Microbial species participate in the genesis of a substantial number of malignancies worldwide, and conservative estimates indicate that > 15% of all cancer cases are attributable to infectious agents. Helicobacter pylori is the most common bacterial infection worldwide, and colonization typically lasts for decades in the absence of targeted antimicrobial therapy. One biological cost to this long-term relationship is a marked increased risk for gastric adenocarcinoma, the second leading cause of cancer-related death in the world, prompting the World Health Organization to designate H. pylori as a class I carcinogen. Approximately 660,000 new cases of gastric cancer per year are attributable to H. pylori, making this pathogen the most common infectious agent linked to malignancy.
Eradication of H. pylori significantly decreases the risk of developing gastric adenocarcinoma in infected individuals; however, only a percentage of colonized persons ever develop neoplasia. Disease risk involves well-choreographed interactions between pathogen and host, which are dependent upon strain-specific bacterial factors, host genotypic traits and/or environmental conditions. H. pylori strains are extremely diverse, freely recombining as panmictic populations. However, the use of broad-range 16S rRNA PCR coupled with high throughput sequencing has demonstrated that H. pylori does not simply exist as a monoculture within the human stomach, but instead is a resident of a distinct gastric microbial ecosystem. While H. pylori is the dominant species, the presence of other microorganisms provides a genetic repository which may facilitate the generation of novel traits that influence gastric carcinogenesis. Host polymorphisms within genes that regulate immunity and oncogenesis also heighten the risk for gastric cancer in conjunction with H. pylori strain-specific constituents. Further, environmental conditions such as iron deficiency and high salt intake can influence H. pylori phenotypes that lower the threshold for disease.
Universal test and treat strategies for H. pylori are not feasible due to the high prevalence of infection as well as the expense and side effects of antibiotic therapy, and eradication rates are often less than 80% in regions of the world where gastric cancer is most prevalent. These observations, in conjunction with evidence that carriage of certain strains is inversely related to esophageal adenocarcinoma, atopic diseases and potentially inflammatory bowel disease, underscore the importance of identifying mechanisms that regulate interactions of H. pylori with its host, which promote carcinogenesis. Delineation of bacterial, host and environmental mediators that augment gastric cancer risk has profound ramifications for both physicians and biomedical researchers, as such findings will not only focus prevention approaches that target H. pylori-infected human populations at increased risk for stomach cancer, but will also provide mechanistic insights into inflammatory carcinomas that develop beyond the gastric niche.
The articles contained in this special issue of Gut Microbes have been authored by world-class investigators and provide fresh insights into specific mediators of H. pylori-induced disease and, importantly, how such mediators may influence strategies for the prevention, diagnosis and treatment of oncogenic consequences stemming from infection. These are critical issues to address since many useful resources for analysis now exist including genome sequences (H. pylori and non-H. pylori constituents of the gastric microbiome; rodent and human), measurable phenotypes (CagA phosphorylation) and innovative humanized animal models. Such resources provide a unique opportunity to address key unanswered questions regarding mechanisms through which the host response to particular H. pylori strains, which may be modified by environmental factors, drives carcinogenesis.