Table 5.

General characteristics of the studies analyzed.

Author, Year	Study Design	Sample Size	Principal Findings
Miskiewicz et al., 2015 [32]	Case control study	Pancreatic cancer n = 18, chronic pancreatitis n = 39, controls n = 119	The activation of the NLRP3 inflammasome present in subjects with periodontitis and pancreatic cancer is analyzed. This activation is linked to both pathologies. A genomic study of this receptor is carried out. All periodontal parameters (BOP and CAL) were significantly worse (p = 0.001 and p = 0.001, respectively) in patients with chronic pancreatitis than in the two other groups. The NLRP2 polymorphism was associated with chronic pancreatitis, whereas the NLRP3 polymorphism was comorbid with pancreatic cancer and the increase of CAL.
Chou et al., 2018 [15]	Retrospective Cohorts	n = 25,485 individuals with periodontitis. Gastrointestinal cancers: 275 mild periodontitis; 324 severe periodontitis	Severe periodontitis not associated with an increased risk of total individual gastrointestinal cancers compared con mild periodontitis
Fan et al., 2017 [31]	Case control study	Pancreatic cancer cases= 361 Control = 371 (were drawn from 2 cohorts the American Cancer Society and National Cancer Institute Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial)	P. gingivalis and Aa > pancreatic cancer risk (OR 1.60). Phylum Fusobacteria and genus Leptotrichia < risk. Oral microbiota may be a role pancreatic cancer aetiology.
Gerlovin et al., 2019 [22]	Cross sectional study (with a Biennial follow-up questionnaire by mail).	n = 59,000 African American women	A total of 78 incidents of pancreatic cancer occurred during follow-ups from 2007 through 2016, with participants contributing an average of 9.85 years of follow-up. Relative to the reference category of women who never reported either tooth loss or periodontal disease, multivariable HRs were 1.77 for periodontal disease with no tooth loss, 1.58, for periodontal disease with tooth loss, and 2.05 for tooth loss without periodontal disease. Results from this study suggest that poor oral health may play a role in racial disparities in pancreatic cancer incidence.
Gnanasekaran et al., 2020 [26]	Experimental study	3 cellular lines of Pancreatic ductal adenocarcinoma (2 humans and 1 mouse cells line). Cells with absence of P. gingivalis vs. cells with P. gingivalis.	This study focuses on the relationship between the mechanism of cell cycle impairment in the event of superinfection by periodontopathogens. Specifically, this study is the first to test the mechanistic involvement of P. gingivalis in pancreatic tumorigenesis, applying in vitro tools and a xenograft pancreatic carcinoma model in vivo. Our results reveal a previously unknown direct effect of P. gingivalis on PDAC progression, highlighting the importance of the interplay between hypoxia and P. gingivalis intracellular survival. P. gingivalis infection enhances PDAC cell proliferation.
Heikkila et al., 2018 [12]	Cohort Longitudinal study	n = 68,273 Periodontal status was defined based on periodontal treatment procedure codes.	This research analyzes the reported history of dental status (number of teeth, health indices, initial caries, decayed/missing/filled teeth) and CPITN. Furthermore, it defines periodontitis as a binary variable (no/yes) based on the above codes. Data support the association between periodontitis and mortality in all types of cancer, especially pancreatic cancer.
Michaud et al., 2013 [34]	Cohort study to select cases and control from a data base	Blood samples from 405 pancreatic cancer cases and 416 matched controls.	This study performed blood tests to detect antibodies to periodontal bacteria. Individuals with high levels of antibodies against P. gingivalis P. gingivalis ATTC 53,978, a pathogenic periodontal bacterium, had a 2-fold higher risk of pancreatic cancer than individuals with lower levels of these antibodies (odds ratio [OR], 2.14; 95% confidence interval [CI], 1.05–4.36; >200 ng/mL vs. ≤200 ng/mL). People with high levels of antibodies against common oral bacteria had a 45% lower risk of pancreatic cancer compared to those with a profile of lower antibody levels. Periodontal disease might increase the risk of pancreatic cancer.
Miskiewiez et al., 2018 [23]	Case control study	Evaluated oral health level and periodontal status among 3 groups: n = 29 cancer pancreas; n = 41 chronic pancreatitis; n = 50 controls	Both pathologies are linked based on the systemic inflammatory mediators present in the blood and the correlation with local inflammation measured with the BOP. Periodontitis in pancreatic cancer is independent of the state of oral hygiene. BOP 62.5%, enzyme activity (lipase and amilasa) and chronic pancreatitis were interrelated.
Kei et al., 2015 [35]	Transversal study	283 pancreatic cancer tissue specimens	The presence of periodontopathogens is detected as biomarkers of malignancy in pancreatic tumors. This study associates bacterial tissue infection with cell cycle changes and carcinogenic potential. Periodontal bacteria were found in those samples from patients with the highest risk. The presence of FN was in 25 samples (8.8%) and largely coincided with high mortality rates.
Nieminen et al., 2018 [14]	Experimental study	149 orodigestive tumor tissue samples Tissue samples comprised squamous cell carcinomas (SCCs) of tongue (n = 29), tonsil (n = 25), esophagus (n = 3), and adenocarcinoma of stomach (n = 32), pancreas (n = 6), and colon (n = 54).	This study associates bacterial tissue infection with cell cycle changes and the inhibition of protective factors. Td-CTLP was present in the majority of orodigestive tumor samples. Td-CTLP was found to convert pro MMP-8 and -9 into their active forms. In addition, Td-CTLP was able to degrade the proteinase inhibitors TIMP-1, TIMP-2, and a-1-antichymotrypsin, as well as complement C1q.
Sugiyama et al., 2022 [10]	Experimental study	2 groups of 5 mice: Received P. gingivalis P. gingivalis -LPS and controls. Effect on P. gingivalis -LPS on the gut flora	Infection with periodontopathogens increases TFNα and other inflammatory mediators that are also increased in cancer patients. This route of infection increases the risk of developing cancerous pathologies. The administration of periodontal pathogens can cause changes in the intestinal flora, affecting its physiological functions increasing the risk of cancer.
Tan et al., 2022 [20]	Case control study	Study intrapancreatic microbiome composition on resected cancer tissue and matched normal adjacent tissues	In this research, a path of association is indicated due to the increase in low-grade systemic inflammation that occurs due to periodontitis because of the invasion of P. gingivalis. Neutrophils (main cells of the innate response to bacterial aggression) are secreters of elastase and are involved in cellular changes that occur in cancer. P. gingivalis modifies the inflammatory tumor microenvironment and recruits neutrophils and enhances the secretion of neutrophils elastase to promote cancer pancreatic
Vogtmann et al., 2019 [33]	Case control study	A total of 273 pancreatic adenocarcinoma cases and 285 controls	The abundance of some specific microbial taxa was also associated with pancreatic cancer, including Haemophilus, Enterobacteriaceae, Lachnospiraceae G7, Bacteroidaceae, and Staphylococcaceae. The microbial community and taxa level differences could be related to the presence of pancreatic cancer or the risk of developing pancreatic cancer. P. gingivalis was not associated with pancreatic cancer and was detected in 76.92% of cases and 76.49% of controls.

Aa: Aggregatibacter actinomycetemcomitans; BOP: bleeding on probing; CAL: clinical attachment loss; CPITN: Community Periodontal Index of Treatment Needs from WHO; FN: Fusobacterium nucleatum; MMP: matrix metalloproteinases; NLRP: nod-like receptor pyrin domain; PDAC: pancreatic ductal adenocarcinoma; P. gingivalis: Porphyromonas gingivalis; Td-CTLP: Treponema denticola chymotrypsin-like proteinase; TIMP: tissue inhibitors of matrix metalloproteinases.