specialties for optimal care of inflammatory bowel disease patients. Further research and clinical vigilance are critical to fully understand and proactively detect the range of oral complications that may arise in the setting of inflammatory bowel disease. Conversely, patients presenting with concerning oral lesions without overt gastrointestinal disease may have undiagnosed inflammatory bowel disease warranting further investigation. In such cases, a comprehensive assessment is necessary to detect subtle IBD and appropriately manage oral lesions, with vigilant follow-up to enable early detection of oral and gastrointestinal malignancies in this population. A high index of suspicion and multidisciplinary coordination between dentistry and gastroenterology is crucial for recognizing occult IBD cases based on oral findings alone and preventing delay in diagnosis and treatment. Financial support and sponsorship Nil. Conflicts of interest There are no conflicts of interest.