Variations of oral microbiota are associated with pancreatic diseases including pancreatic cancer

Objective The associations between oral diseases and increased risk of pancreatic cancer have been reported in several prospective cohort studies. In this study, we measured variations of salivary microbiota and evaluated their potential associations with pancreatic cancer and chronic pancreatitis. Methods This study was divided into three phases: (1) microbial profiling using the Human Oral Microbe Identification Microarray to investigate salivary microbiota variation between 10 resectable patients with pancreatic cancer and 10 matched healthy controls, (2) identification and verification of bacterial candidates by real-time quantitative PCR (qPCR) and (3) validation of bacterial candidates by qPCR on an independent cohort of 28 resectable pancreatic cancer, 28 matched healthy control and 27 chronic pancreatitis samples. Results Comprehensive comparison of the salivary microbiota between patients with pancreatic cancer and healthy control subjects revealed a significant variation of salivary microflora. Thirty-one bacterial species/clusters were increased in the saliva of patients with pancreatic cancer (n=10) in comparison to those of the healthy controls (n=10), whereas 25 bacterial species/clusters were decreased. Two out of six bacterial candidates (Neisseria elongata and Streptococcus mitis) were validated using the independent samples, showing significant variation (p<0.05, qPCR) between patients with pancreatic cancer and controls (n=56). Additionally, two bacteria (Granulicatella adiacens and S mitis) showed significant variation (p<0.05, qPCR) between chronic pancreatitis samples and controls (n=55). The combination of two bacterial biomarkers (N elongata and S mitis) yielded a receiver operating characteristic plot area under the curve value of 0.90 (95% CI 0.78 to 0.96, p<0.0001) with a 96.4% sensitivity and 82.1% specificity in distinguishing patients with pancreatic cancer from healthy subjects. Conclusions The authors observed associations between variations of patients' salivary microbiota with pancreatic cancer and chronic pancreatitis. This report also provides proof of salivary microbiota as an informative source for discovering non-invasive biomarkers of systemic diseases.

[1]  P. Altevogt,et al.  L1CAM–integrin interaction induces constitutive NF-κB activation in pancreatic adenocarcinoma cells by enhancing IL-1β expression , 2010, Oncogene.

[2]  H. Risch,et al.  ABO blood group, Helicobacter pylori seropositivity, and risk of pancreatic cancer: a case-control study. , 2010, Journal of the National Cancer Institute.

[3]  David Elashoff,et al.  Salivary transcriptomic biomarkers for detection of resectable pancreatic cancer. , 2010, Gastroenterology.

[4]  T. Vogel,et al.  Human Pathogens Abundant in the Bacterial Metagenome of Cigarettes , 2009, Environmental health perspectives.

[5]  J. Goedert,et al.  Chlamydia pneumoniae Infection and Risk for Lung Cancer , 2004, Cancer Epidemiology, Biomarkers & Prevention.

[6]  M. Falconi,et al.  Identification of a novel antibody associated with autoimmune pancreatitis. , 2009, The New England journal of medicine.

[7]  B. Paster,et al.  Microarray analysis of the microflora of root caries in elderly , 2009, European Journal of Clinical Microbiology & Infectious Diseases.

[8]  B. Lindkvist,et al.  A prospective study of Helicobacter pylori in relation to the risk for pancreatic cancer , 2008, BMC Cancer.

[9]  Holly Janes,et al.  Pivotal Evaluation of the Accuracy of a Biomarker Used for Classification or Prediction: Standards for Study Design , 2008, Journal of the National Cancer Institute.

[10]  E. Giovannucci,et al.  A review of the relationship between tooth loss, periodontal disease, and cancer , 2008, Cancer Causes & Control.

[11]  C. de Martel,et al.  Helicobacter pylori Infection and Development of Pancreatic Cancer , 2008, Cancer Epidemiology Biomarkers & Prevention.

[12]  A. Rodloff,et al.  Periodontitis is associated with a loss of colonization by Streptococcus sanguinis. , 2008, Journal of medical microbiology.

[13]  A. Jemal,et al.  Cancer Statistics, 2008 , 2008, CA: a cancer journal for clinicians.

[14]  P. François,et al.  Novel Microarray Design Strategy To Study Complex Bacterial Communities , 2008, Applied and Environmental Microbiology.

[15]  G. Rieder,et al.  H pylori infection causes chronic pancreatitis in Mongolian gerbils. , 2007, World journal of gastroenterology.

[16]  J. Kountouras,et al.  Challenge in the pathogenesis of autoimmune pancreatitis: potential role of helicobacter pylori infection via molecular mimicry. , 2007, Gastroenterology.

[17]  E. Giovannucci,et al.  A prospective study of periodontal disease and pancreatic cancer in US male health professionals. , 2006, Journal of the National Cancer Institute.

[18]  R. Goldenberg,et al.  Preterm birth and periodontal disease. , 2006, The New England journal of medicine.

[19]  S. Hasbun,et al.  Periodontal pathogens in atheromatous plaques isolated from patients with chronic periodontitis. , 2006, Journal of periodontal research.

[20]  I. N. Rôças,et al.  Catonella morbi and Granulicatella adiacens: new species in endodontic infections. , 2006, Oral surgery, oral medicine, oral pathology, oral radiology, and endodontics.

[21]  Masafumi Nakamura,et al.  Nuclear factor-kappaB contributes to hedgehog signaling pathway activation through sonic hedgehog induction in pancreatic cancer. , 2006, Cancer research.

[22]  E. Fishman,et al.  Screening for early pancreatic neoplasia in high-risk individuals: a prospective controlled study. , 2006, Clinical gastroenterology and hepatology : the official clinical practice journal of the American Gastroenterological Association.

[23]  M. Karin.  Nuclear factor-κB in cancer development and progression , 2006, Nature.

[24]  U. Stenram,et al.  Helicobacter species ribosomal DNA in the pancreas, stomach and duodenum of pancreatic cancer patients. , 2006, World journal of gastroenterology.

[25]  DL Mager,et al.  Bacteria and cancer: cause, coincidence or cure? A review , 2006, Journal of Translational Medicine.

[26]  F. C. Gibson,et al.  Innate Immune Signaling and Porphyromonas gingivalis-accelerated Atherosclerosis , 2006, Journal of dental research.

[27]  M. Karin.  Nuclear factor-kappaB in cancer development and progression. , 2006, Nature.

[28]  R. DePinho,et al.  Genetics and biology of pancreatic ductal adenocarcinoma , 2006, Genes & development.

[29]  J. A. Aas,et al.  Defining the Normal Bacterial Flora of the Oral Cavity , 2005, Journal of Clinical Microbiology.

[30]  Michael Karin,et al.  IKK/NF-κB signaling: balancing life and death – a new approach to cancer therapy , 2005 .

[31]  M. Posner,et al.  The salivary microbiota as a diagnostic indicator of oral cancer: A descriptive, non-randomized study of cancer-free and oral squamous cell carcinoma subjects , 2005, Journal of Translational Medicine.

[32]  C. Guarneri,et al.  Helicobacter pylori and autoimmune pancreatitis: role of carbonic anhydrase via molecular mimicry? , 2005, Journal of cellular and molecular medicine.

[33]  J. Kountouras,et al.  Autoimmune pancreatitis, Helicobacter pylori infection, and apoptosis: a proposed relationship. , 2005, Pancreas.

[34]  Yihong Li,et al.  Salivary Actinomyces naeslundii genospecies 2 and Lactobacillus casei levels predict pregnancy outcomes. , 2005, Journal of periodontology.

[35]  J. Kountouras,et al.  A concept on the role of Helicobacter pylori infection in autoimmune pancreatitis , 2005, Journal of cellular and molecular medicine.

[36]  Michael Karin,et al.  IKK/NF-kappaB signaling: balancing life and death--a new approach to cancer therapy. , 2005, The Journal of clinical investigation.

[37]  V. Sambri,et al.  Molecular detection of Treponema denticola and Porphyromonas gingivalis in carotid and aortic atheromatous plaques by FISH: report of two cases. , 2005, Journal of medical microbiology.

[38]  J. Meurman,et al.  Oral health, atherosclerosis, and cardiovascular disease. , 2004, Critical reviews in oral biology and medicine : an official publication of the American Association of Oral Biologists.

[39]  J. Tuomilehto,et al.  High serum antibody levels to Porphyromonas gingivalis predict myocardial infarction , 2004, European journal of cardiovascular prevention and rehabilitation : official journal of the European Society of Cardiology, Working Groups on Epidemiology & Prevention and Cardiac Rehabilitation and Exercise Physiology.

[40]  H. C. van der Mei,et al.  The Influence of Biosurfactants Released by S. mitis BMS on the Adhesion of Pioneer Strains and Cariogenic Bacteria , 2004, Biofouling.

[41]  A. van Dorsselaer,et al.  Carcinogenic properties of proteins with pro-inflammatory activity from Streptococcus infantarius (formerly S.bovis). , 2004, Carcinogenesis.

[42]  D. Whitcomb.  Inflammation and Cancer V. Chronic pancreatitis and pancreatic cancer. , 2004, American journal of physiology. Gastrointestinal and liver physiology.

[43]  R. Salem,et al.  Association of Streptococcus bovis bacteremia with colonic neoplasia and extracolonic malignancy. , 2004, Archives of surgery.

[44]  M. Tsuneyoshi,et al.  Interleukin 1β Enhances Invasive Ability of Gastric Carcinoma through Nuclear Factor-κB Activation , 2004, Clinical Cancer Research.

[45]  M. Tsuneyoshi,et al.  Interleukin 1beta enhances invasive ability of gastric carcinoma through nuclear factor-kappaB activation. , 2004, Clinical cancer research : an official journal of the American Association for Cancer Research.

[46]  M. Leinonen,et al.  Chlamydia pneumoniae infection and the risk of female early‐onset lung cancer , 2003, International journal of cancer.

[47]  M. Blaser,et al.  Tooth loss, pancreatic cancer, and Helicobacter pylori. , 2003, The American journal of clinical nutrition.

[48]  Veikko Salomaa,et al.  Antibodies to Periodontal Pathogens Are Associated With Coronary Heart Disease , 2003, Arteriosclerosis, thrombosis, and vascular biology.

[49]  N. Weiss,et al.  An exploration of the periodontitis-cancer association. , 2003, Annals of epidemiology.

[50]  M. Moeschberger,et al.  New Bacterial Species Associated with Chronic Periodontitis , 2003, Journal of dental research.

[51]  K. Yuen,et al.  Granulicatella adiacens and Abiotrophia defectiva bacteraemia characterized by 16S rRNA gene sequencing. , 2003, Journal of medical microbiology.

[52]  P. Maisonneuve,et al.  Chronic Pancreatitis and Pancreatic Cancer , 2002, Digestive Diseases.

[53]  U. Stenram,et al.  Comment on: Helicobacter pylori seropositivity as a risk factor for pancreatic cancer. by Stolzenberg-Solomon R. Z. et al. , 2002 .

[54]  U. Stenram,et al.  Re: Helicobacter pylori seropositivity as a risk factor for pancreatic cancer. , 2002, Journal of the National Cancer Institute.

[55]  F. Dewhirst,et al.  Bacterial Diversity in Human Subgingival Plaque , 2001, Journal of bacteriology.

[56]  Alberto Mantovani,et al.  Inflammation and cancer: back to Virchow? , 2001, The Lancet.

[57]  M. Blaser,et al.  Helicobacter pylori seropositivity as a risk factor for pancreatic cancer. , 2001, Journal of the National Cancer Institute.

[58]  M. Trevisan,et al.  Identification of periodontal pathogens in atheromatous plaques. , 2000, Journal of periodontology.

[59]  Masao Tanaka,et al.  Lipopolysaccharide increases cyclo-oxygenase-2 expression in a colon carcinoma cell line through nuclear factor-κB activation , 2000, Oncogene.

[60]  H. Morrison,et al.  Periodontal Disease and Risk of Fatal Coronary Heart and Cerebrovascular Diseases , 1999, Journal of cardiovascular risk.

[61]  Douglas B. Evans,et al.  The Nuclear Factor-κB RelA Transcription Factor Is Constitutively Activated in Human Pancreatic Adenocarcinoma Cells , 1999 .

[62]  J. Abbruzzese,et al.  The nuclear factor-kappa B RelA transcription factor is constitutively activated in human pancreatic adenocarcinoma cells. , 1999, Clinical cancer research : an official journal of the American Association for Cancer Research.

[63]  M. Meyer,et al.  Dental plaque, platelets, and cardiovascular diseases. , 1998, Annals of periodontology.

[64]  C. Douglass,et al.  Possible explanations for the tooth loss and cardiovascular disease relationship. , 1998, Annals of periodontology.

[65]  T. Azuma,et al.  The effect of eradication therapy for H. pylori on hyperammonemia: Two years follow up study in two effective cases , 1998 .

[66]  W E Moore,et al.  The bacteria of periodontal diseases. , 1994, Periodontology 2000.

[67]  M. Zweig,et al.  Receiver-operating characteristic (ROC) plots: a fundamental evaluation tool in clinical medicine. , 1993, Clinical chemistry.

[68]  J. Janda,et al.  Association of an important Neisseria species, Neisseria elongata subsp. nitroreducens, with bacteremia, endocarditis, and osteomyelitis , 1992, Journal of clinical microbiology.

[69]  D. Roe,et al.  Quantitative relationship between oral nitrate-reducing activity and the endogenous formation of N-nitrosoamino acids in humans. , 1991, Food and chemical toxicology : an international journal published for the British Industrial Biological Research Association.

[70]  J. Hanley,et al.  The meaning and use of the area under a receiver operating characteristic (ROC) curve. , 1982, Radiology.