Tipping the Scale Towards Gastric Disease: a Host-Pathogen Genomic Mismatch?
- 23 Downloads
Purpose of Review
Chronic infection with Helicobacter pylori infection is necessary but not sufficient to initiate development of intestinal-type gastric adenocarcinoma. It is not clear what additional factors tip the scale from commensal bacteria towards a pathogen that facilitates development of gastric cancer. Genetic variants in both the pathogen and host have been implicated, but neither alone explains a substantial portion of disease risk.
In this review, we consider studies that address the important role of human and bacterial genetics and ancestry and their interactions in determining gastric disease risk. We observe gaps in the current literature that should guide future work to confirm the hypothesis of the interacting roles of host and bacterial genetics that will be necessary to translate these findings into clinically relevant information.
We summarize genetic risk factors for gastric disease in both H. pylori and human hosts. However, genetic variation of one or the other organism in isolation insufficiently explains gastric disease risk. The most promising models of gastric disease risk simultaneously consider the genetic variation of both the H. pylori and human host, under a co-evolution model.
KeywordsH. pylori Gastric disease Co-evolution Disease risk Genetic ancestry Genome interaction
Compliance with Ethical Standards
Conflicts of Interest
The following funding provided support in part:
SMW & DM: US National Institutes of Health grants P30 CA068485 and PAR-15-155 (Vanderbilt Ingram Cancer Center), R01CA190612, and P01CA028842.
GT: Howard Hughes Medical Institute: Gilliam Fellowship, Case Western Reserve University Medical Scientist Training Program T32.
Human and Animal Rights and Informed Consent
This article does not contain any studies with human or animal subjects performed by any of the authors.
Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance
- 5.IARC Working Group. IARC monograph on the evaluation of carcinogenic risks to humans: schistosomes, liver flukes and Helicobacter pylori. Lyon: International Agency for Research on Cancer; 1994.Google Scholar
- 8.Correa P. The gastric precancerous process. Cancer Surv. 1983;2:437–50.Google Scholar
- 11.Dominguez-Bello M, Blaser M. The human microbiota as a marker for migrations of individuals and populations. Annu Rev Anthropol. 2011;40:451–74.Google Scholar
- 13.Yamaoka Y. Helicobacter pylori typing as a tool for tracking human migration. Clin Microbiol Infect. 2009;9:829–34.Google Scholar
- 16.Castro L, Vaz CL. Helicobacter pylori in South America. Can J Gastroenterol. 1998;12(7):509–12.Google Scholar
- 23.Ford A, Forman D, Hunt R, Yuan Y, Moayyedi P. Helicobacter pylori eradication for the prevention of gastric neoplasia. Cochrane Database Syst Rev. 2015;7:CD005583.Google Scholar
- 30.•• Kodaman N, et al. Human and Helicobacter pylori coevolution shapes the risk of gastric disease. Proc Natl Acad Sci U S A. 2014;111:1455–60. This is the first study to demonstrate that the interaction between host and H. pylori ancestries completely account for severity of gastric lesions. PubMedPubMedCentralGoogle Scholar
- 31.• Lunet N, Barros H. Helicobacter pylori infection and gastric cancer: facing the enigmas. Int J Cancer. 2003;106(6):953–60. Demonstrates that H. pylori prevalence does not correlate with incidence of gastric disease and that factors beyond mere geographical location must determine gastric cancer risk. PubMedGoogle Scholar
- 58.• Persson C, Canedo P, Machado JC, El-Omar EM, Forman D. Polymorphisms in inflammatory response genes and their association with gastric cancer: a HuGE systematic review and meta-analyses. Am J Epidemiol. 2011;173:259–70. A high quality study that assesses SNPs associated with gastric disease risk in Asian versus non-Asian populations. PubMedGoogle Scholar
- 63.Hill AV. Evolution, revolution and heresy in the genetics of infectious disease susceptibility. Philos Trans R Soc Lond Ser B Biol Sci. 2012;367(1590):840–9.Google Scholar
- 69.Schneider BG, et al. DNA methylation predicts progression of human gastric lesions. Cancer Epidemiol Biomark Prev. 2015;24:1607–13.Google Scholar
- 73.The Cancer Genome Atlas Research Network. Comprehensive molecular characterization of gastric adenocarcinoma. Nature. 2014;513:202–9.Google Scholar
- 79.Kolde R, et al. Host genetic variation and its microbiome interactions within the Human Microbiome Project. BMC Gen Med. 2018;10:6.Google Scholar
- 81.Guglielmi G. How gut microbes are joining the fight against cancer. Nature (News Features). 2018;55:482–4.Google Scholar
- 84.• Noto J, Peek R. The gastric microbiome, its interaction with Helicobacter pylori, and its potential role in the progression to stomach cancer. PLoS Pathog. 2017;13(10):e1006573. This describes some potential drivers of gastric cancer susceptibility, within the complex milieu of the human gastric microbiota. PubMedPubMedCentralGoogle Scholar
- 86.Rothschild D, et al. Environment dominates over host genetics in shaping human gut microbiota. Nature. 2018;55:210–5.Google Scholar
- 87.•• Linz B, et al. An African origin for the intimate association between humans and Helicobacter pylori. Nature. 2007;445(7130):915–8. Study using sequences from large H. pylori dataset describes genetic diversity in H. pylori decreasing with geographic distance from East Africa, from where H. pylori spread around 58,000 years ago, via human migration. PubMedPubMedCentralGoogle Scholar
- 97.• Kodaman N, Sobota RS, Mera R, Schneider BG, Williams SM. Disrupted human-pathogen co-evolution: a model for disease. Front Genet. 2014;5:290. Describes a disrupted co-evolution model between host and pathogen, and the need to study genome-by-genome interactions, to explain disease outcome variation, in the context of multiple infectious diseases. PubMedPubMedCentralGoogle Scholar