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.
Similar content being viewed by others
References
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
Brawner KM, Morrow CD, Smith PD (2014) Gastric microbiome and gastric cancer. Cancer J. https://doi.org/10.1097/PPO.0000000000000043
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
Molloy RM, Sonnenberg A (1997) Relation between gastric cancer and previous peptic ulcer disease. Gut. 40:247–252
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
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
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
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
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
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
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
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
Matsukura N, Onda M, Yamashita K (1995) Helicobacter pylori in peptic ulcer and gastric cancer. Gan To Kagaku Ryoho 22:169–178
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
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
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
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
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
Cheung DY (2017) Atrophic gastritis increases the risk of gastric cancer in asymptomatic population in Korea. Gut Liver. https://doi.org/10.5009/gnl17356
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
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
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
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
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
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
Wang KX, Wang XF (2004) Cloning and sequencing of cagA gene fragment of Helicobacter pylori with coccoid form. World J Gastroenterol 10:3511–3513
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
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
Fox JG, Wang TC (2007) Inflammation, atrophy, and gastric cancer. J Clin Invest. https://doi.org/10.1172/JCI30111
Correa P, Houghton J (2007) Carcinogenesis of Helicobacter pylori. Gastroenterology. https://doi.org/10.1053/j.gastro.2007.06.026
Dixon MF (2001) Prospects for intervention in gastric carcinogenesis: reversibility of gastric atrophy and intestinal metaplasia. Gut. 49:2–4
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
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
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
Basso D, Plebani M, Kusters JG (2010) Pathogenesis of Helicobacter pylori infection. Helicobacter. https://doi.org/10.1111/j.1523-5378.2010.00781.x
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
Correa P, Piazuelo MB (2012) The gastric precancerous cascade. J Dig Dis. https://doi.org/10.1111/j.1751-2980.2011.00550.x
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
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
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
Strand DS, Kim D, Peura DA (2017) 25 years of proton pump inhibitors: a comprehensive review. Gut Liver. https://doi.org/10.5009/gnl15502
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
Corresponding author
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
About this article
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
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s10096-019-03564-5