Abstract
The oral microbiome potentially wields significant influence in the development of cancer. Within the human oral cavity, an impressive diversity of more than 700 bacterial species resides, making it the second most varied microbiome in the body. This finely balanced oral microbiome ecosystem is vital for sustaining oral health. However, disruptions in this equilibrium, often brought about by dietary habits and inadequate oral hygiene, can result in various oral ailments like periodontitis, cavities, gingivitis, and even oral cancer. There is compelling evidence that the oral microbiome is linked to several types of cancer, including oral, pancreatic, colorectal, lung, gastric, and head and neck cancers. This review discussed the critical connections between cancer and members of the human oral microbiota. Extensive searches were conducted across the Web of Science, Scopus, and PubMed databases to provide an up-to-date overview of our understanding of the oral microbiota’s role in various human cancers. By understanding the possible microbial origins of carcinogenesis, healthcare professionals can diagnose neoplastic diseases earlier and design treatments accordingly.
Plain language summary
Interactions between oral microbiota shifts and cancer: The oral microbiome potentially wields significant influence in the development of cancer. Within the human oral cavity, an impressive diversity of more than 700 bacterial species resides, making it the second most varied microbiome in the body. This finely balanced oral microbiome ecosystem is vital for sustaining oral health. However, disruptions in this equilibrium, often brought about by dietary habits and inadequate oral hygiene, can result in various oral ailments like periodontitis, cavities, gingivitis, and even oral cancer. There is compelling evidence that the oral microbiome is linked to several types of cancer, including oral, pancreatic, colorectal, lung, gastric, and head and neck cancers. This review discussed the critical connections between cancer and members of the human oral microbiota. Extensive searches were conducted across the Web of Science, Scopus, and PubMed databases to provide an up-to-date overview of our understanding of the oral microbiota's role in various human cancers. By understanding the possible microbial origins of carcinogenesis, healthcare professionals can diagnose neoplastic diseases earlier and design treatments accordingly.
Introduction
In an increasingly aging population, distinct disease patterns are emerging, with older individuals being more susceptible to the development of multiple chronic ailments.1-3 This impact is expected to significantly expand over the coming generation due to the prolonged life expectancy.4-8 These conditions align with the primary causes of mortality in the developed world, as identified by the WHO, 9 encompassing cardiovascular diseases, malignant conditions, and cerebrovascular diseases. 10 Cancer, in general, is a grave illness, and for most forms of epithelial cancers, there exists a notable exponential correlation between age and cancer incidence or mortality.11-15 Consequently, age is the most critical factor determining cancer risk.16,17 Many nations rank cancer as the second most common cause of death after cardiovascular diseases.18,19 Strikingly, in contrast to the declining prevalence of coronary heart diseases, the incidence of most cancers is on the rise. 20 Among older people, genitourinary, gastrointestinal, and lung cancers represent the most prevalent malignancies. 21 Atherosclerosis, cardiovascular disease, and diabetes are associated with poor oral health7,22-26 and certain cancers.27,28
Oral cancer encompasses cancers affecting the lip and all oral cavity and oropharynx regions. However, this incidence exhibits wide disparities worldwide, contingent on gender, age groups, countries, races, ethnic groups, and socioeconomic conditions. 29 Cancers of the oral cavity, colorectal cavity, and pancreas seem to contribute to bacteria in the oral cavity. 30 The most well-established culprits in this regard are oral periopathogens, specifically F. nucleatum and P. gingivalis. Other bacteria, such as Prevotella sp., Peptostreptococcus sp., Streptococcus sp., and Capnocytophaga gingivalis, also seem to contribute significantly to carcinogenesis. 30 These bacteria exert their oncogenic effects on human cells through mechanisms such as chronic inflammation, antiapoptotic activity, and the production of carcinogenic substances. 31 The oral microbiome is also influenced by host factors.32-39 In oral and oropharyngeal cancers, changes in oral microbiome abundance may not be solely caused by tumorigenesis.14,40,41
Recent studies have illuminated these dynamics. An in vitro study was conducted by Nagy et al. on biofilm samples collected from 21 lesions and adjacent healthy mucosa. Compared to healthy mucosal surfaces in the same patients, oral carcinoma lesions showed significantly higher aerobic and anaerobic bacteria in their biofilms.
42
Next-generation sequencing was used by Lee et al. to identify differences in microbiota between normal individuals, patients with epithelial precursor lesions, and patients with cancer. Several bacteria, such as Bacillus, Parvimonas, Enterococcus, Peptostreptococcus, and Slackia were detected in two distinct clusters, which correlated with their abundance.
43
Yang et al. also studied oral microbes in SCC patients using 16S rRNA amplicon sequencing and revealed a relationship between oral microbes and SCC mutations.
44
As illustrated in Figure 1, many cancer types exhibit aberrantly hyperactivated pathways, which are generally associated with poor clinical outcomes and cell proliferation. SCFA levels and FFAR2 levels are both reduced when oral microbiota composition is altered. TNFAIP8 and IL-6/STAT3 may be promoted by this reduction, potentially causing inflammation and increasing cancer risks.
45
This review presents recent research findings on the relationship between changes in oral microbiota and cancer in aging populations. Oral microbiota-related SCFAs induce cancer and immune responses. ↑: increased, ↓: decreased.
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Oral Cancer
Some Studies of Interactions Between Oral Microbiota and Cancers.
Furthermore, OSCC ranks as the most common cancer affecting the HN region, constituting approximately 2% of all cancer cases worldwide. 56 Recent research indicates that the oral microbiome plays a role in OSCC development. Oro-digestive cancer, increased invasion, and stem cell proliferation are linked to P. gingivalis infection.52,57-59 When microbes reach the bloodstream or propagate locally, inadequate oral hygiene significantly increases the risk of oral cancer and its spread to adjacent tissues. There is an increased risk of tongue, gastrointestinal, or pancreatic cancer among individuals with tooth loss or periodontal disease. 60 The surfaces of oral cancer and cancerous tissues are infested with distinct microorganisms, which differ significantly from normal mucosal bacteria. S. mutans and gingival carbon dioxide phagocytic bacteria have been detected in OSCC patients’ saliva. Diagnostic markers for OSCC could be found in these three bacteria. 61 Sarkar et al. Compared to healthy controls, OSCC lesions are significantly enriched in genera like Corynebacterium, Pseudomonas, Prevotella, Noviherbaspirillum, and Deinococcus, while genera like Actinomyces, Stenotrophomonas, Serratia, Anoxybacillus, and Sutterella are significantly depleted. 62 These data indicate that Streptococcus, Prevotella, Peptostreptococcus, Capnocytophaga gingivalis, and P. gingivalis are the most common oral bacteria in OSCCs. 31 There is also evidence that oral microorganisms are closely related to OSCC. OSCC patients had significantly higher levels of P. gingivalis in their cancerous tissue than healthy individual gingival tissue. Compared to S. gordonii, P.gingivalis stained more densely in cancerous tissue, and its abundance correlated positively with tumor metastasis. In the saliva of patients with OSCC, bacteria were significantly altered by in-depth microbiome sequencing. 63
Furthermore, studies conducted by Nagy et al. unveiled an increased presence of various oral bacteria in keratinizing squamous cell carcinomas. 31 In the research conducted by Mager et al., 40 oral bacterial species were examined in both cancer-free individuals and subjects with OSCC. A significant number of three species were detected at elevated levels in the saliva of OSCC patients. An 80% prediction rate for cancer cases was achieved using these three bacterial species as diagnostic markers. 31 In addition, B. intermedia and F. nucleatum are associated with OSCC. Researchers are exploring how oral microorganisms may contribute to the development of human cancers based on research linking oral and systemic diseases. It has been extensively documented that oral cancer patients have significantly altered microbiota, including changes in Bifidobacteria, Firmicutes, and Lactobacillaceae. Nevertheless, only these groups reported observable differences in the oral microbiome that might serve as biomarkers. This distinction was made because early studies relied on several well-known and cultivable oral bacteria species and other molecular techniques targeting specific phyla rather than high-throughput methods such as next-generation sequencing. 40 The link between poor oral hygiene and OSCC has also been established by research, underlining the need for public health campaigns to improve oral hygiene. 64 Additionally, it should be considered that other recently introduced compounds have been demonstrated to have a significant influence on the oral environment. The use of postbiotics, 65 lysates, 66 and paraprobiotics 67 can modify Clinical Parameters in periodontal patients, so also these products should be considered in future research as adjuvants for possible preventive strategies.
Studying the microbiota of OSCC patients, Zhang et al. found that Porphyromonas were enriched in OSCC samples, among other microorganisms. 68 Sayehmiri et al. investigated the link between P. gingivalis and oral cancer in an evaluation of systematic reviews and meta-analyses. 69 This bacterium could increase cancer risk by up to 1.36 times when present in the body. As well as increasing the number and size of tumors, Wen et al. demonstrated that P. gingivalis also contributed to their progression. 70 OSCC patients’ saliva contained similar levels of Porphyromonas endodontalis (P. endodontalis) in a recent study by Rai et al. 71 Researchers have long recognized the link between Fusobacteria and oral carcinomas, similar to Porphyromonas. 72 According to Zhao et al., OSCC samples contained more Fusobacterium than normal tissues from the same patients. 73 According to Al-hebshi et al., OSCC biopsies contained greater abundances of F. nucleatum than non-cancerous swabs. 74 Researchers found that Fusobacterium was more abundant in the cancer tissues of 50 OSCC patients in a study by Zhang and colleagues. 68 Perera et al.'s 2018 study showed that Fusobacterium was more abundant in OSCC samples than previously reported. 75 As OSCC progressed from stage 1 to stage 4, the abundance of Fusobacterium periodonticum (F. periodonticum) is increased. 76 A negative association has also been found between the abundance of S. mitis, Porphyromonas pasteri (P. pasteri), and Haemophilus parainfluenzae (H. parainfluenzae) and OSCC progression, according to Yang et al. 76 In conclusion, the intricate relationship between oral microbiota and oral cancer underscores the importance of understanding microbial dysbiosis in disease development. Studies reveal alterations in oral microbial composition associated with oral cancer, suggesting a potential role in carcinogenesis. These shifts not only impact local oral health but also exert systemic effects, implicating microbiota as potential biomarkers or therapeutic targets in oral cancer management. However, further research is warranted to elucidate causative mechanisms and exploit microbiota modulation strategies for prevention and treatment. Ultimately, integrating microbiota analysis into clinical practice may offer novel avenues for personalized oral cancer interventions and improved patient outcomes.
Esophageal Cancer
Cancer-related deaths due to esophageal cancer rank sixth in the world and are eighth most prevalent. 77 Notably, smoking is linked to an elevated risk of both squamous cell carcinoma and adenocarcinoma of the esophagus. 78 This heightened risk is believed to stem from the exposure of the esophageal mucosa to tobacco carcinogens, particularly nitrosamines. 79 Smoking cigarettes daily and for an extended period is directly related to the likelihood of esophageal cancer. 78 However, recent research has shed light on changes in the oral microbiome that may predispose individuals to esophageal cancer.80-82 Morita et al. discovered that Streptococcus anginosus (S. anginosus) was more frequently detected in esophageal cancer samples than in oral cancer and exhibited a higher relative abundance. 80 As reported by Narikiyo et al. in 2004, esophageal cancer patients were twice as likely to exhibit S. anginosus and S. mitis infections than non-cancer patients. 81 The association between S. anginosus and esophageal cancer was further highlighted by Kawasaki et al. 82
According to a study, the risk of esophageal cancer may also be raised by oral bacteria. A high percentage of cancerous tissues exhibited P. gingivalis immunohistochemically, with adjacent tissues displaying 12% and the normal esophageal mucosa exhibiting 0%. Additionally, investigators analyzed the distribution of the lysine-specific gingipain in P. gingivalis 16S rDNA. In addition to its association with cancer progression, P. gingivalis infection was shown to infect the esophageal epithelium of esophageal cancer patients. It could also reduce esophageal cancer mortality by eradicating this oral pathogen. 83 According to Chen et al., in 2021, 57% of the participants had an infection with P. gingivalis. P.gingivalis occurred more frequently in advanced ESCC patients and was associated with a poorer outcome. 84 While Kong et al. found a slightly lower prevalence of P. gingivalis infection, between 42% and 46% of esophageal cancer patients, they also confirmed its association with an unfavorable prognosis. 85 Adenocarcinomas (EACs) and ESCCs are linked to specific types of bacteria, while P. gingivalis is associated with ESCC but not EACs. 86 T. forsythia was also associated with esophageal cancer in a study by Kawasaki et al. 82
In conclusion, emerging evidence suggests a potential link between dysbiosis in the oral microbiome and the development of esophageal cancer, indicating a need for further research to elucidate underlying mechanisms. Understanding these interactions could offer novel avenues for early detection, prevention, and therapeutic interventions for esophageal cancer. Additionally, promoting oral hygiene practices and maintaining a healthy oral microbiome may serve as potential strategies to reduce the risk of esophageal cancer, highlighting the importance of holistic approaches to cancer prevention and treatment.
Pancreatic Cancer
The median survival time for pancreatic cancer is seven months, with 2% to 9% surviving after 5 years. Cancer is legendary for its aggressiveness. 87 In addition, PC most commonly affects older people with distinct biological, functional, and psychosocial characteristics. Pancreatic cancer incidence rates rise with age. Only 13% of cases are diagnosed before 60 years old in the United States. This disease presents a unique subgroup of patients due to related pharmacodynamics and pharmacokinetics. 88 The carriage of specific oral pathogens has been linked to an elevated risk of developing pancreatic cancer. Numerous studies have reported associations between P. gingivalis and PC.89-92 Additionally, F. nucleatum has been identified within pancreatic tumors. 93 Notably, the status of Fusobacterium species is independently linked to a worse prognosis in pancreatic cancer, suggesting its potential as a prognostic biomarker. 94 An increased PC risk was related to Alloprevotella and A.a beyond P. gingivalis and F. nucleatum. 89 In addition, Wei et al. found that PC risk increased when patients carried Streptococcus and Leptotrichina. 95 Farrell et al. found an increase in Granulicatella advances among PC patients in an early study exploring the relationship of oral microbiota with the disease. 96
Furthermore, elevated levels of circulating P. gingivalis antibodies have been correlated with heightened pancreatic cancer risk. 97 A greater prevalence of periodontal pathogens, including P. gingivalis, Porphyromonas, S. mitis, and A.a, in the oral cavity has been associated with an increased pancreatic cancer risk. 97 PC patients’ oral microbiomes can be altered before symptoms appear. 98 A.a and P.gingivalis have been associated with pancreatic cancer risk, with S.mutans, P.gingivalis, and Gemella haemolysans being related to cardiovascular disease. 99 Torres et al. examined salivary flora composition in 108 individuals with high-throughput sequencing technology. The saliva of PC patients contained relatively high levels of P. gingivalis. In addition, salivary bacterial DNA analysis revealed that Bacteroides, Streptococcus, Corynebacterium, and Bacillus were less prevalent in pancreatic cancer patients. In contrast, many other bacteria, including Neisseria, Streptococcus, Corynebacterium, and Bacillus, were more abundant. 91 Leptotrichia levels were higher in PC patients than Porphyromonas levels, which is indicative of pancreatic cancer. 63 The oral, gastrointestinal tract and pancreas microbiomes show changes in patients with PC compared with healthy individuals. PC carcinogenesis and oral microbiota are correlated. PC and Helicobacter pylori seropositivity have been linked in epidemiological and clinical studies. The HBV is implicated in pancreatic tumourigenesis, despite the lack of molecular evidence. A pancreatic microbiome study was conducted as well. There is some evidence that PC may originate from bacteria based on multiple research findings. 100 Several research groups have explored the possibility of using specific oral microbiota members as biomarkers as a result of these studies.
The intricate relationship between oral microbiota shifts and pancreatic cancer reveals significant implications for both prevention and treatment strategies. Studies suggest a potential link between certain oral bacteria and pancreatic cancer development, highlighting the importance of oral hygiene in reducing risk. Moreover, microbial dysbiosis in the oral cavity may influence systemic inflammation, which can exacerbate pancreatic cancer progression. Understanding these interactions could lead to innovative diagnostic tools and therapeutic interventions targeting the oral microbiome to mitigate pancreatic cancer risk and improve patient outcomes. Further research is needed to elucidate the precise mechanisms underlying these interactions and to translate findings into clinical practice effectively.
Colorectal Cancer
Colorectal cancer, also known as CRC, is a slow-progressing malignancy originating from abnormal tissue growth or tumors within the inner lining of the rectum or colon. 101 Typically, CRC predominantly affects the elderly population, with nearly half of all cases occurring in individuals over 75 years old. The risk of developing CRC rises significantly with age, doubling approximately every seven years for those aged 50 and older. 102 Age is the primary risk factor associated with colorectal cancer, as the likelihood of its onset substantially increases beyond the fifth decade of life, making cases under the age of fifty relatively uncommon, except for instances of inherited forms of the disease. 103 Patients with colorectal and pancreatic cancer have reported having oral bacteria in tumors outside their mouths. Among colorectal cancer cases, two specific species of bacteria stand out: F. nucleatum, P. gingivalis. and F. nucleatum, in particular, is noteworthy due to its high prevalence at colorectal cancer sites, with a notable presence in regional lymph node metastases and a prevalence of approximately 2% in rectal tumors and around 11% in cecal tumors. 31 Colorectal cancer tissues have been found to contain F. nucleatum, a Gram-negative anaerobic bacterium. Colorectal cancer is more likely to develop in patients with F. nucleatum abundance. 61 F. nucleatum can induce T-cell apoptosis, inhibit myeloid-derived immunity, and expand myeloid-derived immunity. Periodontal diseases, including tooth loss, may be associated with inflammation, immune dysregulation, and gut microbiota changes. Different tumor cells were protected against immune cell attacks by F. nucleatum from oral sources. 104
Compared with adjacent healthy tissue, Fusobacterium species are more abundant in human colonic adenomas, according to Kostic et al.
105
This finding aligns with several other studies by McCoy et al.,
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Li et al.,
107
and Castellarin et al.
108
F. nucleatum is found in greater abundance in cancerous tissue than in healthy tissue. A. odontolyticus was also more prevalent in CRC cases, according to Kageyama et al.
109
Prevotella intermedia and Treponema denticola also increase CRC risk. In CRC patients, Bifidobacteriaceae were more common. Compared to Prevotella denticola, Prevotella melaninogenica has reduced CRC risks. Streptococcus sp. oral taxon 058, Streptococcus sp. oral taxon 068, and Erysipelotrichaceae were related to lower CRC risk.
110
Despite Kato’s findings, the abundance and presence of fusobacterium are unrelated to colorectal cancer. A history of colorectal cancer, however, was associated with a 28% higher relative abundance of Rothia when adjusted for age and batch type.
111
Various microbiota types may either predispose or protect individuals from colorectal cancer, contributing to the heterogeneity of the disease. It is possible to detect colorectal cancer by profiling the oral microbiome.
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In the other pathway, mutations in epithelial cells impair the intestinal barrier, which allows F. nucleatum to adhere and invade cells. It is also necessary to have both intact pre-FadA and mFadA without the signal peptide for FadA to bind to E-cadherin on the epithelial cell (Figure 2). In response, epithelial cells internalize FadA and activate the β- CRT. Additionally, it activates many other oncogenes, such as NF-B and proinflammatory genes.
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F. nucleatum actives the Wnt/β-catenin pathway.
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The interplay between oral microbiota shifts and colorectal cancer presents a complex and intriguing relationship. Research indicates a potential link between alterations in oral microbial communities and the development or progression of colorectal cancer. While the exact mechanisms remain to be fully elucidated, evidence suggests that oral pathogens and their byproducts may migrate to the gut, triggering inflammation and promoting carcinogenesis. Understanding these interactions could offer novel avenues for early detection, prevention, and treatment strategies for colorectal cancer. Further investigation into the dynamic interplay between oral microbiota and colorectal cancer is warranted to unlock the full therapeutic potential of this relationship.
Gastric Cancer (GC)
There has been a substantial increase in the incidence of GC globally, with the mortality rate ranking fourth simultaneously. 56 A higher prevalence of gastric cancer is seen in Eastern Asia, while a lower prevalence is seen in North America. 114 Smoking, alcohol consumption, and Helicobacter pylori infection are well-known gastric cancer risk factors. 115 GC risk is associated with oral hygiene, but a comprehensive study of the direct link between oral microbes and cancer risk remains elusive. 116 Studies show that oral microbiomes are precursors to oral conditions like dental caries, periodontitis, and oral cancer48,117-123; systemic diseases, especially those involving the digestive system, can be caused by this.124,125
An investigation by Wu et al. into tongue coat microbiota found that Streptococcus is associated with an increased risk of gastric carcinoma.
116
. Several studies have been conducted to investigate the association between Alloprevotella and Veillonella and an increased risk of stomach cancer. The authors of Huang et al. reported that salivary microbiota from 293 patients was more likely to contain proinflammatory taxa such as Corynebacterium and Streptococcus than individuals without gastric cancer.
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Furthermore, Kageyama et al. also found that gastric cancer patients were more likely to have Neisseria and P. gingivalis infections.
109
In a study published in the journal Journal of Applied Microbiology, Wu et al. suggested that oral bacteria may contribute to dysbiosis of the gastric microbiome in patients with gastric cancer caused by H. pylori infections.
127
Additionally, Yang et al. noted that the diversity and abundance of microbial taxa, the genes that makeup gene families, and metabolic pathways might play an important role in the etiology of gastric cancer.
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Some cross-sectional studies have implicated the health of the mouth in some of these findings129,130 and cohort studies,131,132 but comprehensive insights are lacking. According to Ndegwa et al., there is an increased risk of gastric cancer associated with lesions associated with dentures and tooth loss due to dentures. Nonetheless, there was a significant relationship between tooth loss and denture-associated lesions and age, with estimated hazard ratios (HRs) for tooth loss at 50 and denture-associated lesions at 75. At 50, the HRs were 4.24 and 5.91, respectively; at 75, they decreased by 4% and 6% per year. As far as gastric cancer risk is concerned, there is no link between dental plaque or Candida-related or tongue lesions and an increased risk of the disease.
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There is also evidence that the tongue-coating microbiota may be able to serve as a noninvasive biomarker for detecting gastric cancer independent of lifestyle factors. Xu et al. proposed this could be the case.
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CRCs and their precursors, such as gastritis and IBDs, have been associated with oral dysbiosis in recent literature. Oral bacteria can alter intestinal and extra-intestinal health by altering intestinal mucosa’s permeability and perpetuating chronic inflammatory states. Hematogenous dissemination of LPSs and other toxins can lead to distant consequences, including CRC and pancreatic cancers (Figure 3).
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Intestinal diseases and oral bacteria. By swallowing (a) and by entering the bloodstream (b), oral bacteria can reach the intestines and stomach. (c) They can establish intestinal dysbiosis by competing with local flora at the mucosal level of the colon. Inflammation, chronic inflammation, and carcinogenesis are all caused by pathogenic bacteria and their toxins. (d) Apoptotic efficiency is reduced by uncontrolled cell cycles, leading to (e) the onset of cancers and chronic inflammatory diseases.
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In conclusion, research indicates that alterations in the oral microbiome, particularly the presence of specific pathogens like Helicobacter pylori, may contribute to gastric carcinogenesis through inflammation, immune dysregulation, and metabolic changes. Moreover, the bidirectional communication between oral and gastric environments highlights the importance of holistic approaches in cancer prevention and treatment. Further investigations into the mechanisms underlying these interactions are crucial for the development of targeted interventions aimed at modulating the microbiota and mitigating gastric cancer risk.
Lung Cancer
Lung cancer ranks among the most prevalent types of cancer. 136 While smoking remains its primary risk factor, 137 it’s noteworthy that 15-20% of male and over 50% of female lung cancer patients are nonsmokers,138,139 suggesting the involvement of additional risk factors. According to recent studies, lung cancer patients’ oral and gut microbiomes are altered.140,141 There was a study in which 114 individuals with lung cancer were compared with 114 healthy controls, in which a low diversity of alpha bacteria in the oral microbiota was associated with a greater risk of lung cancer. 142
According to Yang et al., female lung cancer patients who do not smoke have reduced oral microbial diversity. 143 An analysis of saliva of lung cancer patients found significant levels of Capnocytophaga and Veillonella, suggesting that these organisms might serve as biomarkers for detecting and classifying disease.140,141 Zhang et al. reported an increase in Veillonella and Streptococcus among NSCLC patients belonging to the Phylum Firmicutes. 144 Liu et al. also identified a link between lung cancer progression and P. gingivalis infection. 145 As a result of Hosgood et al.'s study, specific taxa abundances were found to affect lung cancer risks in particular instances: Phyla Bacteroidetes and Spirochaetes relative abundances are associated with reduced lung cancer risks, whereas Firmicutes relative abundances are associated with an elevated lung cancer risk. 142 According to Vogtamann et al., alpha diversity is related to the risk of lung cancer. Abiotrophia, Lactobacillus, Streptococcus, and Peptoniphilus, all of which contribute significantly to lung cancer risk, were found to raise lung cancer risk when the relative abundance of these bacteria was higher. At the same time, Peptostreptococcus, Eubacterium yurii, or Aggregatibacter were associated with lower lung cancer risk. 146 African American and European American low-income populations with poor oral health were at higher risk of lung cancer, with the risk varying by race and smoking behavior. 147 In conclusion, studies suggest that alterations in oral microbiota composition may influence lung cancer development through various mechanisms, including immune modulation, inflammation, and metabolic pathways. Dysbiosis in the oral microbiome could serve as a biomarker for early detection or even prognostication of lung cancer. Moreover, understanding these interactions may open avenues for novel therapeutic strategies targeting the oral microbiota to prevent or mitigate lung cancer progression. Further research into these relationships is essential for advancing our knowledge and improving clinical outcomes in lung cancer management.
Limitations
Interactions between oral microbiota and cancer in the aging community are a complex and emerging field of research that has garnered significant attention in recent years. While this topic offers promising insights into the relationship between oral health and cancer, it also comes with several limitations that are important to consider. This narrative review will delve into some of these limitations, providing a comprehensive understanding of the challenges researchers face in studying this intriguing connection. Correlation vs Causation: One of the primary limitations in this area of research is the difficulty in establishing causation. Many studies have shown correlations between changes in the oral microbiota and the incidence of cancer, but proving that these shifts cause cancer is a complex task. The oral microbiome is influenced by various factors, including diet, smoking, and genetics, which can confound the relationship between microbiota changes and cancer risk. Limited Longitudinal Studies: Longitudinal studies that track individuals over an extended period are crucial for understanding the dynamic interactions between oral microbiota shifts and cancer in the aging community.
However, there is a shortage of such studies, which makes it challenging to draw concrete conclusions about the long-term effects of oral microbiota changes on cancer risk. Sample Size and Diversity: Many studies in this field suffer from small sample sizes, limiting their statistical power and generalizability. Additionally, these studies often lack diversity in their participant pool, potentially excluding essential subgroups of the aging community and restricting the applicability of their findings. Confounding Factors: Numerous confounding factors can complicate the relationship between oral microbiota and cancer. For instance, lifestyle factors such as smoking, alcohol consumption, and diet can significantly affect both the oral microbiome and cancer risk. Failing to account for these factors can lead to misleading conclusions. Microbiota Variability: The oral microbiota is highly diverse and can vary significantly between individuals. This variability makes identifying specific microbial species or profiles consistently associated with cancer risk challenging. Researchers must grapple with this diversity when pinpointing causative agents within the microbiome. Data Collection Methods: Data collection methods in this field are diverse and not standardized. Different studies may use varying techniques for oral microbiota analysis, including 16S rRNA sequencing or metagenomics. This lack of standardization can make it difficult to compare results across studies and establish a clear consensus. Ethical Challenges: Research on the interactions between oral microbiota and cancer in the aging community may pose ethical challenges. Collecting oral samples from elderly individuals may require special consent and consideration, and the invasive nature of some sampling methods can raise ethical concerns.
Limited Intervention Studies: While observational studies have provided valuable insights, intervention studies that manipulate the oral microbiota to assess its impact on cancer risk are limited. Such studies are complex to design and conduct and often require substantial resources. Age-Related Factors: The aging community presents unique challenges in this context. The aging process can lead to changes in oral health, which may complicate the relationship between oral microbiota shifts and cancer risk. Additionally, elderly individuals often have comorbidities and take medications that can affect the oral microbiome. Publication Bias: There is a risk of publication bias in this area of research. Studies that find significant associations between oral microbiota shifts and cancer risk may be more likely to be published, while studies with null findings may go unreported. This can lead to an overestimation of the strength of the relationship.
In conclusion, while studying interactions between oral microbiota shifts and cancer in the aging community is a promising and fascinating field, it faces several limitations. These limitations include establishing causation, the lack of longitudinal studies, small and non-diverse sample sizes, the influence of confounding factors, microbiota variability, data collection methods, ethical concerns, limited intervention studies, age-related factors, and the potential for publication bias. Researchers must address these limitations to advance our understanding of this critical study area and its implications for cancer prevention and treatment in the aging population.
Future Direction
The human oral cavity harbors a complex and diverse microbial community called the oral microbiota. Recent research has shed light on the dynamic relationship between the oral microbiota and various systemic diseases, including cancer. As our understanding of this relationship continues to evolve, exploring how oral microbiota shifts impact cancer in the aging community becomes increasingly important. This narrative review provides an overview of the current state of knowledge and suggests potential future directions for research in this exciting and rapidly expanding field. The human oral cavity is home to over 700 different species of bacteria, and this diverse microbial community plays a vital role in maintaining oral health. However, disruptions in the balance of this community, referred to as dysbiosis, have been associated with various health conditions, including cancer. Current research suggests that oral microbiota shifts can influence cancer development and progression through several mechanisms: Inflammation: Dysbiosis in the oral microbiota can lead to an inflammatory response, a well-established factor in cancer development. Immune Response: The oral microbiota can modulate the immune system, affecting the body’s ability to recognize and combat cancer cells. Metabolism: Certain oral bacteria can produce metabolites that promote tumor growth. Direct Interactions: Some oral bacteria have been found to infiltrate tumor tissue, potentially influencing its progression. Future research directions are listed as follows: Microbiota-Based Biomarkers: Investigating specific oral microbiota profiles associated with cancer in the aging population can lead to the development of novel diagnostic and prognostic tools. Identifying microbial signatures indicative of cancer risk or progression can aid in early detection and personalized treatment strategies.
Therapeutic Approaches: Developing strategies to manipulate the oral microbiota to prevent or treat cancer is a promising avenue. Probiotics, prebiotics, and other interventions may help restore microbial balance and reduce cancer risk or enhance the effectiveness of cancer therapies. Understanding Aging-Related Changes: As the oral microbiota evolves with age, exploring how these changes impact cancer development and progression in the aging community is essential. Longitudinal studies can provide valuable insights into the role of age-related oral microbiota shifts in cancer. Microbiota-Mediated Immune Modulation: Investigating how the oral microbiota influences the immune system in the context of cancer is critical. Understanding how oral bacteria affect immune responses can inform immunotherapeutic strategies for cancer treatment. Interactions with Cancer Treatments: Exploring how oral microbiota shifts influence the efficacy and side effects of cancer treatments, such as chemotherapy and immunotherapy, is a promising area of research. Optimizing treatment protocols based on an individual’s oral microbiota composition may improve therapeutic outcomes. Patient Education and Prevention: Public health campaigns and educational initiatives should highlight the importance of oral hygiene, the impact of a balanced oral microbiota on overall health, and cancer prevention strategies for the aging population. The interactions between oral microbiota shifts and cancer in the aging community represent a multifaceted and evolving area of research. While the current understanding of this relationship is still in its infancy, it holds great promise for improving cancer prevention, diagnosis, and treatment strategies. As we continue to uncover the intricacies of this complex interaction, future research directions should focus on microbiota-based biomarkers, therapeutic interventions, aging-related changes, immune modulation, treatment optimization, and patient education to address the unique challenges and opportunities presented by this critical aspect of cancer in the aging population. Doing so can pave the way for more effective cancer management and improved quality of life for aging individuals.
Conclusion
In the aging community, the interplay between oral microbiota and cancer represents a complex and evolving field of study. The narrative review highlights that shifts in oral microbial communities can significantly influence cancer development and progression, particularly in older adults who are more susceptible to both oral dysbiosis and malignancies. Evidence suggests that certain pathogenic bacteria may promote carcinogenesis through mechanisms such as chronic inflammation, immune modulation, and direct genetic alterations in host cells. Conversely, a balanced oral microbiota can exert protective effects, underscoring the importance of maintaining oral health in older people. The oral microbiota plays an essential role in triggering and promoting cancer progression within or near the oral cavity and other parts of the body that are distant from the oral cavity. However, numerous findings indicate that certain members of the oral microbiota play a significant role in this progression. Several oral bacteria are associated with OSCC, such as P. gingivalis, F. nucleatum, and various Streptococcus species, such as P. gingivalis, F. nucleatum, and other Streptococcus species known to be associated with OSCC. In addition to P. gingivalis, S. anginosus, and S. mitis, which are the most prominent bacteria associated with increased risk of ESCC, several other bacteria have also been implicated. Apart from F. nucleatum and P. gingivalis in pancreatic cancer cases, certain strains of A strains. It also contributes to increased susceptibility. Colorectal cancer (GC) appears to be influenced by two predominant species, F. nucleatum and P. gingivalis. Additionally, a high abundance of H. pylori has been linked to a heightened risk of GC. However, it is imperative to underscore that further research is required to solidify these associations and draw definitive conclusions. By advancing our knowledge in these areas, we can improve the health outcomes and quality of life for older individuals, ultimately paving the way for personalized and effective cancer prevention and treatment strategies in the aging population.
Footnotes
Author Contributions
Conceptualization: S.A., H.R., S.K., L.K.H., R.S.S., A.B.O., M.A., A.B., M.G., K.A., and Z.S.H.; Methodology: S.A., H.R., S.K., L.K.H., R.S.S., A.B.O., M.A., A.B., M.G., K.A., and Z.S.H.; Validation: S.A., H.R., S.K., L.K.H., R.S.S., A.B.O., M.A., A.B., M.G., K.A., and Z.S.H.; Resources: S.A., H.R., S.K., L.K.H., R.S.S., A.B.O., M.A., A.B., M.G., K.A., and Z.S.H.; Writing—original draft preparation: S.A., H.R., S.K., L.K.H., R.S.S., A.B.O., M.A., A.B., M.G., K.A., and Z.S.H.; Writing-review and editing: S S.A., H.R., S.K., L.K.H., R.S.S., A.B.O., M.A., A.B., M.G., K.A., and Z.S.H.; Supervision: S.A., H.R., M.A., and Z.S.H. The published version of the manuscript has been read and approved by all authors.
Declaration of Conflicting Interests
The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
Funding
The author(s) received no financial support for the research, authorship, and/or publication of this article.
Ethical Statement
Data Availability Statement
This is a review article, and all data are included in this text.