How Bacteria and Fungi Influence Oral Cancer
You might not feel it, but your mouth is a bustling metropolis, home to trillions of microscopic residents whose delicate balance could hold clues to understanding one of the most common cancers in the world.
Imagine if we could detect cancer not by examining human cells, but by analyzing the microscopic organisms that live in our mouths. This isn't science fiction—it's the cutting edge of cancer research happening in laboratories right now. Oral squamous cell carcinoma (OSCC) represents over 90% of all oral cancers, and while traditional risk factors like tobacco and alcohol are well-known, scientists have discovered another piece of the puzzle hiding in plain sight: our oral microbiome.
The human mouth hosts a complex ecosystem of bacteria (the bacteriome) and fungi (the mycobiome) that exist in a delicate balance with our bodies. When this balance shifts—a state called dysbiosis—it may actively contribute to cancer development. Recent research from Yemeni and Sri Lankan populations has revealed startling connections between specific microbial communities and oral cancer, opening new possibilities for early detection and innovative treatments 1 4 .
Oral squamous cell carcinoma accounts for the vast majority of oral cancer cases worldwide.
Dysbiosis, or imbalance in oral microbes, may contribute to cancer development.
Studies from Yemeni and Sri Lankan cohorts provide key insights into these connections.
The oral cavity is the second most diverse microbial habitat in the human body, after the gut. This microscopic universe consists of two major components:
This refers to the complete collection of bacteria in the oral cavity. A healthy mouth contains hundreds of bacterial species, with Streptococcus and Rothia typically dominating the landscape 1 4 . These bacteria form complex communities that interact constantly with our oral tissues and immune system.
This is the fungal component of our oral microbiome. Though less diverse than bacteria, fungi play equally important roles. In healthy individuals, the mycobiome is dominated by Ascomycota (72%), followed by Basidiomycota (27.3%) 5 . The most commonly identified fungus in healthy mouths is Candida albicans 8 .
| Microbiome Component | Dominant Members in Health | Potential Role in Oral Cancer |
|---|---|---|
| Bacteriome | Streptococcus mitis, Rothia spp. | Protective when balanced; certain species become enriched in cancer |
| Mycobiome | Candida albicans, Malassezia | Can become dysbiotic and dominated by C. albicans in cancer |
| Functional Attributes | Bacterial mobility, LPS synthesis | Inflammatory pathways enriched in tumors |
Researchers have proposed several mechanisms through which oral microbes might contribute to cancer development:
Certain bacteria produce lipopolysaccharides (LPS) that trigger persistent inflammatory responses 1 . Chronic inflammation creates an environment rich in signaling molecules that can promote tumor growth and progression.
Some microorganisms can directly interfere with normal cell functions, potentially leading to cellular transformation . For instance, certain Candida species may produce carcinogenic byproducts like endogenous nitrosamine 8 .
The oral microbiome constantly interacts with our immune system. Dysbiosis can lead to immune suppression or malfunction, reducing the body's ability to eliminate precancerous cells .
Prior to this study, research on the oral microbiome's connection to oral cancer had produced inconsistent results. Most studies had focused exclusively on bacteria, leaving the fungal component—the mycobiome—virtually unexplored in the context of oral carcinogenesis 1 4 . Researchers aimed to address these gaps by conducting a comprehensive analysis of both bacteriome and mycobiome in distinct population cohorts from Yemen and Sri Lanka.
The study employed a case-control design, collecting samples from individuals with and without OSCC. This approach allowed researchers to directly compare microbial communities between healthy and cancerous states, identifying specific microorganisms associated with the disease.
Conducting this research required sophisticated techniques to identify and characterize the oral microbiome:
The team obtained tissue biopsies from OSCC patients while collecting deep buccal swabs or fibro-epithelial polyps from control subjects 1 4 . This sampling strategy allowed for direct comparison of microbial communities associated with cancerous versus healthy tissues.
Researchers used Illumina's 2x300 bp chemistry to sequence two key genetic markers: the bacterial V1-V3 region of the 16S rRNA gene for identifying bacteria, and the fungal ITS2 region for identifying fungi 1 4 . These specific genetic regions serve as unique "barcodes" for different microbial species.
The massive genetic data generated was analyzed using a BLASTN-algorithm to classify sequences to species level 1 4 . Downstream analyses were performed using specialized bioinformatics tools including QIIME (for community analysis), PICRUSt (for predicting functional potential), and LEfSe (for identifying differentially abundant features) 1 4 .
This methodological rigor ensured that the findings reflected genuine biological differences rather than technical artifacts.
The analysis yielded compelling evidence of distinct microbial signatures associated with oral cancer:
| Microbial Group | Enriched in OSCC | Enriched in Healthy Controls |
|---|---|---|
| Bacteria | Fusobacterium nucleatum subsp. polymorphum, Pseudomonas aeruginosa, Prevotella spp., Campylobacter spp. | Streptococcus mitis, Rothia spp. |
| Fungi | Candida albicans (dominated community) | More diverse fungal community |
| Functional Traits | Bacterial mobility, flagellar assembly, bacterial chemotaxis, LPS synthesis |
The bacteriome analysis revealed that Fusobacterium nucleatum subsp. polymorphum, Pseudomonas aeruginosa, and Prevotella and Campylobacter species were significantly more abundant in OSCC samples 1 4 . Conversely, Streptococcus mitis and Rothia species were overrepresented in controls, suggesting these might play a protective role.
Perhaps even more intriguing were the mycobiome findings. The fungal community associated with OSCC showed dysbiosis—an imbalanced microbial population—characterized by lower diversity and domination by Candida albicans 1 4 . This finding was particularly significant as it represented one of the first explorations of the mycobiome in oral carcinogenesis.
Beyond mere microbial census, the researchers also investigated the functional capabilities of the bacterial communities. They discovered that inflammatory bacterial attributes including bacterial mobility, flagellar assembly, bacterial chemotaxis, and LPS synthesis were enriched in the tumors 1 4 . These functional enhancements might enable bacteria to more effectively colonize tumor tissues and contribute to the inflammatory microenvironment that fuels cancer progression.
Understanding how researchers study the invisible world of the microbiome helps demystify the process. Here are the key tools and reagents that made this research possible:
| Tool/Reagent | Function in Research |
|---|---|
| Tissue biopsies & buccal swabs | Collect microbial samples directly from oral tissues |
| 16S rRNA gene sequencing | Identify and quantify bacterial species present |
| ITS2 region sequencing | Identify and quantify fungal species present |
| Illumina sequencing technology | Generate massive genetic data for analysis |
| BLASTN algorithm | Classify genetic sequences to specific microbial species |
| QIIME software | Analyze microbial community structure and diversity |
| PICRUSt software | Predict functional capabilities of microbial communities |
This toolkit allows scientists to move from a simple swab of the mouth to a comprehensive understanding of the microbial communities inhabiting our oral cavity and how they change in disease states.
The findings from the Yemeni and Sri Lankan cohorts are part of a larger body of evidence linking the oral microbiome to cancer. Subsequent research has continued to build on these foundational insights:
The consistent microbial signatures associated with OSCC suggest potential for early detection strategies. One study developed a diagnostic model using the random forest algorithm on swab samples that achieved an impressive area under the curve (AUC) of 0.918 3 . This high accuracy demonstrates the potential of microbiome-based diagnostics for oral cancer screening.
Different fungal species appear to have contrasting relationships with cancer outcomes. Studies have found that higher salivary carriage of Candida was significantly associated with poor overall survival in OSCC patients, while higher carriage of Malassezia was significantly associated with favorable overall survival 8 . In fact, Malassezia was identified as an independent predictor of survival, suggesting its potential use as a prognostic biomarker 8 .
Associated with significantly worse overall survival in OSCC patients 8 .
Associated with significantly better overall survival in OSCC patients 8 .
Understanding the oral microbiome opens exciting avenues for treatment. Potential approaches include:
To restore healthy microbial balance and potentially counteract dysbiosis associated with cancer.
Targeting specific cancer-associated microbes while preserving beneficial microorganisms.
To enhance effectiveness of conventional cancer treatments like chemotherapy and radiation.
The relationship between microbiome and cancer treatment is bidirectional—cancer therapies themselves significantly impact the oral microbiome. Studies tracking patients through chemo-radiation therapy have observed dynamic changes in microbial communities associated with treatment side effects like oral mucositis 7 . Understanding these changes could lead to interventions that reduce treatment complications.
The investigation into the oral bacteriome and mycobiome associated with oral squamous cell carcinoma represents a paradigm shift in how we approach cancer biology. No longer can we focus exclusively on human cells; we must consider the complex ecosystem of microorganisms that call our bodies home.
The Yemeni and Sri Lankan cohort study provided foundational insights, revealing that specific bacteria and fungi are consistently associated with OSCC and that the functional capabilities of these microbial communities may contribute to the inflammatory microenvironment that fuels cancer progression. Subsequent research has reinforced these findings while expanding them toward practical applications in diagnosis, prognosis, and treatment.
As research advances, we move closer to a future where a simple swab of the mouth could reveal not just the state of our oral health, but our cancer risk—and where treatments might target not just human cells, but the microbial partners that influence their behavior. The hidden world in our mouths, once mapped and understood, may hold keys to unlocking better outcomes for oral cancer patients worldwide.
Sequencing reveals microbial signatures linked to cancer
Potential for early detection and personalized treatments
Research spans diverse populations for broader insights