The term "periodontal disease" refers to a group of chronic inflammatory illnesses caused by specific microorganisms from subgingival biofilm, that affect the tooth-supporting tissues. Recent research has also shown that periodontal infection plays a role in aggravating systemic disease states at distal sites, reinforcing the significance of the oral cavity for general health. Additionally, it has been suggested that gastroenterological malignancies may be promoted by hematogenous, enteral or lymphatic translocation of periopathogens. In the past 25 years, the global burden of pancreatic cancer (PC) has more than doubled, making it one of the major causes of cancer-related mortality. Periodontitis has been linked to at least 50% increased risk of PC and it could be considered a risk factor for this malignancy. A recent study performed on 59000 African American women with a follow up of 21 years showed that participants who had poor dental health had higher chances of PC. The findings, according to researchers, might be related to the inflammation that some oral bacteria trigger. Regarding the mortality of PC, periodontitis considerably raises the chance of dying from PC. Microbiome alterations in the gut, oral cavity and pancreatic tissues of PC patients occur when compared to healthy flora, demonstrating a link between PC and microecology. Inflammation may also contribute to PC development, although the underlying pathway is not yet known. The function of the microbiome in PC risk has drawn more focus over the last decade. Future risk of PC has been linked to the oral microbiome, specifically increased levels of Porphyromonas gingivalis and Aggregatibacter actinomycetemcomitans and decreased relative abundance of Leptotrichia and Fusobacteria, suggesting that it may have an impact on the inflammatory condition by expanding, altering, and regulating the commensal microbiome. Patients who received periodontal treatment had significantly decreased incidence rate ratios for PC. By analyzing patterns in the microbiome composition throughout PC development and establishing strategies to enhance the cancer-associated microbial system, we can increase the efficacy of therapy and eventually find an application for the microbial system. The development of immunogenomics and gut micro-genomics in the life sciences will result in a significant advancement in our understanding of how microbial systems and immunotherapy interact, and it may also have intriguing therapeutic implications for extending the lifetime of PC patients.

The term "periodontal disease" refers to a group of inflammatory illnesses that affect the tooth-supporting tissues, ultimately leading to tooth loss and even resulting in systemic inflammation. Up to 90% of people worldwide are affected by the two most common periodontal disorders, gingivitis and periodontitis[1]. The cornerstone of avoiding periodontitis is the treatment of gingivitis, a reversible inflammation of the gingiva that takes place before periodontitis. By gradually destroying the alveolar bone and periodontal ligament, periodontitis-which is typically caused by Gram-negative bacteria-can result in recession, increased probing depth, or both[1].

Periodontal disease is initiated and progresses due to a dysbiosis of the commensal oral microbiota, which subsequently interacts with the host's immune system[2,3]. Diverse bacteria (or certain gene combinations within the community) may be capable of having various functions within the periodontal ecosystem that collaborate to generate and establish a microbiota that promotes disease. Numerous microbial species were found in the oral cavity, but most of them are commensal bacteria such as Streptococcus, Capnocytophaga, Eikenella corrodens and Veillonella parvula; nevertheless, in condition of some imbalances, they could also become pathogens for the tooth supporting tissues[4]. One of the crucial requirements for the development of a potentially pathogenic community is the ability of certain species to modify host responses in ways that compromise immune surveillance and tip the balance from homeostasis to dysbiosis[5]. Porphyromonas gingivalis (P. gingivalis), Treponema denticola and Tanerella forsythia, Gram-negative and anaerobiotic bacteria, possess a higher virulency and aggressiveness and are also involved in periopathogenesis[4].

Numerous mechanisms, including the systemic dissemination of periodontal pathogens and the systemic leakage of local inflammatory mediators, have been involved in the strong association between periodontitis and a number of systemic disorders[6]. Periodontal and systemic diseases have a two-way relationship; periodontal disease can have negative effects on the overall systemic health, and some systemic conditions increase the risk of periodontal disease onset[6,7]. Recent research has also shown that periodontal infection plays a role in aggravating systemic disease states at distal sites, including cardiovascular disease, adverse pregnancy outcomes, diabetes mellitus, Alzheimer's disease, inflammatory bowel diseases, and various cancer types, reinforcing the significance of the oral cavity for general health[6-9]. Additionally, it has been suggested that gastroenterological malignancies may be promoted by hematogenous (oral-blood axis via the perturbed periodontal tissues), enteral (oral-gut axis via saliva) or lymphatic (via the lymphatic drainage system) translocation of periopathogens[10-12].

In the past 25 years, the global burden of pancreatic cancer (PC) has more than doubled, making it one of the major causes of cancer-related mortality[13]. It comprises for almost 2% of all malignancies and is linked to 5% of deaths caused by cancer[14]. North America, Europe, and Australia have the highest incidence rates of PC[14,15]. While the ageing process of the global population could increase the incidence, other major risk factor, specifically smoking, obesity, diabetes and drinking alcohol should be considered for their modifiable nature[13,15].

Only around 20% of patients are initially diagnosed with early-stage PC, which is surgically resectable, thus explaining the low survival rates[13]. Even after a potentially radical treatment, the majority of patients eventually relapse, and their 5-year survival rate is only 2%–9%[14]. During the initial stages of the disease and its progression to advanced pancreatic metastasis, when tumor cells are very invasive, the majority of patients don't exhibit any apparent symptoms. Considering that it is one of the life-threatening malignant tumors, early diagnosis is imperative[13-15]. Pancreatic ductal adenocarcinomas account for over 90% of pancreatic malignancies[13].

Viral infections have been shown to express a strong relationship with cancer, but also certain bacteria can stimulate or trigger uncontrolled cell development by escaping the immune system or preventing apoptosis. Since periodontitis is a chronic oral bacterial infection, a potential link between periodontitis and PC has been proposed[9].

The purpose of this current review is to update and organize the most recent data on periodontal disease and its implications in PC in order to highlight the fact that there is sufficient evidence to establish a connection between them, through the action of periodontal pathogens, taking into account that periopathogens are essential for the onset and progression of periodontal disease, and their involvement in various systemic disorders has already been proven. This would encourage more exploration into the negative impact of periodontal disease on the development of PC in individuals with both disorders. The findings of future studies may have significant implications for periodontal and gastroenterological practice. For instance, periodontal screening for patients with this type of cancer and periodontal therapy, when necessary, may help lower the risk of PC's adverse evolution while also improving the quality of life for these patients.

Periodontitis has been linked to various malignancies, with risk ranging between 14% and 20%[16,17]. Periodontitis has been linked to at least 50% increased risk of PC and it could be considered a risk factor for this malignancy[1,16,17], whereas other studies reported no significant association between periodontal disease and PC[1,18]. Periodontal disease risk is linked to a number of variables that are known to increase the risk of PC, such as smoking, alcohol drinking, and diabetes. The oral microbiome is thus affected by these exposures and circumstances, leading to dysbiosis and a relative increase in the amount of oral pathogenic microorganisms[19,20].

A 10 years follow-up study showed that the risk of all or specific gastro-intestinal malignancies, including PC, was not significantly associated with the severity of chronic periodontitis. After sex and age stratification, this null connection remained consistent[21]. No associations were found between the risk of PC and the eight single nucleotide polymorphisms, which provide the strongest explanation for a genetic predisposition to developing chronic or aggressive periodontitis[22].

Patients with PC may exhibit increased bleeding on probing when exposed to minimal amounts of dental plaque, which could point to periodontitis’ excessive activity, often known as a hyperactive phenotype. Although dysfunctions of the CD14 axis receptor, nuclear factor kappa B (NF-kB) factors, and NOTCH pathway proteins are hypothesized, the source of high bleeding on probing index values at a relatively low plaque index rate is unknown at this time[23].

A cohort study that followed 5889441 individuals for a median of 7.2 years discovered that, compared to those with a healthy dental status, people with root canal infections, mild inflammation, and periodontitis in the under-50 age group had a 58% higher risk of developing PC, while those with periodontitis had a 56% higher risk. Only the subgroup of those with periodontitis exhibited a 20% elevated risk in the 50–70 age range. In all age categories, people with fewer teeth seemed to be at a higher risk[12]. Another study found that having periodontal disease was linked to a higher risk of developing PC in people 65 years of age or older, but not in people under 65[24].

A recent study performed on 59000 African American women with a follow up of 21 years showed that participants who had poor dental health had higher chances of PC[25]. Participants who reported both gum disease and tooth loss had a 58% higher chance of receiving a PC diagnosis[25]. Furthermore, compared to women who had neither periodontal disease nor tooth loss, those who reported periodontal gum disease but no tooth loss had a 77% higher chance of being diagnosed with PC[25]. Their research revealed that PC diagnoses were twice as likely to occur in women without periodontal disease but with absent teeth. Furthermore, the risk was significantly increased among patients who had at least 5 extracted teeth[25]. The findings, according to researchers, might be related to the inflammation that some oral bacteria trigger[25]. In an older research paper, when periodontal disease and recent tooth loss were evaluated together, the risk of PC significantly rose, with a risk ratio of 2.71 compared to people who had neither periodontal disease nor recent tooth loss. These findings imply that recent tooth loss may be a sign of severe periodontal disease[26].

Compared to the link between tooth loss and PC, the relationship between periodontal disease and PC has showed more consistent evidence[16,24,27,28]. According to a meta-analysis, the summary relative risk for periodontitis and PC was 1.74, while the risk for edentulism was 1.54[18]. Nevertheless, data is inconsistent as other research reported no associations between tooth loss and PC[27,28].

So far, research indicates that, independently of other recognized risk factors, like smoking, periodontal disease may contribute to the development of PC[26,29]. A prospective research of 48375 male health professionals revealed that those who had a history of periodontal disease at baseline had a 64% higher risk of PC[26,27,30]. In people who had never smoked, there was a stronger correlation between periodontal disease and PC[26,27,30]. Smoking is also linked to a two-fold increase in the risk of PC[26].

In a research with a long follow-up (10 years) and a substantial population-based cohort (568273 participants), there was a strong positive association between periodontitis and cancer mortality, particularly PC mortality[31]. After adjusting for age, sex, and additional controls for smoking, education, race/ethnicity, and body mass index (BMI), orodigestive cancer mortality was higher in patients with periodontal disease. Furthermore, the severity of periodontal disease enhanced the risks for orodigestive cancer mortality[32]. With age, sex, smoking, education, race/ethnicity and BMI adjustments, the mortality for PC in periodontal patients increased by nearly four times[32].

Regarding the mortality of PC, periodontitis considerably raises the chance of dying from PC[1].

Multiple diverse organisms, such as bacteria, viruses, fungus, and protozoa, compose the human microbiota, as the presence of certain microorganisms was reported even before birth, in the human placenta[14,33,34]. They are essential for maintaining human health and preventing illnesses. Bacteria's ability to cause cancer is linked to both individual species and dysbiotic ecosystems[11]. Some hepatitis viruses, particular oral, gastrointestinal, and pancreatic microorganisms may have an etiological role in PC development[14,33,35].

Microbial diversity in the colon and other internal organs is decreased as a result of human microbial system dysregulation and, in PC patients, the imbalance of the intestinal microbiota is common[14,33,35]. Regardless of the severity of PC, the bacterial DNA patterns in the pancreatic and duodenal tissue of the same participants were comparable, indicating that bacteria may be traveling from the gut to the pancreas[36]. Microbiome alterations in the gut, oral cavity and pancreatic tissues of PC patients occur when compared to healthy flora, demonstrating a link between PC and microecology (Table 1). Inflammation may also contribute to PC development, although the underlying pathway is not yet known[37].

According to scientific research, the human microbiota has a key contribution to the onset, progression, and prognosis of PC[14,33,35,38]. The NYU Langone study found that, in contrast to other research linking poor oral health to PC, oral microbiome dysbiosis actually occurred before the malignancy took hold[30].

The function of the microbiome in PC risk has drawn more focus over the last decade. Using 16S rRNA fluorescent probes and quantitative real-time polymerase chain reaction, it was discovered that PC patients had an intrapancreatic bacterial load that was 1000 times higher than that of normal pancreatic tissue. The mean relative proportions of certain taxa varied between the healthy cohort, pancreatic benign neoplasm, and PC[35]. A recent case-control study found that there were discrepancies in the overall bacterial communities between those with PC and controls. While the presence of Enterobacteriaceae, Lachnospiraceae G7, Bacteroidaceae, or Staphylococcaceae was linked to an increased risk of PC, increased relative levels of Haemophilus were linked to a lower risk[39]. Currently, Neisseria elongata, P. gingivalis, Streptococcus mitis and Fusobacterium are the key pathogens implicated in PC and it was postulated that Fusobacterium can significantly decrease a patient's survival time when it comes to the prognostic evaluation of PC[11,14].

By causing DNA damage, epigenetic alterations of phagocytosis-related genes, immunological response, chromatin organization, cellular proliferation, and higher DNA mutation rates, the microbiome can influence cancer’s development. The microbiome can also potentially cause signaling pathway disruption, enhanced local inflammation, and impaired epithelial barrier function[11]. According to one study, the point mutations in the PC patient's p53 tumor suppressor gene may be caused by the peptidyl arginine deaminase enzymes that are specific to oral periopathogen P. gingivalis[40].

According to one study, periodontitis, PC and chronic pancreatitis may all share the excessive inflammatory response brought on by the mutations of certain genes, Q705K and F359L, which are amino acids in NLRP2 and NLRP3. It has been shown that rs35829419 (Q705K, NLRP3) polymorphism is more common in people with PC, while rs17699678 (F359L, NLRP2) polymorphism is more common in people with chronic pancreatitis[41].

By triggering systemic inflammation or, alternatively, by increasing the synthesis of bacterial metabolites, such as nitrosamines, reactive oxygen species sulfides, butyrate or acetaldehydes, chronic periodontitis through periopathogens may facilitate pancreatic carcinogenesis[9-11,18]. According to various theories, nitrosamines, acetaldehyde and gastric acidity play a significant role in the development of PC[9,18,27,42], as they can cause DNA alkylation, mutations, damage or impaired repair, which can result in inflammation or tumorigenesis[11].

Although the underlying mechanism connecting periodontitis to gastrointestinal cancers is not fully understood, and it is still uncertain which stage of periodontitis may affect cancer risk, gastroenterological malignancies have a high biological plausibility in relation to oral infections and inflammation[1,19]. Blood antibodies to certain oral pathogens and poor oral health status were linked to an elevated risk of PC[19,43]. A person's chance of developing PC was increased by 70% and 80%, respectively, whether they had oral mucosal lesions, or tongue lesions caused by Candida[1]. PC development was positively associated with tooth loss, although seropositivity to Helicobacter pylori was not significantly correlated with tooth loss[44]. Recent research could not establish a link between Helicobacter pylori and a higher risk of PC[45].

Future risk of PC has been linked to the oral microbiome, specifically increased levels of P. gingivalis and Aggregatibacter actinomycetemcomitans (A. actinomycetemcomitans) and decreased relative abundance of Leptotrichia and Fusobacteria, suggesting that it may have an impact on the inflammatory condition by expanding, altering, and regulating the commensal microbiome[11-13,29]. It's noteworthy that Leptotrichia species, which are opportunistic pathogenic bacteria, are also frequently discovered in immunosuppressed individuals[46]. Using direct bacterial DNA analysis from samples of people's saliva taken years before diagnosis, a cohort research found strong associations between two periopathogens, P. gingivalis and A. actinomycetemcomitans, and PC[1,10,43]. This connection is also confirmed by a research which found that pre-diagnostic blood samples from those diagnosed with PC had more antigens to P. gingivalis than samples from controls[13]; in contrast, phylum Fusobacteria appeared to be linked with a reduced chance of developing PC[10,33]. There are still unanswered doubts regarding the mechanism underlying this connection and whether there is a direct causal correlation[13].

Oral microbiome profiles in patients with PC and controls significantly differ, according to scientific research[47]. Combining immunological dysregulation, genomic damage, and microbial variations between PC cases, early PC cases, and healthy controls, these factors point to a mechanistic role for oral microbiome components in PC development[11].

Bacteria can have a significant impact on carcinogenesis’ mechanisms[43,45]. The bacterial "driver-passenger model" best describes this method of collaboration, in which the "driver" pathogen, such as A. actinomycetemcomitans, causes DNA damage in the host cells. A more stable ecosystem results from the modifications this driving pathogen makes to the microenvironment around the host cell. These changes make it easier for other germs to proliferate and survive. Once the cancer cells have been located, the "passenger" bacteria, such as F. nucleatum, will operate as a connecting organism between the early colonization microorganisms (A. actinomycetemcomitans) and the late colonizing microbes (P. gingivalis). P. gingivalis has the ability to block cancer cell death and encourage tumor growth[43,45]. The three microorganisms could have a significant synergistic impact on the onset and progression of cancer. This means that a diversified microbial environment is both more stable and harmful than a single species of bacterium, which may be a key element in the development of cancer[45].

Previous research has demonstrated a connection between microbes and the development and spread of PC. The development of biomarkers that may control how responsive cancers are to therapeutic drugs may be regulated by the human microbial system, which is particularly advantageous for enhancing PC's clinical efficiency. Chemotherapy and immunotherapy can be paired with microbial systems, which may provide PC patients a significant amount of hope. But there is still a lot of disagreement in this area[14].

These researches support the hypothesis that certain characteristics of the human microbiome play a significant role in shaping the immune response in a manner that facilitates tumor development. Given the growing epidemiological data linking periodontal disease to PC and the rapid unraveling of new molecular links between periopathogens and cancer development, the impact of bacterial infection on pancreatic carcinogenesis has to be given more consideration. More research in this field is expected to improve our knowledge of this aggressive malignancy and provide us with new chances for early identification and/or the development of treatments.