Risk factors associated with gastric malignancy during chronic Helicobacter pylori infection
Main Article Content
Abstract
Chronic Helicobacter pylori (Hp) infection is considered to be the single most important risk factor for the development of gastric adenocarcinoma in humans, which is a leading cause of cancer-related death worldwide. Nonetheless, Hp infection does not always progress to malignancy, and, gastric adenocarcinoma can occur in the absence of detectable Hp carriage, highlighting the complex and multifactorial nature of gastric cancer. Here we review known contributors to gastric malignancy, including Hp virulence factors, featuring the vacuolating cytotoxin (VacA), the cytotoxin-associated gene A (CagA), and other bacterial components that promote chemotaxis, colonization, and the establishment of chronic inflammation. In addition, we discuss host factors including sex, age, and genetic polymorphisms associated with host inflammation. Moreover, we consider environmental variables that influence cancer risk, such as nutritional status, socio-economic status, and smoking. In addition to these relatively well-studied contributors to gastric cancer risk, the resident gastric microflora in humans have more recently been proposed as an additional risk factor for disease progression in Hp-infected individuals. Molecular approaches for microbe identification have revealed differences in the gastric microbiota composition between cancer and non-cancerous patients, as well as infected and uninfected individuals. Although the reasons underlying differences in microbial community structures are not entirely understood, gastric atrophy and hypochlorhydria that accompany chronic Hp infection may be a critical driver of gastric dysbiosis that promote colonization of microbes that contribute to increased risk of malignancy. However, definitive evidence that the gastric microbiota influences the emergence of gastric cancer does not exist. In summary, while controversial and unresolved, the importance of the gastric microbiota as a risk factor for gastric malignancy is a vital area of current research.
Keywords:
Helicobacter pylori, gastric cancer, adenocarcinoma, risk factors, virulence factors, vacuolating cytotoxin, VacA, CagA, gastric microbiota, microbiome, host factors, polymorphism, co-infection, hypochlorhydria, inflammation, nutritional factors
Article Details
How to Cite
SEEGER, Ami Y et al.
Risk factors associated with gastric malignancy during chronic Helicobacter pylori infection.
Medical Research Archives, [S.l.], v. 8, n. 3, mar. 2020.
ISSN 2375-1924.
Available at: <https://esmed.org/MRA/mra/article/view/2068>. Date accessed: 23 apr. 2024.
doi: https://doi.org/10.18103/mra.v8i3.2068.
Section
Research Articles
The Medical Research Archives grants authors the right to publish and reproduce the unrevised contribution in whole or in part at any time and in any form for any scholarly non-commercial purpose with the condition that all publications of the contribution include a full citation to the journal as published by the Medical Research Archives.
References
1 Ferlay, J. et al. Estimating the global cancer incidence and mortality in 2018: GLOBOCAN sources and methods. International Journal of Cancer 144, 1941-1953, doi:10.1002/ijc.31937 (2019).
2 Forman, D. Gastric cancer and Helicobacter pylori: a combined analysis of 12 case control studies nested within prospective cohorts. 49, 347-353, doi:10.1136/gut.49.3.347 (2001).
3 IARC Working Group on the Evaluation of Carcinogenic Risks to Humans. Personal habits and indoor combustions. Volume 100 E. A review of human carcinogens. IARC Monogr Eval Carcinog Risks Hum 100, 1-538 (2012).
4 Correa, P. A human model of gastric carcinogenesis. Cancer Res 48, 3554-3560 (1988).
5 Suzuki, H. & Matsuzaki, J. Gastric cancer: evidence boosts Helicobacter pylori eradication. Nature Reviews Gastroenterology & Hepatology, doi:10.1038/s41575-018-0023-8 (2018).
6 Choi, I. J. et al. Helicobacter pylori Therapy for the Prevention of Metachronous Gastric Cancer. N Engl J Med 378, 1085-1095, doi:10.1056/NEJMoa1708423 (2018).
7 Fukase, K. et al. Effect of eradication of Helicobacter pylori on incidence of metachronous gastric carcinoma after endoscopic resection of early gastric cancer: an open-label, randomised controlled trial. The Lancet 372, 392-397, doi:10.1016/s0140-6736(08)61159-9 (2008).
8 Ma, J.-L. et al. Fifteen-year effects of Helicobacter pylori, garlic, and vitamin treatments on gastric cancer incidence and mortality. JNCI: Journal of the National Cancer Institute 104, 488-492, doi:10.1093/jnci/djs003 (2012).
9 Mera, R. et al. Dynamics of Helicobacter pylori infection as a determinant of progression of gastric precancerous lesions: 16-year follow-up of an eradication trial. Gut 67, 1239-1246 (2018).
10 Sugano, K. et al. Kyoto global consensus report on Helicobacter pylori gastritis. Gut 64, 1353-1367, doi:10.1136/gutjnl-2015-309252 (2015).
11 Suzuki, H. & Mori, H. Helicobacter pylori gastritis—a novel distinct disease entity. Nature Reviews Gastroenterology & Hepatology 12, 556-557, doi:10.1038/nrgastro.2015.158 (2015).
12 Malfertheiner, P. et al. Management of Helicobacter pylori infection-the Maastricht V/Florence Consensus Report. Gut 66, 6-30, doi:10.1136/gutjnl-2016-312288 (2016).
13 Sugano, K. Effect of Helicobacter pylori eradication on the incidence of gastric cancer: a systematic review and meta-analysis. Gastric Cancer 22, 435-445, doi:10.1007/s10120-018-0876-0 (2019).
14 Borbet, T. C., Zhang, X., Muller, A. & Blaser, M. J. The role of the changing human microbiome in the asthma pandemic. J Allergy Clin Immunol 144, 1457-1466, doi:10.1016/j.jaci.2019.10.022 (2019).
15 Lankarani, K. B., Honarvar, B. & Athari, S. S. The mechanisms underlying Helicobacter pylori-mediated protection against allergic asthma. Tanaffos 16, 251-259 (2017).
16 Hooi, J. K. Y. et al. Global Prevalence of Helicobacter pylori Infection: Systematic Review and Meta-Analysis. Gastroenterology 153, 420-429, doi:10.1053/j.gastro.2017.04.022 (2017).
17 Zamani, M. et al. Systematic review with meta-analysis: the worldwide prevalence of Helicobacter pylori infection. Alimentary Pharmacology & Therapeutics 47, 868-876, doi:10.1111/apt.14561 (2018).
18 Miwa, H. H. pylori and gastric cancer: the Asian enigma. 97, 1106-1112, doi:10.1016/s0002-9270(02)04019-4 (2002).
19 Saeki, N., Ono, H., Sakamoto, H. & Yoshida, T. Genetic factors related to gastric cancer susceptibility identified using a genome-wide association study. Cancer Sci 104, 1-8, doi:10.1111/cas.12042 (2013).
20 Inoue, M. Changing epidemiology of Helicobacter pylori in Japan. Gastric Cancer 20, 3-7, doi:10.1007/s10120-016-0658-5 (2017).
21 Ekstrom, A. M., Held, M., Hansson, L. E., Engstrand, L. & Nyren, O. Helicobacter pylori in gastric cancer established by CagA immunoblot as a marker of past infection. Gastroenterology 121, 784-791, doi:10.1053/gast.2001.27999 (2001).
22 Malfertheiner, P., Link, A. & Selgrad, M. Helicobacter pylori: perspectives and time trends. Nature Reviews Gastroenterology & Hepatology 11, 628-638, doi:10.1038/nrgastro.2014.99 (2014).
23 Yang, C. & Ottemann, K. M. Control of bacterial colonization in the glands and crypts. Curr Opin Microbiol 47, 38-44, doi:10.1016/j.mib.2018.11.004 (2019).
24 Johnson, K. S. & Ottemann, K. M. Colonization, localization, and inflammation: the roles of H. pylori chemotaxis in vivo. Curr Opin Microbiol 41, 51-57, doi:10.1016/j.mib.2017.11.019 (2018).
25 Fung, C. et al. High-resolution mapping reveals that microniches in the gastric glands control Helicobacter pylori colonization of the stomach. PLoS Biol 17, e3000231, doi:10.1371/journal.pbio.3000231 (2019).
26 Sterbenc, A., Jarc, E., Poljak, M. & Homan, M. Helicobacter pylori virulence genes. World J Gastroenterol 25, 4870-4884, doi:10.3748/wjg.v25.i33.4870 (2019).
27 Ansari, S. & Yamaoka, Y. Helicobacter pylori virulence factors exploiting gastric colonization and its pathogenicity. Toxins (Basel) 11, doi:10.3390/toxins11110677 (2019).
28 Su, M. et al. Cryo-EM Analysis Reveals Structural Basis of Helicobacter pylori VacA Toxin Oligomerization. J Mol Biol 431, 1956-1965, doi:10.1016/j.jmb.2019.03.029 (2019).
29 Forsyth, M. H., Atherton, J. C., Blaser, M. J. & Cover, T. L. Heterogeneity in levels of vacuolating cytotoxin gene (vacA) transcription among Helicobacter pylori strains. Infect Immun 66, 3088-3094 (1998).
30 de Bernard, M. et al. Helicobacter pylori toxin VacA induces vacuole formation by acting in the cell cytosol. Mol Microbiol 26, 665-674, doi:10.1046/j.1365-2958.1997.5881952.x (1997).
31 Javed, S., Skoog, E. C. & Solnick, J. V. Impact of Helicobacter pylori Virulence Factors on the Host Immune Response and Gastric Pathology. Curr Top Microbiol Immunol 421, 21-52, doi:10.1007/978-3-030-15138-6_2 (2019).
32 Kim, I. J. & Blanke, S. R. Remodeling the host environment: modulation of the gastric epithelium by the Helicobacter pylori vacuolating toxin (VacA). Front Cell Infect Microbiol 2, 37, doi:10.3389/fcimb.2012.00037 (2012).
33 Rudnicka, K., Backert, S. & Chmiela, M. Genetic Polymorphisms in Inflammatory and Other Regulators in Gastric Cancer: Risks and Clinical Consequences. Curr Top Microbiol Immunol 421, 53-76, doi:10.1007/978-3-030-15138-6_3 (2019).
34 Whitmire, J. M. & Merrell, D. S. Helicobacter pylori Genetic Polymorphisms in Gastric Disease Development. Adv Exp Med Biol 1149, 173-194, doi:10.1007/5584_2019_365 (2019).
35 Atherton, J. C. et al. Mosaicism in vacuolating cytotoxin alleles of Helicobacter pylori. Association of specific vacA types with cytotoxin production and peptic ulceration. J Biol Chem 270, 17771-17777, doi:10.1074/jbc.270.30.17771 (1995).
36 Winter, J. A. et al. A role for the vacuolating cytotoxin, VacA, in colonization and Helicobacter pylori-induced metaplasia in the stomach. J Infect Dis 210, 954-963, doi:10.1093/infdis/jiu154 (2014).
37 Salama, N. R., Otto, G., Tompkins, L. & Falkow, S. Vacuolating cytotoxin of Helicobacter pylori plays a role during colonization in a mouse model of infection. Infect Immun 69, 730-736, doi:10.1128/iai.69.2.730-736.2001 (2001).
38 Altobelli, A., Bauer, M., Velez, K., Cover, T. L. & Muller, A. Helicobacter pylori VacA Targets Myeloid Cells in the Gastric Lamina Propria To Promote Peripherally Induced Regulatory T-Cell Differentiation and Persistent Infection. mBio 10, doi:10.1128/mBio.00261-19 (2019).
39 Cover, T. L. & Blanke, S. R. Helicobacter pylori VacA, a paradigm for toxin multifunctionality. Nat Rev Microbiol 3, 320-332, doi:10.1038/nrmicro1095 (2005).
40 Tan, S., Noto, J. M., Romero-Gallo, J., Peek, R. M., Jr. & Amieva, M. R. Helicobacter pylori perturbs iron trafficking in the epithelium to grow on the cell surface. PLoS Pathog 7, e1002050, doi:10.1371/journal.ppat.1002050 (2011).
41 Konturek, P. C. et al. Mouse model of Helicobacter pylori infection: studies of gastric function and ulcer healing. Aliment Pharmacol Ther 13, 333-346, doi:10.1046/j.1365-2036.1999.00476.x (1999).
42 Zhu, P. et al. Helicobacter pylori VacA induces autophagic cell death in gastric epithelial cells via the endoplasmic reticulum stress pathway. Cell Death Dis 8, 3207, doi:10.1038/s41419-017-0011-x (2017).
43 Chang, H. et al. Cortactin Mediates Apoptosis of Gastric Epithelial Cells Induced by VacA Protein of Helicobacter pylori. Dig Dis Sci 61, 80-90, doi:10.1007/s10620-015-3836-0 (2016).
44 Yahiro, K. et al. Helicobacter pylori VacA induces apoptosis by accumulation of connexin 43 in autophagic vesicles via a Rac1/ERK-dependent pathway. Cell Death Discov 1, 15035, doi:10.1038/cddiscovery.2015.35 (2015).
45 Cover, T. L., Dooley, C. P. & Blaser, M. J. Characterization of and human serologic response to proteins in Helicobacter pylori broth culture supernatants with vacuolizing cytotoxin activity. Infect Immun 58, 603-610 (1990).
46 Kim, I. J. et al. Helicobacter pylori Infection Modulates Host Cell Metabolism through VacA-Dependent Inhibition of mTORC1. Cell Host Microbe 23, 583-593.e588, doi:10.1016/j.chom.2018.04.006 (2018).
47 Maleki Kakelar, H. et al. Pathogenicity of Helicobacter pylori in cancer development and impacts of vaccination. Gastric Cancer 22, 23-36, doi:10.1007/s10120-018-0867-1 (2019).
48 Knorr, J., Ricci, V., Hatakeyama, M. & Backert, S. Classification of Helicobacter pylori Virulence Factors: Is CagA a Toxin or Not? Trends Microbiol 27, 731-738, doi:10.1016/j.tim.2019.04.010 (2019).
49 Uotani, T. et al. Changes of tight junction and interleukin-8 expression using a human gastroid monolayer model of Helicobacter pylori infection. Helicobacter 24, e12583, doi:10.1111/hel.12583 (2019).
50 Backert, S., Schmidt, T. P., Harrer, A. & Wessler, S. Exploiting the Gastric Epithelial Barrier: Helicobacter pylori's Attack on Tight and Adherens Junctions. Curr Top Microbiol Immunol 400, 195-226, doi:10.1007/978-3-319-50520-6_9 (2017).
51 Capurro, M. I., Prashar, A. & Jones, N. L. MCOLN1/TRPML1 inhibition - a novel strategy used by Helicobacter pylori to escape autophagic killing and antibiotic eradication therapy in vivo. Autophagy 16, 169-170, doi:10.1080/15548627.2019.1677322 (2020).
52 Capurro, M. I. et al. VacA generates a protective intracellular reservoir for Helicobacter pylori that is eliminated by activation of the lysosomal calcium channel TRPML1. Nat Microbiol 4, 1411-1423, doi:10.1038/s41564-019-0441-6 (2019).
53 Fagoonee, S. & Pellicano, R. Helicobacter pylori: molecular basis for colonization and survival in gastric environment and resistance to antibiotics. A short review. Infect Dis (Lond) 51, 399-408, doi:10.1080/23744235.2019.1588472 (2019).
54 Yao, X. & Smolka, A. J. Gastric Parietal Cell Physiology and Helicobacter pylori-Induced Disease. Gastroenterology 156, 2158-2173, doi:10.1053/j.gastro.2019.02.036 (2019).
55 Lehours, P. & Ferrero, R. L. Review: Helicobacter: Inflammation, immunology, and vaccines. Helicobacter 24 Suppl 1, e12644, doi:10.1111/hel.12644 (2019).
56 Djekic, A. & Muller, A. The Immunomodulator VacA Promotes Immune Tolerance and Persistent Helicobacter pylori Infection through Its Activities on T-Cells and Antigen-Presenting Cells. Toxins (Basel) 8, doi:10.3390/toxins8060187 (2016).
57 Witherell, H. L. et al. Risk for gastric lymphoma in persons with CagA+ and CagA- Helicobacter pylori infection. J Infect Dis 176, 1641-1644, doi:10.1086/517346 (1997).
58 Murata-Kamiya, N., Kikuchi, K., Hayashi, T., Higashi, H. & Hatakeyama, M. Helicobacter pylori exploits host membrane phosphatidylserine for delivery, localization, and pathophysiological action of the CagA oncoprotein. Cell Host Microbe 7, 399-411, doi:10.1016/j.chom.2010.04.005 (2010).
59 Backert, S., Feller, S. M. & Wessler, S. Emerging roles of Abl family tyrosine kinases in microbial pathogenesis. Trends Biochem Sci 33, 80-90, doi:10.1016/j.tibs.2007.10.006 (2008).
60 Mueller, D. et al. c-Src and c-Abl kinases control hierarchic phosphorylation and function of the CagA effector protein in Western and East Asian Helicobacter pylori strains. J Clin Invest 122, 1553-1566, doi:10.1172/jci61143 (2012).
61 Tegtmeyer, N., Neddermann, M., Asche, C. I. & Backert, S. Subversion of host kinases: a key network in cellular signaling hijacked by Helicobacter pylori CagA. Mol Microbiol 105, 358-372, doi:10.1111/mmi.13707 (2017).
62 Backert, S. & Blaser, M. J. The Role of CagA in the Gastric Biology of Helicobacter pylori. Cancer Res 76, 4028-4031, doi:10.1158/0008-5472.Can-16-1680 (2016).
63 Franco, A. T. et al. Activation of beta-catenin by carcinogenic Helicobacter pylori. Proc Natl Acad Sci U S A 102, 10646-10651, doi:10.1073/pnas.0504927102 (2005).
64 Hanyu, H. et al. Helicobacter pylori Uses the TlpB Receptor To Sense Sites of Gastric Injury. Infect Immun 87, doi:10.1128/iai.00202-19 (2019).
65 Mahdavi, J. et al. Helicobacter pylori SabA adhesin in persistent infection and chronic inflammation. Science 297, 573-578, doi:10.1126/science.1069076 (2002).
66 Ferrand, J., Lehours, P., Schmid-Alliana, A., Megraud, F. & Varon, C. Helicobacter pylori infection of gastrointestinal epithelial cells in vitro induces mesenchymal stem cell migration through an NF-kappaB-dependent pathway. PLoS One 6, e29007, doi:10.1371/journal.pone.0029007 (2011).
67 Blaser, N., Backert, S. & Pachathundikandi, S. K. Immune Cell Signaling by Helicobacter pylori: Impact on Gastric Pathology. Adv Exp Med Biol 1149, 77-106, doi:10.1007/5584_2019_360 (2019).
68 Yamaoka, Y., Kato, M. & Asaka, M. Geographic Differences in Gastric Cancer Incidence Can be Explained by Differences between Helicobacter pylori Strains. Internal Medicine 47, 1077-1083, doi:10.2169/internalmedicine.47.0975 (2008).
69 Rowland, M. et al. Age-specific incidence of Helicobacter pylori. Gastroenterology 130, 65-72; quiz 211, doi:10.1053/j.gastro.2005.11.004 (2006).
70 Drumm, B., Perez-Perez, G. I., Blaser, M. J. & Sherman, P. M. Intrafamilial clustering of Helicobacter pylori infection. New England Journal of Medicine 322, 359-363, doi:10.1056/nejm199002083220603 (1990).
71 Kandulski, A., Malfertheiner, P. & Wex, T. Role of regulatory T-cells in H. pylori-induced gastritis and gastric cancer. Anticancer Res 30, 1093-1103 (2010).
72 El-Omar, E. M., Chow, W. H. & Rabkin, C. S. Gastric cancer and H. pylori: Host genetics open the way. Gastroenterology 121, 1002-1004 (2001).
73 Rad, R. et al. Cytokine gene polymorphisms influence mucosal cytokine expression, gastric inflammation, and host specific colonisation during Helicobacter pylori infection. Gut 53, 1082-1089, doi:10.1136/gut.2003.029736 (2004).
74 Hwang, I. R. et al. Effect of interleukin 1 polymorphisms on gastric mucosal interleukin 1beta production in Helicobacter pylori infection. Gastroenterology 123, 1793-1803, doi:10.1053/gast.2002.37043 (2002).
75 Wilson, K. T. & Crabtree, J. E. Immunology of Helicobacter pylori: Insights Into the Failure of the Immune Response and Perspectives on Vaccine Studies. Gastroenterology 133, 288-308, doi:10.1053/j.gastro.2007.05.008 (2007).
76 Crabtree, J. E., Shallcross, T. M., Heatley, R. V. & Wyatt, J. I. Mucosal tumour necrosis factor alpha and interleukin-6 in patients with Helicobacter pylori associated gastritis. Gut 32, 1473-1477, doi:10.1136/gut.32.12.1473 (1991).
77 Allen, R. D. Polymorphism of the human TNF-α promoter — random variation or functional diversity? Molecular Immunology 36, 1017-1027, doi:10.1016/s0161-5890(99)00127-3 (1999).
78 Machado, J. C. et al. A proinflammatory genetic profile increases the risk for chronic atrophic gastritis and gastric carcinoma. Gastroenterology 125, 364-371, doi:10.1016/s0016-5085(03)00899-0 (2003).
79 El-Omar, E. M. et al. Increased risk of noncardia gastric cancer associated with proinflammatory cytokine gene polymorphisms. Gastroenterology 124, 1193-1201, doi:10.1016/s0016-5085(03)00157-4 (2003).
80 Zheng, W. et al. The relationship between tumor necrosis factor-α polymorphisms and gastric cancer risk: An updated meta-analysis. Biomed Rep 7, 133-142, doi:10.3892/br.2017.934 (2017).
81 Baggiolini, M. & Clark-Lewis, I. Interleukin-8, a chemotactic and inflammatory cytokine. FEBS Lett 307, 97-101, doi:10.1016/0014-5793(92)80909-z (1992).
82 Lee, K. E. et al. Helicobacter pylori and interleukin-8 in gastric cancer. World J Gastroenterol 19, 8192-8202, doi:10.3748/wjg.v19.i45.8192 (2013).
83 Macri, A. et al. Serum levels of interleukin 1beta, interleukin 8 and tumour necrosis factor alpha as markers of gastric cancer. Biomarkers 11, 184-193, doi:10.1080/13547500600565677 (2006).
84 Ohyauchi, M. et al. The polymorphism interleukin 8 -251 A/T influences the susceptibility of Helicobacter pylori related gastric diseases in the Japanese population. Gut 54, 330-335, doi:10.1136/gut.2003.033050 (2005).
85 Kang, J. M. et al. The effects of genetic polymorphisms of IL-6, IL-8, and IL-10 on Helicobacter pylori-induced gastroduodenal diseases in Korea. J Clin Gastroenterol 43, 420-428, doi:10.1097/MCG.0b013e318178d1d3 (2009).
86 Rutz, S. & Ouyang, W. Regulation of Interleukin-10 Expression. Adv Exp Med Biol 941, 89-116, doi:10.1007/978-94-024-0921-5_5 (2016).
87 Zambon, C. F. et al. Pro- and anti-inflammatory cytokines gene polymorphisms and Helicobacter pylori infection: interactions influence outcome. Cytokine 29, 141-152, doi:10.1016/j.cyto.2004.10.013 (2005).
88 Rosenstock, S. J., Andersen, L. P., Rosenstock, C. V., Bonnevie, O. & Jorgensen, T. Socioeconomic factors in Helicobacter pylori infection among Danish adults. American Journal of Public Health 86, 1539-1544, doi:Doi 10.2105/Ajph.86.11.1539 (1996).
89 Hosni, H., Kotb, M. A. & Kamel, M. M. Histopathological Study of the Upper Gastrointestinal Tract for Helicobacter pylori and Giardiasis in Egyptian Children. American Journal of Clinical Pathology 138, A020-A020, doi:10.1093/ajcp/138.suppl2.324 (2012).
90 Krzyzek, P. & Gosciniak, G. Frequency and immunological consequences of Helicobacter pylori and intestinal parasite co-infections: a brief review. Ann Parasitol 63, 255-263, doi:10.17420/ap6304.112 (2017).
91 Whary, M. T. et al. Intestinal helminthiasis in Colombian children promotes a Th2 response to Helicobacter pylori: possible implications for gastric carcinogenesis. Cancer Epidemiol Biomarkers Prev 14, 1464-1469, doi:10.1158/1055-9965.Epi-05-0095 (2005).
92 Ek, C. et al. Serologic evidence that Ascaris and Toxoplasma infections impact inflammatory responses to Helicobacter pylori in Colombians. Helicobacter 17, 107-115, doi:10.1111/j.1523-5378.2011.00916.x (2012).
93 Fox, J. G. et al. High-salt diet induces gastric epithelial hyperplasia and parietal cell loss, and enhances Helicobacter pylori colonization in C57BL/6 mice. Cancer Res 59, 4823-4828 (1999).
94 Gaddy, J. A. et al. High dietary salt intake exacerbates Helicobacter pylori-induced gastric carcinogenesis. Infect Immun 81, 2258-2267, doi:10.1128/iai.01271-12 (2013).
95 Amieva, M. & Peek, R. M. Pathobiology of Helicobacter pylori–Induced Gastric Cancer. Gastroenterology 150, 64-78, doi:10.1053/j.gastro.2015.09.004 (2016).
96 Noto, J. M. et al. Iron deficiency accelerates Helicobacter pylori–induced carcinogenesis in rodents and humans. 123, 479-492, doi:10.1172/jci64373 (2013).
97 Zaidi, S. F., Ahmed, K., Saeed, S. A., Khan, U. & Sugiyama, T. Can diet modulate Helicobacter pylori-associated gastric pathogenesis? An evidence-based analysis. Nutrition and Cancer 69, 979-989, doi:10.1080/01635581.2017.1359310 (2017).
98 Yamaguchi, N. & Kakizoe, T. Synergistic interaction between Helicobacter pylori gastritis and diet in gastric cancer. The Lancet Oncology 2, 88-94, doi:10.1016/s1470-2045(00)00225-4 (2001).
99 Zatonski, W. et al. Urinary excretion of N-nitrosamino acids and nitrate by inhabitants of high- and low-risk areas for stomach cancer in Poland. International Journal of Cancer 44, 823-827, doi:10.1002/ijc.2910440513 (1989).
100 Sierra, R. et al. In vivo nitrosoproline formation and other risk factors in Costa Rican children from high- and low-risk areas for gastric cancer. 2, 563-568 (1993).
101 Ruiz, B. et al. Vitamin C concentration in gastric juice before and after anti-Helicobacter pylori treatment. Am J Gastroenterol 89, 533-539 (1994).
102 Machida-Montani, A. et al. Association of Helicobacter pylori infection and environmental factors in non-cardia gastric cancer in Japan. Gastric Cancer 7, 46-53, doi:10.1007/s10120-004-0268-5 (2004).
103 Mirvish, S. S. Role of N-nitroso compounds (NOC) and N-nitrosation in etiology of gastric, esophageal, nasopharyngeal and bladder cancer and contribution to cancer of known exposures to NOC. Cancer Letters 93, 17-48, doi:10.1016/0304-3835(95)03786-v (1995).
104 Buiatti, E. et al. Determinants of plasma anti-oxidant vitamin levels in a population at high risk for stomach cancer. Int J Cancer 65, 317-322, doi:10.1002/(sici)1097-0215(19960126)65:3<317::Aid-ijc7>3.0.Co;2-2 (1996).
105 Schulz, C., Schutte, K., Mayerle, J. & Malfertheiner, P. The role of the gastric bacterial microbiome in gastric cancer: Helicobacter pylori and beyond. Therap Adv Gastroenterol 12, 1756284819894062, doi:10.1177/1756284819894062 (2019).
106 Maldonado-Contreras, A. et al. Structure of the human gastric bacterial community in relation to Helicobacter pylori status. ISME J 5, 574-579, doi:10.1038/ismej.2010.149 (2011).
107 Schulz, C. et al. The active bacterial assemblages of the upper GI tract in individuals with and without Helicobacter infection. Gut 67, 216-225, doi:10.1136/gutjnl-2016-312904 (2018).
108 Bik, E. M. et al. Molecular analysis of the bacterial microbiota in the human stomach. Proc Natl Acad Sci U S A 103, 732-737, doi:10.1073/pnas.0506655103 (2006).
109 Klymiuk, I. et al. The Human Gastric Microbiome Is Predicated upon Infection with Helicobacter pylori. Front Microbiol 8, 2508, doi:10.3389/fmicb.2017.02508 (2017).
110 Llorca, L. et al. Characterization of the Gastric Microbiota in a Pediatric Population According to Helicobacter pylori Status. Pediatr Infect Dis J 36, 173-178, doi:10.1097/inf.0000000000001383 (2017).
111 Wroblewski, L. E., Peek, R. M., Jr. & Wilson, K. T. Helicobacter pylori and gastric cancer: factors that modulate disease risk. Clin Microbiol Rev 23, 713-739, doi:10.1128/cmr.00011-10 (2010).
112 Ferreira, R. M. et al. Gastric microbial community profiling reveals a dysbiotic cancer-associated microbiota. Gut 67, 226-236, doi:10.1136/gutjnl-2017-314205 (2018).
113 Wang, L. et al. Bacterial overgrowth and diversification of microbiota in gastric cancer. Eur J Gastroenterol Hepatol 28, 261-266, doi:10.1097/meg.0000000000000542 (2016).
114 Mukaisho, K., Nakayama, T., Hagiwara, T., Hattori, T. & Sugihara, H. Two distinct etiologies of gastric cardia adenocarcinoma: interactions among pH, Helicobacter pylori, and bile acids. Front Microbiol 6, 412, doi:10.3389/fmicb.2015.00412 (2015).
115 Suo, M., Mukaisho, K., Shimomura, A., Sugihara, H. & Hattori, T. Thioproline prevents carcinogenesis in the remnant stomach induced by duodenal reflux. Cancer Lett 237, 256-262, doi:10.1016/j.canlet.2005.06.019 (2006).
116 Argent, R. H. et al. Toxigenic Helicobacter pylori infection precedes gastric hypochlorhydria in cancer relatives, and H. pylori virulence evolves in these families. Clin Cancer Res 14, 2227-2235, doi:10.1158/1078-0432.Ccr-07-2022 (2008).
117 Iijima, K. et al. Long-term effect of Helicobacter pylori eradication on the reversibility of acid secretion in profound hypochlorhydria. Aliment Pharmacol Ther 19, 1181-1188, doi:10.1111/j.1365-2036.2004.01948.x (2004).
118 Wang, F. et al. Helicobacter pylori VacA disrupts apical membrane-cytoskeletal interactions in gastric parietal cells. J Biol Chem 283, 26714-26725, doi:10.1074/jbc.M800527200 (2008).
119 Murayama, Y. et al. Morphological and functional restoration of parietal cells in Helicobacter pylori associated enlarged fold gastritis after eradication. Gut 45, 653-661, doi:10.1136/gut.45.5.653 (1999).
120 Mowat, C. et al. Omeprazole, Helicobacter pylori status, and alterations in the intragastric milieu facilitating bacterial N-nitrosation. Gastroenterology 119, 339-347, doi:10.1053/gast.2000.9367 (2000).
121 Litvak, Y., Byndloss, M. X. & Baumler, A. J. Colonocyte metabolism shapes the gut microbiota. Science 362, doi:10.1126/science.aat9076 (2018).
122 Byndloss, M. X. & Baumler, A. J. The germ-organ theory of non-communicable diseases. Nat Rev Microbiol 16, 103-110, doi:10.1038/nrmicro.2017.158 (2018).
123 Winter, S. E., Lopez, C. A. & Baumler, A. J. The dynamics of gut-associated microbial communities during inflammation. EMBO Rep 14, 319-327, doi:10.1038/embor.2013.27 (2013).
124 Sharma, B. K. et al. Intragastric bacterial activity and nitrosation before, during, and after treatment with omeprazole. Br Med J (Clin Res Ed) 289, 717-719, doi:10.1136/bmj.289.6447.717 (1984).
125 Schulz, C., Schutte, K. & Malfertheiner, P. Helicobacter pylori and other gastric microbiota in gastroduodenal pathologies. Dig Dis 34, 210-216, doi:10.1159/000443353 (2016).
126 Abrams, J. A., Gonsalves, L. & Neugut, A. I. Diverging Trends in the Incidence of Reflux-related and Helicobacter pylori-related Gastric Cardia Cancer. Journal of Clinical Gastroenterology 47, 322-327, doi:10.1097/mcg.0b013e318260177a (2013).
127 Lofgren, J. L. et al. Lack of commensal flora in Helicobacter pylori-infected INS-GAS mice reduces gastritis and delays intraepithelial neoplasia. Gastroenterology 140, 210-220, doi:10.1053/j.gastro.2010.09.048 (2011).
128 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 63, 54-63, doi:10.1136/gutjnl-2013-305178 (2014).
129 Schütte, K., Malfertheiner, P. & Schulz, C. What is the relevance of gastric microbiota beyond H. pylori? Current Treatment Options in Gastroenterology 17, 619-627, doi:10.1007/s11938-019-00245-2 (2019).
130 Shirazi, M. S. R., Al-Alo, K. Z. K., Al-Yasiri, M. H., Lateef, Z. M. & Ghasemian, A. Microbiome Dysbiosis and Predominant Bacterial Species as Human Cancer Biomarkers. J Gastrointest Cancer, doi:10.1007/s12029-019-00311-z (2019).
2 Forman, D. Gastric cancer and Helicobacter pylori: a combined analysis of 12 case control studies nested within prospective cohorts. 49, 347-353, doi:10.1136/gut.49.3.347 (2001).
3 IARC Working Group on the Evaluation of Carcinogenic Risks to Humans. Personal habits and indoor combustions. Volume 100 E. A review of human carcinogens. IARC Monogr Eval Carcinog Risks Hum 100, 1-538 (2012).
4 Correa, P. A human model of gastric carcinogenesis. Cancer Res 48, 3554-3560 (1988).
5 Suzuki, H. & Matsuzaki, J. Gastric cancer: evidence boosts Helicobacter pylori eradication. Nature Reviews Gastroenterology & Hepatology, doi:10.1038/s41575-018-0023-8 (2018).
6 Choi, I. J. et al. Helicobacter pylori Therapy for the Prevention of Metachronous Gastric Cancer. N Engl J Med 378, 1085-1095, doi:10.1056/NEJMoa1708423 (2018).
7 Fukase, K. et al. Effect of eradication of Helicobacter pylori on incidence of metachronous gastric carcinoma after endoscopic resection of early gastric cancer: an open-label, randomised controlled trial. The Lancet 372, 392-397, doi:10.1016/s0140-6736(08)61159-9 (2008).
8 Ma, J.-L. et al. Fifteen-year effects of Helicobacter pylori, garlic, and vitamin treatments on gastric cancer incidence and mortality. JNCI: Journal of the National Cancer Institute 104, 488-492, doi:10.1093/jnci/djs003 (2012).
9 Mera, R. et al. Dynamics of Helicobacter pylori infection as a determinant of progression of gastric precancerous lesions: 16-year follow-up of an eradication trial. Gut 67, 1239-1246 (2018).
10 Sugano, K. et al. Kyoto global consensus report on Helicobacter pylori gastritis. Gut 64, 1353-1367, doi:10.1136/gutjnl-2015-309252 (2015).
11 Suzuki, H. & Mori, H. Helicobacter pylori gastritis—a novel distinct disease entity. Nature Reviews Gastroenterology & Hepatology 12, 556-557, doi:10.1038/nrgastro.2015.158 (2015).
12 Malfertheiner, P. et al. Management of Helicobacter pylori infection-the Maastricht V/Florence Consensus Report. Gut 66, 6-30, doi:10.1136/gutjnl-2016-312288 (2016).
13 Sugano, K. Effect of Helicobacter pylori eradication on the incidence of gastric cancer: a systematic review and meta-analysis. Gastric Cancer 22, 435-445, doi:10.1007/s10120-018-0876-0 (2019).
14 Borbet, T. C., Zhang, X., Muller, A. & Blaser, M. J. The role of the changing human microbiome in the asthma pandemic. J Allergy Clin Immunol 144, 1457-1466, doi:10.1016/j.jaci.2019.10.022 (2019).
15 Lankarani, K. B., Honarvar, B. & Athari, S. S. The mechanisms underlying Helicobacter pylori-mediated protection against allergic asthma. Tanaffos 16, 251-259 (2017).
16 Hooi, J. K. Y. et al. Global Prevalence of Helicobacter pylori Infection: Systematic Review and Meta-Analysis. Gastroenterology 153, 420-429, doi:10.1053/j.gastro.2017.04.022 (2017).
17 Zamani, M. et al. Systematic review with meta-analysis: the worldwide prevalence of Helicobacter pylori infection. Alimentary Pharmacology & Therapeutics 47, 868-876, doi:10.1111/apt.14561 (2018).
18 Miwa, H. H. pylori and gastric cancer: the Asian enigma. 97, 1106-1112, doi:10.1016/s0002-9270(02)04019-4 (2002).
19 Saeki, N., Ono, H., Sakamoto, H. & Yoshida, T. Genetic factors related to gastric cancer susceptibility identified using a genome-wide association study. Cancer Sci 104, 1-8, doi:10.1111/cas.12042 (2013).
20 Inoue, M. Changing epidemiology of Helicobacter pylori in Japan. Gastric Cancer 20, 3-7, doi:10.1007/s10120-016-0658-5 (2017).
21 Ekstrom, A. M., Held, M., Hansson, L. E., Engstrand, L. & Nyren, O. Helicobacter pylori in gastric cancer established by CagA immunoblot as a marker of past infection. Gastroenterology 121, 784-791, doi:10.1053/gast.2001.27999 (2001).
22 Malfertheiner, P., Link, A. & Selgrad, M. Helicobacter pylori: perspectives and time trends. Nature Reviews Gastroenterology & Hepatology 11, 628-638, doi:10.1038/nrgastro.2014.99 (2014).
23 Yang, C. & Ottemann, K. M. Control of bacterial colonization in the glands and crypts. Curr Opin Microbiol 47, 38-44, doi:10.1016/j.mib.2018.11.004 (2019).
24 Johnson, K. S. & Ottemann, K. M. Colonization, localization, and inflammation: the roles of H. pylori chemotaxis in vivo. Curr Opin Microbiol 41, 51-57, doi:10.1016/j.mib.2017.11.019 (2018).
25 Fung, C. et al. High-resolution mapping reveals that microniches in the gastric glands control Helicobacter pylori colonization of the stomach. PLoS Biol 17, e3000231, doi:10.1371/journal.pbio.3000231 (2019).
26 Sterbenc, A., Jarc, E., Poljak, M. & Homan, M. Helicobacter pylori virulence genes. World J Gastroenterol 25, 4870-4884, doi:10.3748/wjg.v25.i33.4870 (2019).
27 Ansari, S. & Yamaoka, Y. Helicobacter pylori virulence factors exploiting gastric colonization and its pathogenicity. Toxins (Basel) 11, doi:10.3390/toxins11110677 (2019).
28 Su, M. et al. Cryo-EM Analysis Reveals Structural Basis of Helicobacter pylori VacA Toxin Oligomerization. J Mol Biol 431, 1956-1965, doi:10.1016/j.jmb.2019.03.029 (2019).
29 Forsyth, M. H., Atherton, J. C., Blaser, M. J. & Cover, T. L. Heterogeneity in levels of vacuolating cytotoxin gene (vacA) transcription among Helicobacter pylori strains. Infect Immun 66, 3088-3094 (1998).
30 de Bernard, M. et al. Helicobacter pylori toxin VacA induces vacuole formation by acting in the cell cytosol. Mol Microbiol 26, 665-674, doi:10.1046/j.1365-2958.1997.5881952.x (1997).
31 Javed, S., Skoog, E. C. & Solnick, J. V. Impact of Helicobacter pylori Virulence Factors on the Host Immune Response and Gastric Pathology. Curr Top Microbiol Immunol 421, 21-52, doi:10.1007/978-3-030-15138-6_2 (2019).
32 Kim, I. J. & Blanke, S. R. Remodeling the host environment: modulation of the gastric epithelium by the Helicobacter pylori vacuolating toxin (VacA). Front Cell Infect Microbiol 2, 37, doi:10.3389/fcimb.2012.00037 (2012).
33 Rudnicka, K., Backert, S. & Chmiela, M. Genetic Polymorphisms in Inflammatory and Other Regulators in Gastric Cancer: Risks and Clinical Consequences. Curr Top Microbiol Immunol 421, 53-76, doi:10.1007/978-3-030-15138-6_3 (2019).
34 Whitmire, J. M. & Merrell, D. S. Helicobacter pylori Genetic Polymorphisms in Gastric Disease Development. Adv Exp Med Biol 1149, 173-194, doi:10.1007/5584_2019_365 (2019).
35 Atherton, J. C. et al. Mosaicism in vacuolating cytotoxin alleles of Helicobacter pylori. Association of specific vacA types with cytotoxin production and peptic ulceration. J Biol Chem 270, 17771-17777, doi:10.1074/jbc.270.30.17771 (1995).
36 Winter, J. A. et al. A role for the vacuolating cytotoxin, VacA, in colonization and Helicobacter pylori-induced metaplasia in the stomach. J Infect Dis 210, 954-963, doi:10.1093/infdis/jiu154 (2014).
37 Salama, N. R., Otto, G., Tompkins, L. & Falkow, S. Vacuolating cytotoxin of Helicobacter pylori plays a role during colonization in a mouse model of infection. Infect Immun 69, 730-736, doi:10.1128/iai.69.2.730-736.2001 (2001).
38 Altobelli, A., Bauer, M., Velez, K., Cover, T. L. & Muller, A. Helicobacter pylori VacA Targets Myeloid Cells in the Gastric Lamina Propria To Promote Peripherally Induced Regulatory T-Cell Differentiation and Persistent Infection. mBio 10, doi:10.1128/mBio.00261-19 (2019).
39 Cover, T. L. & Blanke, S. R. Helicobacter pylori VacA, a paradigm for toxin multifunctionality. Nat Rev Microbiol 3, 320-332, doi:10.1038/nrmicro1095 (2005).
40 Tan, S., Noto, J. M., Romero-Gallo, J., Peek, R. M., Jr. & Amieva, M. R. Helicobacter pylori perturbs iron trafficking in the epithelium to grow on the cell surface. PLoS Pathog 7, e1002050, doi:10.1371/journal.ppat.1002050 (2011).
41 Konturek, P. C. et al. Mouse model of Helicobacter pylori infection: studies of gastric function and ulcer healing. Aliment Pharmacol Ther 13, 333-346, doi:10.1046/j.1365-2036.1999.00476.x (1999).
42 Zhu, P. et al. Helicobacter pylori VacA induces autophagic cell death in gastric epithelial cells via the endoplasmic reticulum stress pathway. Cell Death Dis 8, 3207, doi:10.1038/s41419-017-0011-x (2017).
43 Chang, H. et al. Cortactin Mediates Apoptosis of Gastric Epithelial Cells Induced by VacA Protein of Helicobacter pylori. Dig Dis Sci 61, 80-90, doi:10.1007/s10620-015-3836-0 (2016).
44 Yahiro, K. et al. Helicobacter pylori VacA induces apoptosis by accumulation of connexin 43 in autophagic vesicles via a Rac1/ERK-dependent pathway. Cell Death Discov 1, 15035, doi:10.1038/cddiscovery.2015.35 (2015).
45 Cover, T. L., Dooley, C. P. & Blaser, M. J. Characterization of and human serologic response to proteins in Helicobacter pylori broth culture supernatants with vacuolizing cytotoxin activity. Infect Immun 58, 603-610 (1990).
46 Kim, I. J. et al. Helicobacter pylori Infection Modulates Host Cell Metabolism through VacA-Dependent Inhibition of mTORC1. Cell Host Microbe 23, 583-593.e588, doi:10.1016/j.chom.2018.04.006 (2018).
47 Maleki Kakelar, H. et al. Pathogenicity of Helicobacter pylori in cancer development and impacts of vaccination. Gastric Cancer 22, 23-36, doi:10.1007/s10120-018-0867-1 (2019).
48 Knorr, J., Ricci, V., Hatakeyama, M. & Backert, S. Classification of Helicobacter pylori Virulence Factors: Is CagA a Toxin or Not? Trends Microbiol 27, 731-738, doi:10.1016/j.tim.2019.04.010 (2019).
49 Uotani, T. et al. Changes of tight junction and interleukin-8 expression using a human gastroid monolayer model of Helicobacter pylori infection. Helicobacter 24, e12583, doi:10.1111/hel.12583 (2019).
50 Backert, S., Schmidt, T. P., Harrer, A. & Wessler, S. Exploiting the Gastric Epithelial Barrier: Helicobacter pylori's Attack on Tight and Adherens Junctions. Curr Top Microbiol Immunol 400, 195-226, doi:10.1007/978-3-319-50520-6_9 (2017).
51 Capurro, M. I., Prashar, A. & Jones, N. L. MCOLN1/TRPML1 inhibition - a novel strategy used by Helicobacter pylori to escape autophagic killing and antibiotic eradication therapy in vivo. Autophagy 16, 169-170, doi:10.1080/15548627.2019.1677322 (2020).
52 Capurro, M. I. et al. VacA generates a protective intracellular reservoir for Helicobacter pylori that is eliminated by activation of the lysosomal calcium channel TRPML1. Nat Microbiol 4, 1411-1423, doi:10.1038/s41564-019-0441-6 (2019).
53 Fagoonee, S. & Pellicano, R. Helicobacter pylori: molecular basis for colonization and survival in gastric environment and resistance to antibiotics. A short review. Infect Dis (Lond) 51, 399-408, doi:10.1080/23744235.2019.1588472 (2019).
54 Yao, X. & Smolka, A. J. Gastric Parietal Cell Physiology and Helicobacter pylori-Induced Disease. Gastroenterology 156, 2158-2173, doi:10.1053/j.gastro.2019.02.036 (2019).
55 Lehours, P. & Ferrero, R. L. Review: Helicobacter: Inflammation, immunology, and vaccines. Helicobacter 24 Suppl 1, e12644, doi:10.1111/hel.12644 (2019).
56 Djekic, A. & Muller, A. The Immunomodulator VacA Promotes Immune Tolerance and Persistent Helicobacter pylori Infection through Its Activities on T-Cells and Antigen-Presenting Cells. Toxins (Basel) 8, doi:10.3390/toxins8060187 (2016).
57 Witherell, H. L. et al. Risk for gastric lymphoma in persons with CagA+ and CagA- Helicobacter pylori infection. J Infect Dis 176, 1641-1644, doi:10.1086/517346 (1997).
58 Murata-Kamiya, N., Kikuchi, K., Hayashi, T., Higashi, H. & Hatakeyama, M. Helicobacter pylori exploits host membrane phosphatidylserine for delivery, localization, and pathophysiological action of the CagA oncoprotein. Cell Host Microbe 7, 399-411, doi:10.1016/j.chom.2010.04.005 (2010).
59 Backert, S., Feller, S. M. & Wessler, S. Emerging roles of Abl family tyrosine kinases in microbial pathogenesis. Trends Biochem Sci 33, 80-90, doi:10.1016/j.tibs.2007.10.006 (2008).
60 Mueller, D. et al. c-Src and c-Abl kinases control hierarchic phosphorylation and function of the CagA effector protein in Western and East Asian Helicobacter pylori strains. J Clin Invest 122, 1553-1566, doi:10.1172/jci61143 (2012).
61 Tegtmeyer, N., Neddermann, M., Asche, C. I. & Backert, S. Subversion of host kinases: a key network in cellular signaling hijacked by Helicobacter pylori CagA. Mol Microbiol 105, 358-372, doi:10.1111/mmi.13707 (2017).
62 Backert, S. & Blaser, M. J. The Role of CagA in the Gastric Biology of Helicobacter pylori. Cancer Res 76, 4028-4031, doi:10.1158/0008-5472.Can-16-1680 (2016).
63 Franco, A. T. et al. Activation of beta-catenin by carcinogenic Helicobacter pylori. Proc Natl Acad Sci U S A 102, 10646-10651, doi:10.1073/pnas.0504927102 (2005).
64 Hanyu, H. et al. Helicobacter pylori Uses the TlpB Receptor To Sense Sites of Gastric Injury. Infect Immun 87, doi:10.1128/iai.00202-19 (2019).
65 Mahdavi, J. et al. Helicobacter pylori SabA adhesin in persistent infection and chronic inflammation. Science 297, 573-578, doi:10.1126/science.1069076 (2002).
66 Ferrand, J., Lehours, P., Schmid-Alliana, A., Megraud, F. & Varon, C. Helicobacter pylori infection of gastrointestinal epithelial cells in vitro induces mesenchymal stem cell migration through an NF-kappaB-dependent pathway. PLoS One 6, e29007, doi:10.1371/journal.pone.0029007 (2011).
67 Blaser, N., Backert, S. & Pachathundikandi, S. K. Immune Cell Signaling by Helicobacter pylori: Impact on Gastric Pathology. Adv Exp Med Biol 1149, 77-106, doi:10.1007/5584_2019_360 (2019).
68 Yamaoka, Y., Kato, M. & Asaka, M. Geographic Differences in Gastric Cancer Incidence Can be Explained by Differences between Helicobacter pylori Strains. Internal Medicine 47, 1077-1083, doi:10.2169/internalmedicine.47.0975 (2008).
69 Rowland, M. et al. Age-specific incidence of Helicobacter pylori. Gastroenterology 130, 65-72; quiz 211, doi:10.1053/j.gastro.2005.11.004 (2006).
70 Drumm, B., Perez-Perez, G. I., Blaser, M. J. & Sherman, P. M. Intrafamilial clustering of Helicobacter pylori infection. New England Journal of Medicine 322, 359-363, doi:10.1056/nejm199002083220603 (1990).
71 Kandulski, A., Malfertheiner, P. & Wex, T. Role of regulatory T-cells in H. pylori-induced gastritis and gastric cancer. Anticancer Res 30, 1093-1103 (2010).
72 El-Omar, E. M., Chow, W. H. & Rabkin, C. S. Gastric cancer and H. pylori: Host genetics open the way. Gastroenterology 121, 1002-1004 (2001).
73 Rad, R. et al. Cytokine gene polymorphisms influence mucosal cytokine expression, gastric inflammation, and host specific colonisation during Helicobacter pylori infection. Gut 53, 1082-1089, doi:10.1136/gut.2003.029736 (2004).
74 Hwang, I. R. et al. Effect of interleukin 1 polymorphisms on gastric mucosal interleukin 1beta production in Helicobacter pylori infection. Gastroenterology 123, 1793-1803, doi:10.1053/gast.2002.37043 (2002).
75 Wilson, K. T. & Crabtree, J. E. Immunology of Helicobacter pylori: Insights Into the Failure of the Immune Response and Perspectives on Vaccine Studies. Gastroenterology 133, 288-308, doi:10.1053/j.gastro.2007.05.008 (2007).
76 Crabtree, J. E., Shallcross, T. M., Heatley, R. V. & Wyatt, J. I. Mucosal tumour necrosis factor alpha and interleukin-6 in patients with Helicobacter pylori associated gastritis. Gut 32, 1473-1477, doi:10.1136/gut.32.12.1473 (1991).
77 Allen, R. D. Polymorphism of the human TNF-α promoter — random variation or functional diversity? Molecular Immunology 36, 1017-1027, doi:10.1016/s0161-5890(99)00127-3 (1999).
78 Machado, J. C. et al. A proinflammatory genetic profile increases the risk for chronic atrophic gastritis and gastric carcinoma. Gastroenterology 125, 364-371, doi:10.1016/s0016-5085(03)00899-0 (2003).
79 El-Omar, E. M. et al. Increased risk of noncardia gastric cancer associated with proinflammatory cytokine gene polymorphisms. Gastroenterology 124, 1193-1201, doi:10.1016/s0016-5085(03)00157-4 (2003).
80 Zheng, W. et al. The relationship between tumor necrosis factor-α polymorphisms and gastric cancer risk: An updated meta-analysis. Biomed Rep 7, 133-142, doi:10.3892/br.2017.934 (2017).
81 Baggiolini, M. & Clark-Lewis, I. Interleukin-8, a chemotactic and inflammatory cytokine. FEBS Lett 307, 97-101, doi:10.1016/0014-5793(92)80909-z (1992).
82 Lee, K. E. et al. Helicobacter pylori and interleukin-8 in gastric cancer. World J Gastroenterol 19, 8192-8202, doi:10.3748/wjg.v19.i45.8192 (2013).
83 Macri, A. et al. Serum levels of interleukin 1beta, interleukin 8 and tumour necrosis factor alpha as markers of gastric cancer. Biomarkers 11, 184-193, doi:10.1080/13547500600565677 (2006).
84 Ohyauchi, M. et al. The polymorphism interleukin 8 -251 A/T influences the susceptibility of Helicobacter pylori related gastric diseases in the Japanese population. Gut 54, 330-335, doi:10.1136/gut.2003.033050 (2005).
85 Kang, J. M. et al. The effects of genetic polymorphisms of IL-6, IL-8, and IL-10 on Helicobacter pylori-induced gastroduodenal diseases in Korea. J Clin Gastroenterol 43, 420-428, doi:10.1097/MCG.0b013e318178d1d3 (2009).
86 Rutz, S. & Ouyang, W. Regulation of Interleukin-10 Expression. Adv Exp Med Biol 941, 89-116, doi:10.1007/978-94-024-0921-5_5 (2016).
87 Zambon, C. F. et al. Pro- and anti-inflammatory cytokines gene polymorphisms and Helicobacter pylori infection: interactions influence outcome. Cytokine 29, 141-152, doi:10.1016/j.cyto.2004.10.013 (2005).
88 Rosenstock, S. J., Andersen, L. P., Rosenstock, C. V., Bonnevie, O. & Jorgensen, T. Socioeconomic factors in Helicobacter pylori infection among Danish adults. American Journal of Public Health 86, 1539-1544, doi:Doi 10.2105/Ajph.86.11.1539 (1996).
89 Hosni, H., Kotb, M. A. & Kamel, M. M. Histopathological Study of the Upper Gastrointestinal Tract for Helicobacter pylori and Giardiasis in Egyptian Children. American Journal of Clinical Pathology 138, A020-A020, doi:10.1093/ajcp/138.suppl2.324 (2012).
90 Krzyzek, P. & Gosciniak, G. Frequency and immunological consequences of Helicobacter pylori and intestinal parasite co-infections: a brief review. Ann Parasitol 63, 255-263, doi:10.17420/ap6304.112 (2017).
91 Whary, M. T. et al. Intestinal helminthiasis in Colombian children promotes a Th2 response to Helicobacter pylori: possible implications for gastric carcinogenesis. Cancer Epidemiol Biomarkers Prev 14, 1464-1469, doi:10.1158/1055-9965.Epi-05-0095 (2005).
92 Ek, C. et al. Serologic evidence that Ascaris and Toxoplasma infections impact inflammatory responses to Helicobacter pylori in Colombians. Helicobacter 17, 107-115, doi:10.1111/j.1523-5378.2011.00916.x (2012).
93 Fox, J. G. et al. High-salt diet induces gastric epithelial hyperplasia and parietal cell loss, and enhances Helicobacter pylori colonization in C57BL/6 mice. Cancer Res 59, 4823-4828 (1999).
94 Gaddy, J. A. et al. High dietary salt intake exacerbates Helicobacter pylori-induced gastric carcinogenesis. Infect Immun 81, 2258-2267, doi:10.1128/iai.01271-12 (2013).
95 Amieva, M. & Peek, R. M. Pathobiology of Helicobacter pylori–Induced Gastric Cancer. Gastroenterology 150, 64-78, doi:10.1053/j.gastro.2015.09.004 (2016).
96 Noto, J. M. et al. Iron deficiency accelerates Helicobacter pylori–induced carcinogenesis in rodents and humans. 123, 479-492, doi:10.1172/jci64373 (2013).
97 Zaidi, S. F., Ahmed, K., Saeed, S. A., Khan, U. & Sugiyama, T. Can diet modulate Helicobacter pylori-associated gastric pathogenesis? An evidence-based analysis. Nutrition and Cancer 69, 979-989, doi:10.1080/01635581.2017.1359310 (2017).
98 Yamaguchi, N. & Kakizoe, T. Synergistic interaction between Helicobacter pylori gastritis and diet in gastric cancer. The Lancet Oncology 2, 88-94, doi:10.1016/s1470-2045(00)00225-4 (2001).
99 Zatonski, W. et al. Urinary excretion of N-nitrosamino acids and nitrate by inhabitants of high- and low-risk areas for stomach cancer in Poland. International Journal of Cancer 44, 823-827, doi:10.1002/ijc.2910440513 (1989).
100 Sierra, R. et al. In vivo nitrosoproline formation and other risk factors in Costa Rican children from high- and low-risk areas for gastric cancer. 2, 563-568 (1993).
101 Ruiz, B. et al. Vitamin C concentration in gastric juice before and after anti-Helicobacter pylori treatment. Am J Gastroenterol 89, 533-539 (1994).
102 Machida-Montani, A. et al. Association of Helicobacter pylori infection and environmental factors in non-cardia gastric cancer in Japan. Gastric Cancer 7, 46-53, doi:10.1007/s10120-004-0268-5 (2004).
103 Mirvish, S. S. Role of N-nitroso compounds (NOC) and N-nitrosation in etiology of gastric, esophageal, nasopharyngeal and bladder cancer and contribution to cancer of known exposures to NOC. Cancer Letters 93, 17-48, doi:10.1016/0304-3835(95)03786-v (1995).
104 Buiatti, E. et al. Determinants of plasma anti-oxidant vitamin levels in a population at high risk for stomach cancer. Int J Cancer 65, 317-322, doi:10.1002/(sici)1097-0215(19960126)65:3<317::Aid-ijc7>3.0.Co;2-2 (1996).
105 Schulz, C., Schutte, K., Mayerle, J. & Malfertheiner, P. The role of the gastric bacterial microbiome in gastric cancer: Helicobacter pylori and beyond. Therap Adv Gastroenterol 12, 1756284819894062, doi:10.1177/1756284819894062 (2019).
106 Maldonado-Contreras, A. et al. Structure of the human gastric bacterial community in relation to Helicobacter pylori status. ISME J 5, 574-579, doi:10.1038/ismej.2010.149 (2011).
107 Schulz, C. et al. The active bacterial assemblages of the upper GI tract in individuals with and without Helicobacter infection. Gut 67, 216-225, doi:10.1136/gutjnl-2016-312904 (2018).
108 Bik, E. M. et al. Molecular analysis of the bacterial microbiota in the human stomach. Proc Natl Acad Sci U S A 103, 732-737, doi:10.1073/pnas.0506655103 (2006).
109 Klymiuk, I. et al. The Human Gastric Microbiome Is Predicated upon Infection with Helicobacter pylori. Front Microbiol 8, 2508, doi:10.3389/fmicb.2017.02508 (2017).
110 Llorca, L. et al. Characterization of the Gastric Microbiota in a Pediatric Population According to Helicobacter pylori Status. Pediatr Infect Dis J 36, 173-178, doi:10.1097/inf.0000000000001383 (2017).
111 Wroblewski, L. E., Peek, R. M., Jr. & Wilson, K. T. Helicobacter pylori and gastric cancer: factors that modulate disease risk. Clin Microbiol Rev 23, 713-739, doi:10.1128/cmr.00011-10 (2010).
112 Ferreira, R. M. et al. Gastric microbial community profiling reveals a dysbiotic cancer-associated microbiota. Gut 67, 226-236, doi:10.1136/gutjnl-2017-314205 (2018).
113 Wang, L. et al. Bacterial overgrowth and diversification of microbiota in gastric cancer. Eur J Gastroenterol Hepatol 28, 261-266, doi:10.1097/meg.0000000000000542 (2016).
114 Mukaisho, K., Nakayama, T., Hagiwara, T., Hattori, T. & Sugihara, H. Two distinct etiologies of gastric cardia adenocarcinoma: interactions among pH, Helicobacter pylori, and bile acids. Front Microbiol 6, 412, doi:10.3389/fmicb.2015.00412 (2015).
115 Suo, M., Mukaisho, K., Shimomura, A., Sugihara, H. & Hattori, T. Thioproline prevents carcinogenesis in the remnant stomach induced by duodenal reflux. Cancer Lett 237, 256-262, doi:10.1016/j.canlet.2005.06.019 (2006).
116 Argent, R. H. et al. Toxigenic Helicobacter pylori infection precedes gastric hypochlorhydria in cancer relatives, and H. pylori virulence evolves in these families. Clin Cancer Res 14, 2227-2235, doi:10.1158/1078-0432.Ccr-07-2022 (2008).
117 Iijima, K. et al. Long-term effect of Helicobacter pylori eradication on the reversibility of acid secretion in profound hypochlorhydria. Aliment Pharmacol Ther 19, 1181-1188, doi:10.1111/j.1365-2036.2004.01948.x (2004).
118 Wang, F. et al. Helicobacter pylori VacA disrupts apical membrane-cytoskeletal interactions in gastric parietal cells. J Biol Chem 283, 26714-26725, doi:10.1074/jbc.M800527200 (2008).
119 Murayama, Y. et al. Morphological and functional restoration of parietal cells in Helicobacter pylori associated enlarged fold gastritis after eradication. Gut 45, 653-661, doi:10.1136/gut.45.5.653 (1999).
120 Mowat, C. et al. Omeprazole, Helicobacter pylori status, and alterations in the intragastric milieu facilitating bacterial N-nitrosation. Gastroenterology 119, 339-347, doi:10.1053/gast.2000.9367 (2000).
121 Litvak, Y., Byndloss, M. X. & Baumler, A. J. Colonocyte metabolism shapes the gut microbiota. Science 362, doi:10.1126/science.aat9076 (2018).
122 Byndloss, M. X. & Baumler, A. J. The germ-organ theory of non-communicable diseases. Nat Rev Microbiol 16, 103-110, doi:10.1038/nrmicro.2017.158 (2018).
123 Winter, S. E., Lopez, C. A. & Baumler, A. J. The dynamics of gut-associated microbial communities during inflammation. EMBO Rep 14, 319-327, doi:10.1038/embor.2013.27 (2013).
124 Sharma, B. K. et al. Intragastric bacterial activity and nitrosation before, during, and after treatment with omeprazole. Br Med J (Clin Res Ed) 289, 717-719, doi:10.1136/bmj.289.6447.717 (1984).
125 Schulz, C., Schutte, K. & Malfertheiner, P. Helicobacter pylori and other gastric microbiota in gastroduodenal pathologies. Dig Dis 34, 210-216, doi:10.1159/000443353 (2016).
126 Abrams, J. A., Gonsalves, L. & Neugut, A. I. Diverging Trends in the Incidence of Reflux-related and Helicobacter pylori-related Gastric Cardia Cancer. Journal of Clinical Gastroenterology 47, 322-327, doi:10.1097/mcg.0b013e318260177a (2013).
127 Lofgren, J. L. et al. Lack of commensal flora in Helicobacter pylori-infected INS-GAS mice reduces gastritis and delays intraepithelial neoplasia. Gastroenterology 140, 210-220, doi:10.1053/j.gastro.2010.09.048 (2011).
128 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 63, 54-63, doi:10.1136/gutjnl-2013-305178 (2014).
129 Schütte, K., Malfertheiner, P. & Schulz, C. What is the relevance of gastric microbiota beyond H. pylori? Current Treatment Options in Gastroenterology 17, 619-627, doi:10.1007/s11938-019-00245-2 (2019).
130 Shirazi, M. S. R., Al-Alo, K. Z. K., Al-Yasiri, M. H., Lateef, Z. M. & Ghasemian, A. Microbiome Dysbiosis and Predominant Bacterial Species as Human Cancer Biomarkers. J Gastrointest Cancer, doi:10.1007/s12029-019-00311-z (2019).