Skip to main content

Suicide journey of H. pylori through gastric carcinogenesis: the role of non-H. pylori microbiome and potential consequences for clinical practice

Abstract

Despite being one of the most studied cancer-related infections, the relationship between Helicobacter pylori infection and gastric adenocarcinoma (GC) remains, in some points, obscure. Based on a critical analysis of the available literature regarding stomach microbiota, we aimed to shed light to a possible new interpretation of the current understanding about the Helicobacter pylori-related GC carcinogenesis. We analyzed data from the literature on Helicobacter pylori and other potential carcinogenic pathogens, in both benignant conditions and gastric adenocarcinoma. Helicobacter pylori is the dominant microorganism in benignant conditions as non-complicated gastritis. In atrophic gastritis, metaplasia and, mainly, in gastric adenocarcinoma, a strong reduction in Helicobacter pylori abundance, and increased occurrence of other microorganisms is strongly demonstrated by metagenomic experiments. While causing peptic disease and keeping the stomach’s high acidity, Helicobacter pylori infection avoids gastric infection by carcinogenic intestinal microbiota. Nevertheless, Helicobacter pylori persistence may also provoke an atrophic gastritis, a condition that causes its own decline, due to a microenvironment modification, including reduced acidity, resulting in Helicobacter pylori substitution by a cancer-prone microbiota. This new interpretation might result in a dramatic modification on clinical management of Helicobacter pylori-related gastric disease.

This is a preview of subscription content, access via your institution.

Fig. 1
Fig. 2
Fig. 3
Fig. 4

References

  1. Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA, Jemal A (2018) Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. https://doi.org/10.3322/caac.21492

  2. Sitarz R, Skierucha M, Mielko J, Offerhaus GJA, Maciejewski R, Polkowski WP (2018) Gastric cancer: epidemiology, prevention, classification, and treatment. Cancer Manag Res. https://doi.org/10.2147/CMAR.S149619

  3. Graham DY (2014) History of helicobacter pylori, duodenal ulcer, gastric ulcer and gastric cancer. World J Gastroenterol. https://doi.org/10.3748/wjg.v20.i18.5191

  4. Nagini S (2012) Carcinoma of the stomach: a review of epidemiology, pathogenesis, molecular genetics and chemoprevention. World J Gastrointest Oncol. https://doi.org/10.4251/wjgo.v4.i7.156

  5. Suzuki H, Mori H (2018) World trends for H. pylori eradication therapy and gastric cancer prevention strategy by H. pylori test-and-treat. J Gastroenterol. https://doi.org/10.1007/s00535-017-1407-1

  6. Asaka M, Mabe K (2014) Strategies for eliminating death from gastric cancer in Japan. Proc Jpn Acad Ser B Phys Biol Sci 90:251–258

    Article  PubMed  PubMed Central  Google Scholar 

  7. Kiriyama Y, Tahara T, Shibata T, Okubo M, Nakagawa M, Okabe A, Ohmiya N, Kuroda M, Sugioka A, Ichinose M, Tatematsu M, Tsukamoto T (2016) Gastric-and-intestinal mixed intestinal metaplasia is irreversible point with eradication of Helicobacter pylori. Open J Pathol. https://doi.org/10.4236/ojpathology.2016.62012

  8. Lee YC, Chen TH, Chiu HM, Shun CT, Chiang H, Liu TY, Wu MS, Lin JT (2013) The benefit of mass eradication of Helicobacter pylori infection: a community-based study of gastric cancer prevention. Gut. https://doi.org/10.1136/gutjnl-2012-302240

  9. Annibale B, Aprile MR, D’ambra G, Caruana P, Bordi C, Delle Fave G (2000) Cure of Helicobacter pylori infection in atrophic body gastritis patients does not improve mucosal atrophy but reduces hypergastrinemia and its related effects on body ECL-cell hyperplasia. Aliment Pharmacol Ther 14:625–634

    Article  CAS  PubMed  Google Scholar 

  10. Forbes GM, Warren JR, Glaser ME, Cullen DJ, Marshall BJ, Collins BJ (2017) Long-term follow-up of gastric histology after Helicobacter pylori eradication. J Gastroenterol Hepatol 11:670–673

    Article  Google Scholar 

  11. Bjorkman DJ, Steenblik M (2017) Best practice recommendations for diagnosis and management of Helicobacter pylori-synthesizing the guidelines. Curr Treat Options Gastroenterol. https://doi.org/10.1007/s11938-017-0157-8

  12. Li Q, Liu J, Gong Y, Yuan Y (2016) Serum VacA antibody is associated with risks of peptic ulcer and gastric cancer: a meta-analysis. Microb Pathog. https://doi.org/10.1016/j.micpath.2016.08.030

  13. Sitas F (2016) Twenty five years since the first prospective study by Forman et al. (1991) on Helicobacter pylori and stomach cancer risk. Cancer Epidemiol. https://doi.org/10.1016/j.canep.2016.02.002

  14. Hwang JJ, Lee DH, Lee AR, Yoon H, Shin CM, Park YS, Kim N (2015) Characteristics of gastric cancer in peptic ulcer patients with Helicobacter pylori infection. World J Gastroenterol. https://doi.org/10.3748/wjg.v21.i16.4954

  15. Uemura N, Okamoto S, Yamamoto S, Matsumura N, Yamaguchi S, Yamakido M, Taniyama K, Sasaki N, Schlemper RJ (2001) Helicobacter pylori infection and the development of gastric cancer. N Engl J Med. https://doi.org/10.1056/NEJMoa001999

  16. Hansson LE, Nyrén O, Hsing AW, Bergström R, Josefsson S, Chow WH, Fraumeni JF Jr, Adami HO (1996) The risk of stomach cancer in patients with gastric or duodenal ulcer disease. N Engl J Med. https://doi.org/10.1056/NEJM199607253350404

  17. Brawner KM, Morrow CD, Smith PD (2014) Gastric microbiome and gastric cancer. Cancer J. https://doi.org/10.1097/PPO.0000000000000043

  18. Hong JB, Zuo W, Wang AJ, Xu S, Tu LX, Chen YX, Zhu X, Lu NH (2014) Gastric ulcer patients are more susceptible to developing gastric cancer compared with concomitant gastric and duodenal ulcer patients. Oncol Lett. https://doi.org/10.3892/ol.2014.2583

  19. Molloy RM, Sonnenberg A (1997) Relation between gastric cancer and previous peptic ulcer disease. Gut. 40:247–252

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Ferreira RM, Pereira-Marques J, Pinto-Ribeiro I, Costa JL, Carneiro F, Machado JC, Figueiredo C (2018) Gastric microbial community profiling reveals a dysbiotic cancer-associated microbiota. Gut. https://doi.org/10.1136/gutjnl-2017-314205

  21. Hsieh YY, Tung SY, Pan HY, Yen CW, Xu HW, Lin YJ, Deng YF, Hsu WT, Wu CS, Li C (2018) Increased abundance of Clostridium and Fusobacterium in gastric microbiota of patients with gastric cancer in Taiwan. Sci Rep. https://doi.org/10.1038/s41598-017-18596-0

  22. Yu G, Torres J, Hu N, Medrano-Guzman R, Herrera-Goepfert R, Humphrys MS, Wang L, Wang C, Ding T, Ravel J, Taylor PR, Abnet CC, Goldstein AM (2017) Molecular characterization of the human stomach microbiota in gastric cancer patients. Front Cell Infect Microbiol. https://doi.org/10.3389/fcimb.2017.00302

  23. Aviles-Jimenez F, Vazquez-Jimenez F, Medrano-Guzman R, Mantilla A, Torres J (2014) Stomach microbiota composition varies between patients with non-atrophic gastritis and patients with intestinal type of gastric cancer. Sci Rep. https://doi.org/10.1038/srep04202

  24. Dicksved J, Lindberg M, Rosenquist M, Enroth H, Jansson JK, Engstrand L (2009) Molecular characterization of the stomach microbiota in patients with gastric cancer and in controls. J Med Microbiol. https://doi.org/10.1099/jmm.0.007302-0

  25. Miftahussurur M, Yamaoka Y (2016) Diagnostic methods of helicobacter pylori infection for epidemiological studies: critical importance of indirect test validation. Biomed Res Int. https://doi.org/10.1155/2016/4819423

  26. Lee JY, Kim N (2015) Diagnosis of helicobacter pylori by invasive test: histology. Ann Transl Med. https://doi.org/10.3978/j.issn.2305-5839.2014.11.03

  27. Kokkola A, Rautelin H, Puolakkainen P, Sipponen P, Färkkilä M, Haapiainen R, Kosunen TU (2000) Diagnosis of Helicobacter pylori infection in patients with atrophic gastritis: comparison of histology, 13C-urea breath test, and serology. Scand J Gastroenterol 35:138–141

    Article  CAS  PubMed  Google Scholar 

  28. Matsukura N, Onda M, Yamashita K (1995) Helicobacter pylori in peptic ulcer and gastric cancer. Gan To Kagaku Ryoho 22:169–178

    CAS  PubMed  Google Scholar 

  29. Dias-Jácome E, Libânio D, Borges-Canha M, Galaghar A, Pimentel-Nunes P (2016) Gastric microbiota and carcinogenesis: the role of non-Helicobacter pylori bacteria—a systematic review. Rev Esp Enferm Dig. https://doi.org/10.17235/reed.2016.4261/2016

  30. Cao L, Yu J (2015) Effect of Helicobacter pylori infection on the composition of gastric microbiota in the development of gastric cancer. Gastrointest Tumors. https://doi.org/10.1159/000380893

  31. Noto JM, Peek RM Jr (2017) The gastric microbiome, its interaction with Helicobacter pylori, and its potential role in the progression to stomach cancer. PLoS Pathog. https://doi.org/10.1371/journal.ppat.1006573

  32. Huang JY, Goers Sweeney E, Guillemin K, Amieva MR (2017) Multiple acid sensors control Helicobacter pylori colonization of the stomach. PLoS Pathog. https://doi.org/10.1371/journal.ppat.1006118

  33. Testerman TL, Morris J (2014) Beyond the stomach: an updated view of Helicobacter pylori pathogenesis, diagnosis, and treatment. World J Gastroenterol. https://doi.org/10.3748/wjg.v20.i36.12781

  34. Cheung DY (2017) Atrophic gastritis increases the risk of gastric cancer in asymptomatic population in Korea. Gut Liver. https://doi.org/10.5009/gnl17356

  35. Hunt RH, Camilleri M, Crowe SE, El-Omar EM, Fox JG, Kuipers EJ, Malfertheiner P, McColl KE, Pritchard DM, Rugge M, Sonnenberg A, Sugano K, Tack J (2015) The stomach in health and disease. Gut. https://doi.org/10.1136/gutjnl-2014-307595

  36. Loke MF, Ng CG, Vilashni Y, Lim J, Ho B (2016) Understanding the dimorphic lifestyles of human gastric pathogen Helicobacter pylori using the SWATH-based proteomics approach. Sci Rep. https://doi.org/10.1038/srep26784

  37. Reshetnyak VI, Reshetnyak TM (2017) Significance of dormant forms of Helicobacter pylori in ulcerogenesis. World J Gastroenterol. https://doi.org/10.3748/wjg.v23.i27.4867

  38. Meng W, Bai B, Sheng L, Li Y, Yue P, Li X, Qiao L (2015) Role of Helicobacter pylori in gastric cancer: advances and controversies. Discov Med 20:285–293

    PubMed  Google Scholar 

  39. Assumpção MB, Martins LC, Melo Barbosa HP, Barile KA, de Almeida SS, Assumpção PP, Corvelo TC (2010) Helicobacter pylori in dental plaque and stomach of patients from Northern Brazil. World J Gastroenterol 16:3033–3039

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Bumann D, Habibi H, Kan B, Schmid M, Goosmann C, Brinkmann V, Meyer TF, Jungblut PR (2004) Lack of stage-specific proteins in coccoid Helicobacter pylori cells. Infect Immun. https://doi.org/10.1128/IAI.72.11.6738-6742.2004

  41. Wang KX, Wang XF (2004) Cloning and sequencing of cagA gene fragment of Helicobacter pylori with coccoid form. World J Gastroenterol 10:3511–3513

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Coati I, Fassan M, Farinati F, Graham DY, Genta RM, Rugge M (2015) Autoimmune gastritis: pathologist’s viewpoint. World J Gastroenterol. https://doi.org/10.3748/wjg.v21.i42.12179

  43. Lee K, Hwang H, Nam KT (2014) Immune response and the tumor microenvironment: how they communicate to regulate gastric cancer. Gut Liver. https://doi.org/10.5009/gnl.2014.8.2.131

  44. Fox JG, Wang TC (2007) Inflammation, atrophy, and gastric cancer. J Clin Invest. https://doi.org/10.1172/JCI30111

  45. Correa P, Houghton J (2007) Carcinogenesis of Helicobacter pylori. Gastroenterology. https://doi.org/10.1053/j.gastro.2007.06.026

  46. Dixon MF (2001) Prospects for intervention in gastric carcinogenesis: reversibility of gastric atrophy and intestinal metaplasia. Gut. 49:2–4

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Lofgren JL, Whary MT, Ge Z, Muthupalani S, Taylor NS, Mobley M, Potter A, Varro A, Eibach D, Suerbaum S, Wang TC, Fox JG (2011) Lack of commensal flora in Helicobacter pylori-infected INS-GAS mice reduces gastritis and delays intraepithelial neoplasia. Gastroenterology. https://doi.org/10.1053/j.gastro.2010.09.048

  48. IARC Working Group on the Evaluation of Carcinogenic Risks to Humans (1994) Schistosomes, liver flukes and Helicobacter pylori. Lyon, 1994. IARC Monogr Eval Carcinog Risks Hum 61:1–241

    Google Scholar 

  49. Lee JY, Kim N, Choi YJ, Nam RH, Choi YJ, Kwon YH, Yoon K, Suh JH, Lee SM, Lee HS, Lee DH (2014) Histologic findings and inflammatory reactions after long-term colonization of Helicobacter felis in C57BL/6 mice. J Cancer Prev. https://doi.org/10.15430/JCP.2014.19.3.224

  50. Basso D, Plebani M, Kusters JG (2010) Pathogenesis of Helicobacter pylori infection. Helicobacter. https://doi.org/10.1111/j.1523-5378.2010.00781.x

  51. Shao J, Sartor RB, Dial E, Lichtenberger LM, Schepp W, Alpers DH (2000) Expression of intrinsic factor in rat and murine gastric mucosal cell lineages is modified by inflammation. Am J Pathol 157:1197–1205

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Correa P, Piazuelo MB (2012) The gastric precancerous cascade. J Dig Dis. https://doi.org/10.1111/j.1751-2980.2011.00550.x

  53. Zhang W, Lu H, Graham DY (2014) An update on Helicobacter pylori as the cause of gastric cancer. Gastrointest Tumors. https://doi.org/10.1159/000365310

  54. Wroblewski LE, Peek RM Jr, Wilson KT (2010) Helicobacter pylori and gastric cancer: factors that modulate disease risk. Clin Microbiol Rev. https://doi.org/10.1128/CMR.00011-10

  55. Cheung KS, Chan EW, Wong AYS, Chen L, Wong ICK, Leung WK (2018) Long-term proton pump inhibitors and risk of gastric cancer development after treatment for Helicobacter pylori: a population-based study. Gut. https://doi.org/10.1136/gutjnl-2017-314605

  56. Strand DS, Kim D, Peura DA (2017) 25 years of proton pump inhibitors: a comprehensive review. Gut Liver. https://doi.org/10.5009/gnl15502

Download references

Acknowledgments

We acknowledge Universidade Federal do Pará (PROPESP and Fadesp) for technical support and Conselho Nacional de Desenvolvimento Científico e Teconlógico (CNPq) and Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES) for fellowship support.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Paulo Pimentel de Assumpção.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interest.

Additional information

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

de Assumpção, P.P., Araújo, T.M.T., de Assumpção, P.B. et al. Suicide journey of H. pylori through gastric carcinogenesis: the role of non-H. pylori microbiome and potential consequences for clinical practice. Eur J Clin Microbiol Infect Dis 38, 1591–1597 (2019). https://doi.org/10.1007/s10096-019-03564-5

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10096-019-03564-5

Keywords

  • Helicobacter pylori
  • Gastric cancer
  • Microbiota
  • Dysbiosis
  • Carcinogenesis