Advertisement

Helicobacter pylori, Cancer, and the Gastric Microbiota

  • Lydia E. Wroblewski
  • Richard M. PeekJr.Email author
Chapter
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 908)

Abstract

Gastric adenocarcinoma is one of the leading causes of cancer-related death worldwide and Helicobacter pylori infection is the strongest known risk factor for this disease. Although the stomach was once thought to be a sterile environment, it is now known to house many bacterial species leading to a complex interplay between H. pylori and other residents of the gastric microbiota. In addition to the role of H. pylori virulence factors, host genetic polymorphisms, and diet, it is now becoming clear that components of the gastrointestinal microbiota may also influence H. pylori-induced pathogenesis. In this chapter, we discuss emerging data regarding the gastric microbiota in humans and animal models and alterations that occur to the composition of the gastric microbiota in the presence of H. pylori infection that may augment the risk of developing gastric cancer.

Keywords

Helicobacter pylori Gastric adenocarcinoma Microbiota Mongolian gerbil Pyrosequencing Firmicutes 

Notes

Disclosures/Conflict of Interest

The authors declare there are no conflicts of interest.

References

  1. 1.
    Ferlay J, et al. Cancer incidence and mortality worldwide: sources, methods and major patterns in GLOBOCAN 2012. Int J Cancer. 2015;136(5):E359–86.PubMedCrossRefGoogle Scholar
  2. 2.
    de Martel C, et al. Global burden of cancers attributable to infections in 2008: a review and synthetic analysis. Lancet Oncol. 2012;13(6):607–15.PubMedCrossRefGoogle Scholar
  3. 3.
    Parkin DM, et al. Global cancer statistics, 2002. CA Cancer J Clin. 2005;55(2):74–108.PubMedCrossRefGoogle Scholar
  4. 4.
    Correa P. Human gastric carcinogenesis: a multistep and multifactorial process—First American Cancer Society Award Lecture on cancer epidemiology and prevention. Cancer Res. 1992;52(24):6735–40.PubMedGoogle Scholar
  5. 5.
    Cancer Genome Atlas Research Network. Comprehensive molecular characterization of gastric adenocarcinoma. Nature. 2014;513(7517):202–9.CrossRefGoogle Scholar
  6. 6.
    Cristescu R, et al. Molecular analysis of gastric cancer identifies subtypes associated with distinct clinical outcomes. Nat Med. 2015;21(5):449–56.PubMedCrossRefGoogle Scholar
  7. 7.
    Fuchs CS, Mayer RJ. Gastric carcinoma. N Engl J Med. 1995;333(1):32–41.PubMedCrossRefGoogle Scholar
  8. 8.
    Howson CP, Hiyama T, Wynder EL. The decline in gastric cancer: epidemiology of an unplanned triumph. Epidemiol Rev. 1986;8:1–27.PubMedGoogle Scholar
  9. 9.
    Blot WJ, et al. Rising incidence of adenocarcinoma of the esophagus and gastric cardia. JAMA. 1991;265(10):1287–9.PubMedCrossRefGoogle Scholar
  10. 10.
    Pera M, et al. Increasing incidence of adenocarcinoma of the esophagus and esophagogastric junction. Gastroenterology. 1993;104(2):510–3.PubMedGoogle Scholar
  11. 11.
    Plummer M, et al. Global burden of gastric cancer attributable to pylori. Int J Cancer. 2014.Google Scholar
  12. 12.
    Uemura N, et al. Helicobacter pylori infection and the development of gastric cancer. N Engl J Med. 2001;345(11):784–9.PubMedCrossRefGoogle Scholar
  13. 13.
    Polk DB, Peek Jr RM. Helicobacter pylori: gastric cancer and beyond. Nat Rev Cancer. 2010;10(6):403–14.PubMedPubMedCentralCrossRefGoogle Scholar
  14. 14.
    Fox JG, Wang TC. Inflammation, atrophy, and gastric cancer. J Clin Invest. 2007;117(1):60–9.PubMedCrossRefGoogle Scholar
  15. 15.
    Wroblewski LE, Peek Jr RM, Wilson KT. Helicobacter pylori and gastric cancer: factors that modulate disease risk. Clin Microbiol Rev. 2010;23(4):713–39.PubMedPubMedCentralCrossRefGoogle Scholar
  16. 16.
    Linz B, et al. An African origin for the intimate association between humans and Helicobacter pylori. Nature. 2007;445(7130):915–8.PubMedPubMedCentralCrossRefGoogle Scholar
  17. 17.
    Peek Jr RM, Crabtree JE. Helicobacter infection and gastric neoplasia. J Pathol. 2006;208(2):233–48.PubMedCrossRefGoogle Scholar
  18. 18.
    Wroblewski LE, Peek Jr RM. Helicobacter pylori in gastric carcinogenesis: mechanisms. Gastroenterol Clin North Am. 2013;42(2):285–98.PubMedPubMedCentralCrossRefGoogle Scholar
  19. 19.
    Odenbreit S, et al. Translocation of Helicobacter pylori CagA into gastric epithelial cells by type IV secretion. Science. 2000;287(5457):1497–500.PubMedCrossRefGoogle Scholar
  20. 20.
    Fischer W, et al. Systematic mutagenesis of the Helicobacter pylori cag pathogenicity island: essential genes for CagA translocation in host cells and induction of interleukin-8. Mol Microbiol. 2001;42(5):1337–48.PubMedCrossRefGoogle Scholar
  21. 21.
    Kwok T, et al. Helicobacter exploits integrin for type IV secretion and kinase activation. Nature. 2007;449(7164):862–6.PubMedCrossRefGoogle Scholar
  22. 22.
    Shaffer CL, et al. Helicobacter pylori exploits a unique repertoire of type IV secretion system components for pilus assembly at the bacteria-host cell interface. PLoS Pathog. 2011;7(9):e1002237.PubMedPubMedCentralCrossRefGoogle Scholar
  23. 23.
    Parsonnet J, et al. Risk for gastric cancer in people with CagA positive or CagA negative Helicobacter pylori infection. Gut. 1997;40(3):297–301.PubMedPubMedCentralCrossRefGoogle Scholar
  24. 24.
    Huang JQ, et al. Meta-analysis of the relationship between cagA seropositivity and gastric cancer. Gastroenterology. 2003;125(6):1636–44.PubMedCrossRefGoogle Scholar
  25. 25.
    Hatakeyama M. Oncogenic mechanisms of the Helicobacter pylori CagA protein. Nat Rev Cancer. 2004;4(9):688–94.PubMedCrossRefGoogle Scholar
  26. 26.
    Higashi H, et al. EPIYA motif is a membrane-targeting signal of Helicobacter pylori virulence factor CagA in mammalian cells. J Biol Chem. 2005;280(24):23130–7.PubMedCrossRefGoogle Scholar
  27. 27.
    Naito M, et al. Influence of EPIYA-repeat polymorphism on the phosphorylation-dependent biological activity of Helicobacter pylori CagA. Gastroenterology. 2006;130(4):1181–90.PubMedCrossRefGoogle Scholar
  28. 28.
    Basso D, et al. Clinical relevance of Helicobacter pylori cagA and vacA gene polymorphisms. Gastroenterology. 2008;135(1):91–9.PubMedCrossRefGoogle Scholar
  29. 29.
    Argent RH, et al. Differences in Helicobacter pylori CagA tyrosine phosphorylation motif patterns between western and East Asian strains, and influences on interleukin-8 secretion. J Med Microbiol. 2008;57(Pt 9):1062–7.PubMedCrossRefGoogle Scholar
  30. 30.
    Mimuro H, et al. Grb2 is a key mediator of helicobacter pylori CagA protein activities. Mol Cell. 2002;10(4):745–55.PubMedCrossRefGoogle Scholar
  31. 31.
    Saadat I, et al. Helicobacter pylori CagA targets PAR1/MARK kinase to disrupt epithelial cell polarity. Nature. 2007;447(7142):330–3.PubMedCrossRefGoogle Scholar
  32. 32.
    Murata-Kamiya N, et al. Helicobacter pylori CagA interacts with E-cadherin and deregulates the beta-catenin signal that promotes intestinal transdifferentiation in gastric epithelial cells. Oncogene. 2007;26(32):4617–26.PubMedCrossRefGoogle Scholar
  33. 33.
    Churin Y, et al. Helicobacter pylori CagA protein targets the c-Met receptor and enhances the motogenic response. J Cell Biol. 2003;161(2):249–55.PubMedPubMedCentralCrossRefGoogle Scholar
  34. 34.
    Amieva MR, et al. Disruption of the epithelial apical-junctional complex by Helicobacter pylori CagA. Science. 2003;300(5624):1430–4.PubMedPubMedCentralCrossRefGoogle Scholar
  35. 35.
    Franco AT, et al. Activation of beta-catenin by carcinogenic Helicobacter pylori. Proc Natl Acad Sci U S A. 2005;102(30):10646–51.PubMedPubMedCentralCrossRefGoogle Scholar
  36. 36.
    Bagnoli F, et al. Helicobacter pylori CagA induces a transition from polarized to invasive phenotypes in MDCK cells. Proc Natl Acad Sci U S A. 2005;102(45):16339–44.PubMedPubMedCentralCrossRefGoogle Scholar
  37. 37.
    Suzuki M, et al. Interaction of CagA with Crk plays an important role in Helicobacter pylori-induced loss of gastric epithelial cell adhesion. J Exp Med. 2005;202(9):1235–47.PubMedPubMedCentralCrossRefGoogle Scholar
  38. 38.
    Wroblewski LE, et al. Helicobacter pylori dysregulation of gastric epithelial tight junctions by urease-mediated myosin II activation. Gastroenterology. 2009;136(1):236–46.PubMedCrossRefGoogle Scholar
  39. 39.
    Wroblewski LE, et al. Helicobacter pylori targets cancer-associated apical-junctional constituents in gastroids and gastric epithelial cells. Gut. 2015;64(5):720–30.PubMedCrossRefGoogle Scholar
  40. 40.
    Cover TL, Blanke SR. Helicobacter pylori VacA, a paradigm for toxin multifunctionality. Nat Rev Microbiol. 2005;3(4):320–32.PubMedCrossRefGoogle Scholar
  41. 41.
    Boquet P, Ricci V. Intoxication strategy of Helicobacter pylori VacA toxin. Trends Microbiol. 2012;20(4):165–74.PubMedCrossRefGoogle Scholar
  42. 42.
    Atherton JC, et al. Mosaicism in vacuolating cytotoxin alleles of Helicobacter pylori. Association of specific vacA types with cytotoxin production and peptic ulceration. J Biol Chem. 1995;270(30):17771–7.PubMedCrossRefGoogle Scholar
  43. 43.
    Rhead JL, et al. A new Helicobacter pylori vacuolating cytotoxin determinant, the intermediate region, is associated with gastric cancer. Gastroenterology. 2007;133(3):926–36.PubMedCrossRefGoogle Scholar
  44. 44.
    Atherton JC, et al. Clinical and pathological importance of heterogeneity in vacA, the vacuolating cytotoxin gene of Helicobacter pylori. Gastroenterology. 1997;112(1):92–9.PubMedCrossRefGoogle Scholar
  45. 45.
    Miehlke S, et al. The Helicobacter pylori vacA s1, m1 genotype and cagA is associated with gastric carcinoma in Germany. Int J Cancer. 2000;87(3):322–7.PubMedCrossRefGoogle Scholar
  46. 46.
    Memon AA, et al. Vacuolating cytotoxin genotypes are strong markers of gastric cancer and duodenal ulcer-associated Helicobacter pylori strains: a matched case/control study. J Clin Microbiol. 2014;52(8):2984–9.PubMedPubMedCentralCrossRefGoogle Scholar
  47. 47.
    Winter JA, et al. A role for the vacuolating cytotoxin, VacA, in colonization and Helicobacter pylori-induced metaplasia in the stomach. J Infect Dis. 2014;210(6):954–63.PubMedPubMedCentralCrossRefGoogle Scholar
  48. 48.
    Backert S, Tegtmeyer N. The versatility of the Helicobacter pylori vacuolating cytotoxin VacA in signal transduction and molecular crosstalk. Toxins (Basel). 2010;2(1):69–92.CrossRefGoogle Scholar
  49. 49.
    Barker N, et al. Lgr5(+ve) stem cells drive self-renewal in the stomach and build long-lived gastric units in vitro. Cell Stem Cell. 2010;6(1):25–36.PubMedCrossRefGoogle Scholar
  50. 50.
    Uehara T, et al. H. pylori infection is associated with DNA damage of Lgr5-positive epithelial stem cells in the stomach of patients with gastric cancer. Dig Dis Sci. 2013;58(1):140–9.PubMedCrossRefGoogle Scholar
  51. 51.
    Tsugawa H, et al. Reactive oxygen species-induced autophagic degradation of Helicobacter pylori CagA is specifically suppressed in cancer stem-like cells. Cell Host Microbe. 2012;12(6):764–77.PubMedCrossRefGoogle Scholar
  52. 52.
    El-Omar EM, et al. Interleukin-1 polymorphisms associated with increased risk of gastric cancer. Nature. 2000;404(6776):398–402.PubMedCrossRefGoogle Scholar
  53. 53.
    Figueiredo C, et al. Helicobacter pylori and interleukin 1 genotyping: an opportunity to identify high-risk individuals for gastric carcinoma. J Natl Cancer Inst. 2002;94(22):1680–7.PubMedCrossRefGoogle Scholar
  54. 54.
    El-Omar EM, et al. Increased risk of noncardia gastric cancer associated with proinflammatory cytokine gene polymorphisms. Gastroenterology. 2003;124(5):1193–201.PubMedCrossRefGoogle Scholar
  55. 55.
    Tsugane S, Sasazuki S. Diet and the risk of gastric cancer: review of epidemiological evidence. Gastric Cancer. 2007;10(2):75–83.PubMedCrossRefGoogle Scholar
  56. 56.
    Epplein M, et al. Association of Helicobacter pylori infection and diet on the risk of gastric cancer: a case-control study in Hawaii. Cancer Causes Control. 2008;19(8):869–77.PubMedPubMedCentralCrossRefGoogle Scholar
  57. 57.
    Gonzalez CA, et al. Meat intake and risk of stomach and esophageal adenocarcinoma within the European Prospective Investigation Into Cancer and Nutrition (EPIC). J Natl Cancer Inst. 2006;98(5):345–54.PubMedCrossRefGoogle Scholar
  58. 58.
    Gonzalez CA, et al. Fruit and vegetable intake and the risk of gastric adenocarcinoma: a reanalysis of the European Prospective Investigation into Cancer and Nutrition (EPIC-EURGAST) study after a longer follow-up. Int J Cancer. 2012;131(12):2910–9.PubMedCrossRefGoogle Scholar
  59. 59.
    Kim HJ, et al. Fresh and pickled vegetable consumption and gastric cancer in Japanese and Korean populations: a meta-analysis of observational studies. Cancer Sci. 2010;101(2):508–16.PubMedCrossRefGoogle Scholar
  60. 60.
    Ren JS, et al. Pickled food and risk of gastric cancer—a systematic review and meta-analysis of English and Chinese literature. Cancer Epidemiol Biomarkers Prev. 2012;21(6):905–15.PubMedCrossRefGoogle Scholar
  61. 61.
    Kim MK, et al. Prospective study of three major dietary patterns and risk of gastric cancer in Japan. Int J Cancer. 2004;110(3):435–42.PubMedCrossRefGoogle Scholar
  62. 62.
    Lee SA, et al. Effect of diet and Helicobacter pylori infection to the risk of early gastric cancer. J Epidemiol. 2003;13(3):162–8.PubMedCrossRefGoogle Scholar
  63. 63.
    Shikata K, et al. A prospective study of dietary salt intake and gastric cancer incidence in a defined Japanese population: the Hisayama study. Int J Cancer. 2006;119(1):196–201.PubMedCrossRefGoogle Scholar
  64. 64.
    Noto JM, et al. Iron deficiency accelerates Helicobacter pylori-induced carcinogenesis in rodents and humans. J Clin Invest. 2013;123(1):479–92.PubMedCrossRefGoogle Scholar
  65. 65.
    Ma JL, et al. Fifteen-year effects of Helicobacter pylori, garlic, and vitamin treatments on gastric cancer incidence and mortality. J Natl Cancer Inst. 2012;104(6):488–92.PubMedPubMedCentralCrossRefGoogle Scholar
  66. 66.
    Sheh A, Fox JG. The role of the gastrointestinal microbiome in Helicobacter pylori pathogenesis. Gut Microbes. 2013;4(6):505–31.PubMedPubMedCentralCrossRefGoogle Scholar
  67. 67.
    Abreu MT, Peek Jr RM. Gastrointestinal malignancy and the microbiome. Gastroenterology. 2014;146(6):1534–46. e3.PubMedPubMedCentralCrossRefGoogle Scholar
  68. 68.
    Bik EM, et al. Molecular analysis of the bacterial microbiota in the human stomach. Proc Natl Acad Sci U S A. 2006;103(3):732–7.PubMedPubMedCentralCrossRefGoogle Scholar
  69. 69.
    Cho I, Blaser MJ. The human microbiome: at the interface of health and disease. Nat Rev Genet. 2012;13(4):260–70.PubMedPubMedCentralGoogle Scholar
  70. 70.
    Andersson AF, et al. Comparative analysis of human gut microbiota by barcoded pyrosequencing. PLoS One. 2008;3(7):e2836.PubMedPubMedCentralCrossRefGoogle Scholar
  71. 71.
    Maldonado-Contreras A, et al. Structure of the human gastric bacterial community in relation to Helicobacter pylori status. ISME J. 2011;5(4):574–9.PubMedCrossRefGoogle Scholar
  72. 72.
    Dicksved J, et al. Molecular characterization of the stomach microbiota in patients with gastric cancer and in controls. J Med Microbiol. 2009;58(Pt 4):509–16.PubMedCrossRefGoogle Scholar
  73. 73.
    Eun CS, et al. Differences in gastric mucosal microbiota profiling in patients with chronic gastritis, intestinal metaplasia, and gastric cancer using pyrosequencing methods. Helicobacter. 2014;19(6):407–16.PubMedCrossRefGoogle Scholar
  74. 74.
    Peek Jr RM, Blaser MJ. Helicobacter pylori and gastrointestinal tract adenocarcinomas. Nat Rev Cancer. 2002;2(1):28–37.PubMedCrossRefGoogle Scholar
  75. 75.
    Watanabe T, et al. Helicobacter pylori infection induces gastric cancer in mongolian gerbils [see comments]. Gastroenterology. 1998;115(3):642–8.PubMedCrossRefGoogle Scholar
  76. 76.
    Honda S, et al. Development of Helicobacter pylori-induced gastric carcinoma in Mongolian gerbils. Cancer Res. 1998;58(19):4255–9.PubMedGoogle Scholar
  77. 77.
    Ogura K, et al. Virulence factors of Helicobacter pylori responsible for gastric diseases in Mongolian gerbil. J Exp Med. 2000;192(11):1601–10.PubMedPubMedCentralCrossRefGoogle Scholar
  78. 78.
    Peek RM, et al. Helicobacter pylori alters gastric epithelial cell cycle events and gastrin secretion in Mongolian gerbils. Gastroenterology. 2000;118(1):48–59.PubMedCrossRefGoogle Scholar
  79. 79.
    Israel DA, et al. Helicobacter pylori strain-specific differences in genetic content, identified by microarray, influence host inflammatory responses. J Clin Invest. 2001;107(5):611–20.PubMedPubMedCentralCrossRefGoogle Scholar
  80. 80.
    Franco AT, et al. Regulation of gastric carcinogenesis by Helicobacter pylori virulence factors. Cancer Res. 2008;68(2):379–87.PubMedPubMedCentralCrossRefGoogle Scholar
  81. 81.
    Fox J, Sheh A. The role of the gastrointestinal microbiome in Helicobacter pylori pathogenesis. Gut Microbes. 2013;4(6):505–31.PubMedPubMedCentralCrossRefGoogle Scholar
  82. 82.
    Yang I, Nell S, Suerbaum S. Survival in hostile territory: the microbiota of the stomach. FEMS Microbiol Rev. 2013;37(5):736–61.PubMedCrossRefGoogle Scholar
  83. 83.
    Sun YQ, et al. Profiling and identification of eubacteria in the stomach of Mongolian gerbils with and without Helicobacter pylori infection. Helicobacter. 2003;8(2):149–57.PubMedCrossRefGoogle Scholar
  84. 84.
    Osaki T, et al. Comparative analysis of gastric bacterial microbiota in Mongolian gerbils after long-term infection with Helicobacter pylori. Microb Pathog. 2012;53(1):12–8.PubMedCrossRefGoogle Scholar
  85. 85.
    Zaman C, et al. Analysis of the microbial ecology between Helicobacter pylori and the gastric microbiota of Mongolian gerbils. J Med Microbiol. 2014;63(Pt 1):129–37.PubMedCrossRefGoogle Scholar
  86. 86.
    Rolig AS, et al. The degree of Helicobacter pylori-triggered inflammation is manipulated by preinfection host microbiota. Infect Immun. 2013;81(5):1382–9.PubMedPubMedCentralCrossRefGoogle Scholar
  87. 87.
    Zavros Y, et al. Gastritis and hypergastrinemia due to Acinetobacter lwoffii in mice. Infect Immun. 2002;70(5):2630–9.PubMedPubMedCentralCrossRefGoogle Scholar
  88. 88.
    Sigal M, et al. Helicobacter pylori activates and expands Lgr5 stem cells through direct colonization of the gastric glands. Gastroenterology. 2015;148(7):1392–404.e21.PubMedCrossRefGoogle Scholar
  89. 89.
    Aebischer T, et al. Vaccination prevents Helicobacter pylori-induced alterations of the gastric flora in mice. FEMS Immunol Med Microbiol. 2006;46(2):221–9.PubMedCrossRefGoogle Scholar
  90. 90.
    Tan MP, et al. Chronic Helicobacter pylori infection does not significantly alter the microbiota of the murine stomach. Appl Environ Microbiol. 2007;73(3):1010–3.PubMedCrossRefGoogle Scholar
  91. 91.
    Lofgren JL, et al. Lack of commensal flora in Helicobacter pylori-infected INS-GAS mice reduces gastritis and delays intraepithelial neoplasia. Gastroenterology. 2011;140(1):210–20.PubMedCrossRefGoogle Scholar
  92. 92.
    Thomson MJ, et al. Gastric Helicobacter infection induces iron deficiency in the INS-GAS mouse. PLoS One. 2012;7(11):e50194.PubMedPubMedCentralCrossRefGoogle Scholar
  93. 93.
    Wang J, et al. Helicobacter pylori modulates lymphoepithelial cell interactions leading to epithelial cell damage through Fas/Fas ligand interactions. Infect Immun. 2000;68(7):4303–11.PubMedPubMedCentralCrossRefGoogle Scholar
  94. 94.
    Lertpiriyapong K, et al. Gastric colonisation with a restricted commensal microbiota replicates the promotion of neoplastic lesions by diverse intestinal microbiota in the Helicobacter pylori INS-GAS mouse model of gastric carcinogenesis. Gut. 2014;63(1):54–63.PubMedCrossRefGoogle Scholar
  95. 95.
    Ge Z, et al. Coinfection with enterohepatic Helicobacter species can ameliorate or promote Helicobacter pylori-induced gastric pathology in C57BL/6 mice. Infect Immun. 2011;79(10):3861–71.PubMedPubMedCentralCrossRefGoogle Scholar
  96. 96.
    Lemke LB, et al. Concurrent Helicobacter bilis infection in C57BL/6 mice attenuates proinflammatory H. pylori-induced gastric pathology. Infect Immun. 2009;77(5):2147–58.PubMedPubMedCentralCrossRefGoogle Scholar
  97. 97.
    Whary MT, et al. Helminth co-infection in Helicobacter pylori infected INS-GAS mice attenuates gastric premalignant lesions of epithelial dysplasia and glandular atrophy and preserves colonization resistance of the stomach to lower bowel microbiota. Microbes Infect. 2014;16(4):345–55.PubMedPubMedCentralCrossRefGoogle Scholar
  98. 98.
    Martin ME, et al. The impact of Helicobacter pylori infection on the gastric microbiota of the rhesus macaque. PLoS One. 2013;8(10):e76375.PubMedPubMedCentralCrossRefGoogle Scholar
  99. 99.
    DeWeerdt S. Microbiome: a complicated relationship status. Nature. 2014;508(7496):S61–3.PubMedCrossRefGoogle Scholar

Copyright information

© Springer International Publishing Switzerland 2016

Authors and Affiliations

  1. 1.Division of Gastroenterology, Department of MedicineVanderbilt University School of MedicineNashvilleUSA

Personalised recommendations