Gastric adenocarcinoma is the second leading cause of cancer-related death in the world1. Epidemiological and interventional studies in humans, as well as experiments in rodents, have associated Helicobacter pylori — a member of a large family of related bacteria that colonize the mammalian stomach — with peptic ulcers, non-Hodgkin's lymphoma of the stomach, gastric atrophy and distal gastric adenocarcinoma2,3,4,5,6,7,8,9,10. However, only a small percentage (probably less than 3%) of individuals that carry H. pylori ever develop neoplasias related to its presence, indicating that other factors are involved. Such observations, along with recent evidence that certain H. pylori strains might reduce the risk of GASTROESOPHAGEAL REFLUX DISEASE (GERD) and its complications (for example, oesophageal adenocarcinoma)11,12, underscore the importance of understanding the biological interactions of these organisms with their host.

H. pylori epidemiology

H. pylori is present in the stomachs of at least half of the world's population. It is usually acquired in childhood, and when left untreated generally persists for the host's lifetime13. Once established, H. pylori has no significant bacterial competitors and — except for transient bacteria — the stomach is essentially a monoculture of H. pylori. Although people in all geographical zones carry the bacteria, the prevalence of H. pylori is higher in developing countries than in developed countries13,14. In the United States, H. pylori is present in 10–15% of children who are less than 12 years old, compared with 50–60% of people greater than 60 years old13,14,15. The rate of acquisition of new H. pylori infections among adults in developed countries is less than 1% per year14, and most American carriers probably acquired H. pylori during childhood. Over the past half-century, however, progressively fewer children have been shown to carry H. pylori — this decrease has been accelerated by the widespread use of antibiotics. Risk factors for H. pylori acquisition include low socioeconomic status, household crowding, country of origin and ethnicity13,16. Colonization is related to intrafamilial clustering, but not to the presence of non-primate reservoirs, indicating that transmission of H. pylori from person to person occurs13. Induction of regurgitation and catharsis increased the chance of obtaining a positive H. pylori culture from vomitus and diarrhoeal specimens17, which indicates that H. pylori transmission might be associated with childhood episodes of GASTROENTERITIS.

H. pylori and gastric cancer

Two histologically distinct variants of gastric adenocarcinoma have been described, each having different epidemiological and pathophysiological features. Intestinal-type gastric adenocarcinoma usually occurs at a late age, predominates in men and progresses through a relatively well-defined series of histological steps18. Diffuse-type gastric adenocarcinoma more commonly affects younger people, affects men and women equally and consists of individually infiltrating neoplastic cells that do not form glandular structures and are not associated with intestinal metaplasia18. Although H. pylori significantly increases the risk of developing both subtypes of gastric adenocarcinoma, the mechanisms underpinning the development of intestinal-type cancer are more well-characterized; therefore, the remainder of this review will focus predominantly on the relationships between H. pylori and intestinal-type gastric adenocarcinoma.

The chain of events that occurs during development of intestinal-type gastric cancer involves a transition from normal mucosa to chronic superficial GASTRITIS, which then leads to ATROPHIC GASTRITIS and INTESTINAL METAPLASIA, and finally to DYSPLASIA and ADENOCARCINOMA1(Fig. 1). The risk of developing gastric cancer increases exponentially as the extent of atrophic gastritis and intestinal metaplasia increases, and patients with severe multifocal atrophic gastritis have over a 90-fold greater risk of developing adenocarcinoma than those with normal mucosa18. In contrast to the apparent 'orderly' sequence of genetic mutations that accumulate during colorectal carcinogenesis, no mutational events are consistently associated with intermediate steps in the progression to intestinal-type gastric adenocarcinoma (Fig. 1)19,20,21. The ability of H. pylori to induce superficial gastritis22, however, indicates that this organism — or the host inflammatory response to it — could be important in the initiation and promotion of gastric neoplasia.

Figure 1: Progression to intestinal-type gastric adenocarcinoma.
figure 1

Helicobacter pylori colonization usually occurs during childhood and, over a period of days to weeks, leads to superficial gastritis. The presence of host TP53 mutations, host polymorphisms that promote high expression levels of the cytokine interleukin (IL)-1β, and the cag island within infecting H. pylori isolates all contribute to the development of atrophic gastritis, intestinal metaplasia, dysplasia and, eventually, gastric adenocarcinoma over the course of many years. Additional mutations in oncogenes that encode RAS or deleted in colorectal cancer (DCC) might also contribute to intestinal-type gastric carcinogenesis.

Epidemiological studies indicate that H. pylori colonization increases the risk of developing distal (non-cardia) gastric cancer (Fig. 2). The progressive decline in H. pylori acquisition during the last century by people living in developed countries has been mirrored by a decreasing incidence of these gastric cancers23,24. Several case-controlled studies have shown that H. pylori seropositivity is associated with a significantly increased risk of gastric cancer (2.1–16.7-fold greater than in seronegative persons) 5,6,7,8,9,10,25,26,27,28,29,30. In developed countries, H. pylori probably increases the risk of developing gastric cancer by sixfold31. The actual risk of gastric cancer that is attributable to H. pylori might be even higher, because H. pylori colonization diminishes in the presence of premalignant lesions, such as gastric atrophy or intestinal metaplasia, making it difficult to detect in all patients. Importantly, prospective studies have shown that the longer the time interval between H. pylori detection and gastric cancer diagnosis, the higher the risk of developing cancer31.

Figure 2: Gastric anatomy.
figure 2

Anatomical arrangement of the distal oesophagus, stomach and proximal duodenum. Helicobacter pylori-induced inflammation can occur at any site within the stomach. However, most intestinal-type and diffuse gastric adenocarcinomas associated with H. pylori occur in the gastric antrum, body, or (less likely) fundus. Oesophageal adenocarcinomas — which are a complication of gastroesophageal reflux disease and Barrett's oesophagus, and are inversely related to the presence of H. pylori — occur in the distal oesophagus, just above and/or involving the lower oesophageal sphincter.

Results from several studies, reporting that antimicrobial treatment alters gastric carcinogenesis, also implicate H. pylori in the progression to neoplasia. A randomized controlled chemoprevention trial showed that antimicrobial therapy directed against H. pylori increased the regression rate of gastric atrophy and intestinal metaplasia, compared with patients receiving placebo32. In Japanese patients with early gastric cancer, therapy to eliminate H. pylori resulted in a significantly lower rate of gastric cancer recurrence and reduced progression of atrophic gastritis33. In a recent long-term prospective study, H. pylori eradication prevented, or at least delayed, the development of gastric adenocarcinoma during a mean follow-up period of 4.8 years34.

H. pylori also induces gastric cancer in rodent models. Following experimental challenge with H. pylori, Mongolian gerbils consistently develop pan-gastritis35, which leads, over the course of 1–2 years, to gastric atrophy, intestinal metaplasia and intestinal-type gastric adenocarcinoma in up to one-third of animals36,37. The pattern of gastric cancer development in these animals parallels that of humans (Fig. 1), making this a good model of gastric carcinogenesis. Malignancy can be induced by H. pylori colonization alone, without the exogenous administration of co-carcinogens. Accordingly, the World Health Organization has classified H. pylori as a class I carcinogen of gastric cancer38.

Strain variation and disease risk

If H. pylori is the strongest identified risk factor for the development of distal gastric cancer, why do most carriers never develop this malignancy? Cancer risk is believed to be related to H. pylori strain differences, inflammatory responses governed by host genetics, and specific interactions between host and microbial determinants. H. pylori populations are extremely diverse39, owing to point mutations, substitutions, insertions and/or deletions in their genomes40. A single host can carry several H. pylori strains, and isolates within an individual can change over time as endogenous mutations, chromosomal rearrangements or recombination between strains occurs40,41. Although this extraordinary diversity has made it difficult to search for bacterial factors that are associated with malignancy, several genetic loci have been identified, including the cag pathogenicity island, the vacA gene and the babA2 gene (Table 1). These markers seem to be interdependent, and are not absolutes, but reflect degree of risk42,43.

Table 1 H. pylori genes associated with gastric cancer

The cag island. The most important distinguishing factor of H. pylori strains is presence of the cag island, a HORIZONTALLY ACQUIRED locus of approximately 40 kb that contains 31 genes44,45. Several cag island genes have homology to genes that encode type IV secretion system proteins, which export proteins from bacterial cells. The terminal gene in the island, cagA, is commonly used as a marker for the entire cag locus. Following H. pylori adherence to epithelial cells, the secretion system translocates the CagA protein from H. pylori into the epithelial cell, where it undergoes tyrosine phosphorylation — a process that is associated with dephosphorylation of host-cell proteins46,47,48 and host-cell morphological changes49. The phosphorylated form of CagA might therefore function as a phosphatase that regulates organization of the actin cytoskeleton.

Compared with cagA strains, H. pylori cagA+ strains significantly increase the risk of developing severe gastritis, atrophic gastritis, peptic ulcer disease and distal gastric cancer50,51,52,53,54,55,56 (Fig. 1). In vitro studies have shown that several genes within the cag island (cagE (picB), cagG, cagH, cagI, cagL, cagM, but not cagA) are required for release of pro-inflammatory cytokines induced by H. pylori, such as interleukin (IL)-8, from gastric epithelial cells57,58,59. Inactivation of these same genes also results in decreased activation of the nuclear factor-κB (NF-κB) and mitogen-activated protein kinase (MAPK) signal-transduction cascades, which regulate pro-inflammatory cytokine production59,60,61,62,63. These in vitro observations mirror in vivo events, as cag+ strains are associated with increased mucosal expression of IL-8 and inflammation in human gastric tissue52,64. Furthermore, loss of cagE or the entire cag locus profoundly attenuates the severity of gastritis and development of atrophy in Mongolian gerbils infected with H. pylori65,66.

The vacA gene. Another gene that is associated with carcinogenesis induced by H. pylori is vacA. vacA encodes a secreted protein that induces vacuole formation in eukaryotic cells and stimulates epithelial-cell apoptosis67,68,69,70. Approximately 50% of H. pylori strains express the VacA protein71, and expression is correlated with expression of cagA72,73. However, vacA and cagA map to separate loci on the H. pylori chromosome, and an inactivating cagA mutation does not affect VacA production74. H. pylori VacA-secreting strains are more common among patients with distal gastric cancer than among patients with gastritis alone75. Unlike the cag island, all H. pylori strains possess the vacA gene76, and expression differences between strains are due to sequence variations in vacA76. Regions of major sequence diversity are localized to both the vacA secretion-signal sequence (allele types s1a, s1b, s1c or s2) and the mid-region (allele types m1 or m2)76,77,78. Strains possessing the m1 allele are associated with enhanced gastric epithelial-cell injury79,80 and distal gastric cancer43,78 compared with vacA m2 strains.

The babA2 gene. BabA, encoded by the strain-specific gene babA2, is a member of a family of highly conserved outer-membrane proteins, and binds the Lewisb (Leb) histo-blood-group antigen on gastric epithelial cells43,81. H. pylori strains that possess the babA2 gene are associated with an increased incidence of gastric adenocarcinoma43. The presence of babA2 is correlated with the presence of cagA and vacA s1; strains that possess all three of these genes carry the highest risk of gastric cancer43. Following challenge with babA2+ H. pylori strains, transgenic Leb-expressing mice are more likely to develop severe gastritis, atrophy and anti-PARIETAL CELL antibodies (reflecting autoimmune tissue destruction) than their wild-type littermates82. BabA-expressing strains also adhere more tightly to epithelial cells, which might promote pathogenesis.

Host polymorphisms and gastric cancer

Just as certain H. pylori genetic elements are associated with gastric cancer, several human polymorphisms are also associated with the disease. Most of these occur within immune response genes. H. pylori induces a T-helper (TH)1-type cellular immune response in humans, whereas a closely related bacteria, Helicobacter felis, induces the same reaction in mice83,84. Experimental induction of a TH2-type immune response attenuates the gastritis and atrophy response that is observed in mice infected with H. felis85, indicating that mucosal inflammation might promote tumorigenesis.

Expression levels of the TH1 cytokine IL-1β are increased within the gastric mucosa of H. pylori+ individuals86, and several polymorphisms have been identified in the IL-1β gene promoter region that affect protein expression. Individuals that are colonized by H. pylori, and that possess promoter-region polymorphisms associated with higher-than-average expression levels of IL-1β, are at significantly increased risk of developing HYPOCHLORHYDRIA, gastric atrophy and distal gastric adenocarcinoma than individuals with polymorphisms linked to lower expression levels of IL-1β (Ref. 87; Fig. 1; Table 2).

Table 2 Human genetic polymorphisms that influence development of distal gastric cancer

Experiments in rodent models have led to similar findings. In Mongolian gerbils infected with H. pylori, gastric mucosal IL-1β levels increase 6–12 weeks after bacterial infection, accompanied by a reciprocal decrease in gastric-acid production88. Administration of recombinant IL-1 receptor antagonist to gerbils infected with H. pylori normalizes acid levels88, indicating that IL-1β is an important determinant of acid secretion within inflamed mucosa. As IL-1β is the most powerful inhibitor of acid secretion known, is profoundly pro-inflammatory, and is upregulated by H. pylori, this cytokine probably has a pivotal role in initiating the progression towards gastric adenocarcinoma89.

Expression of tumour necrosis factor (TNF)-α — another TH1 (pro-inflammatory and acid-suppressive) cytokine — is also increased within mucosa90 colonized by H. pylori. Polymorphisms in the gene that encode it have been associated with an increased risk of gastric cancer and its precursors91 (Table 2). Two different H. pylori proteins (urease B and membrane protein 1) have recently been shown to induce TNF-α expression and transformation in cells that constitutively overexpress the oncogenic protein RAS, indicating that enhanced levels of mucosal TNF-α produced by H. pylori in genetically susceptible individuals might contribute to carcinogenesis by interacting with activating RAS mutations92. Conversely, polymorphisms that reduce expression of the anti-inflammatory cytokine IL-10 have been associated with an enhanced risk of distal gastric cancer93 (Table 2).

Some studies indicate that particular MAJOR HISTOCOMPATABILITY COMPLEX (MHC) genotypes also influence gastric carcinogenesis that is induced by H. pylori. Cells that express class II MHC molecules regulate the immune response by binding antigen, processing it and presenting it to CD4+ T cells. Class II MHC molecules are expressed on gastric epithelial-cell surfaces and are upregulated in the presence of H. pylori94, indicating that the host MHC class II haplotype might partially determine the epithelial-cell response to the pathogen. For example, host possession of the MHC DQA1*0102 allele was reported to increase the risk of atrophic gastritis and intestinal-type gastric adenocarcinoma associated with H. pylori95. Other studies have shown that inactivating mutations in CDH1 , the gene that encodes E-cadherin, are associated with familial diffuse-type gastric cancer96; however, a relationship between E-cadherin and H. pylori has not been established.

Biological effects of H. pylori

Proliferation. What effect does H. pylori have on the gastric epithelium that leads to cellular transformation? One effect is interference with epithelial-cell proliferation. Co-culture of H. pylori with epithelial cells has been shown to reduce expression of the cell-cycle regulatory protein p27, which leads to epithelial-cell G1 arrest97,98. Cell-cycle arrest might be induced by DNA damage to epithelial cells. When H. pylori is incubated with epithelial cells, direct damage to host-cell DNA occurs through the synthesis of reactive oxygen species, as reflected by the formation of DNA adducts99,100.

The host response to H. pylori can also induce epithelial-cell proliferation. These pathogens have been reported to induce hypergastrinaemia101 — the increased production of the hormone gastrin by mucosal G-CELLS. Gastrin stimulates gastric epithelial-cell proliferation in vitro by activating its receptor, CCK-β102. Gastrin-deficient and gastrin-receptor-deficient mice develop altered glandular architecture103 as a result of altered epithelial-cell proliferation. The ability to stimulate gastrin production might be an important aspect of tumorigenesis induced by H. pylori. In transgenic mice that overexpress gastrin, gastric adenocarcinomas developed in 75% of animals over 20 months old104. When these transgenic mice were infected with H. felis, 85% developed gastric carcinomas by eight months of age104. High gastrin levels might therefore synergize with other consequences of H. pylori colonization to promote gastric cancer.

Inflammation. H. pylori also activates pro-inflammatory cyclooxygenase (COX) enzymes (Fig. 3). The COX enzymes (COX-1 or COX-2) catalyse key steps in the formation of inflammatory prostaglandins105. COX-1 is expressed constitutively, whereas COX-2 is induced by cytokines such as TNF-α, interferon (IFN)-γ, and IL-1 (Ref. 105). COX-2 expression is increased in epithelial cells that are co-cultured with H. pylori106 and within gastric mucosa of individuals infected with H. pylori107,108. COX-2 expression is further increased within pre-malignant (atrophic gastritis and intestinal metaplasia) and malignant (adenocarcinoma) lesions induced by H. pylori109,110, and COX-inhibitors such as aspirin and other non-steroidal anti-inflammatory drugs have been shown to decrease the risk of distal gastric cancer111,112. H. pylori also activates phospholipase A2, an enzyme that catalyses the formation of the prostaglandin precursor arachadonic acid, both in vitro and in vivo113,114.

Figure 3: H. pylori cag+ strains can induce or prevent gastric epithelial-cell apoptosis.
figure 3

H. pylori can regulate gastric epithelial apoptosis through several mechanisms. Following adherence, signalling by the cag secretion system (but not CagA per se) leads to activation of an unknown factor(s) X that leads to activation of nuclear factor-κB (NF-κB). NF-κB translocates to the nucleus to activate transcription of pro-apoptotic genes. H. pylori can also induce apoptosis by stimulating expression of FAS and its ligand (FASL). The H. pylori protein urease can induce apoptosis by binding to class II major histocompatability complex (MHC) molecules. The H. pylori vacA gene product causes mitochondrial release of cytochrome c (cyt c), which leads to activation of caspase-3 and apoptosis. H. pylori also activates pathways that downregulate apoptosis. H. pylori binding to the epithelial-cell surface generates arachadonic acid, which is metabolized to prostaglandin E2 (PGE2) and prostaglandin 15-deoxyΔ12,14-J2 (15d-PGJ2) by cyclooxygenase (COX) enzymes. These enzymes are inhibited by non-steroidal anti-inflammatory drugs (NSAIDs). 15d-PGJ2 is an endogenous ligand of peroxisome proliferator-activated receptor-γ (PPARγ), a nuclear hormone receptor that heterodimerizes with the retinoid (RAR) family of nuclear receptors to activate transcription of target genes. These gene products inhibit NF-κB activation, however, preventing apoptosis. The COX-generated metabolite PGE2 also attenuates apoptosis. So, H. pylori has the capacity to stimulate and inhibit gastric epithelial-cell apoptosis, which might influence the risk of gastric carcinogenesis.

The inflammatory response induced by H. pylori leads to the release of mutagenic substances, such as metabolites of inducible nitric oxide synthase (iNOS), which promote oncogenesis108,115. Nitric oxide, generated by iNOS, can be converted to reactive nitrogen species that modify various cellular targets, including DNA and proteins.

Superoxide anion radicals generated by neutrophils also induce DNA damage through the formation of DNA adducts99. Serum levels of vitamin C, a scavenger of reactive oxygen species and nitrates, are inversely proportional to the prevalence of gastric cancer116. Eradication of H. pylori has been reported to raise gastric intraluminal ascorbic acid levels117, so the presence of H. pylori also affects gastric mucosal antioxidant defence mechanisms.

Apoptosis. H. pylori has been associated with both increased and reduced levels of apoptosis in the gastric epithelium, depending on the human population studied (Fig. 3). In vitro, H. pylori reproducibly stimulates gastric epithelial-cell apoptosis67,68,118,119. H. pylori urease, an enzyme that generates ammonia and is present within the lamina propria of colonized individuals, has been shown to bind to class II MHC molecules on the surfaces of gastric epithelial cells in vitro and induce apoptosis120. H. pylori VacA has been reported to insert into mitochondrial membranes, induce cytochrome c release, and activate the caspase-3-dependent cell-death signalling cascade69.

Another mechanism by which H. pylori can stimulate apoptosis is by inducing expression of the cell-surface receptor FAS and FAS ligand67,118,121,122 (Fig. 3). Helicobacter infection of Ifn-γ-deficient and Fas-deficient mice is associated with reduced levels of inflammation and apoptosis compared with wild-type control mice123,124,125. This indicates that release of TH1 cytokines induced by H. pylori, such as IFN-γ, might induce epithelial-cell apoptosis through a Fas-mediated pathway.

H. pylori has also been reported to induce apoptosis in gastric epithelial cells in vitro through activation of the transcription factor NF-κB126 (Fig. 3). In colonic epithelial cells, however, NF-κB is negatively regulated by the nuclear hormone receptor peroxisome proliferator-activated receptor-γ (PPARγ)127,128, and activation of PPARγ similarly inhibits H. pylori-induced activation of NF-κB and apoptosis in gastric cells126 (Fig. 3). Putative endogenous PPARγ agonist ligands include the prostaglandin 15-deoxyΔ12,14-J2 (15d-PGJ2), a COX metabolite129. Another COX-2-generated metabolite, prostaglandin E2 (PGE2) also inhibits apoptosis130; in contrast to pro-inflammatory cytokines, prostaglandins might limit the apoptotic response that develops in response to H. pylori.

Different H. pylori strains have different effects on cellular turnover, and mucosal levels of apoptosis seem to vary substantially between individuals carrying H. pylori67,131,132,133. Two studies showed that gastric epithelial cells from people carrying H. pylori cagA+ isolates have significantly higher proliferation rates, but lower apoptotic indices, than either cagA or uninfected persons134,135, although a recent study reported that apoptotic indices are increased within H. pylori cagA+-colonized mucosa136. How could altered levels of apoptosis increase the risk of gastric cancer? Enhanced rates of apoptosis could potentially accelerate progression to atrophic gastritis, with a concomitant increase in the risk of distal gastric adenocarcinoma. By contrast, reduced rates of cell loss, especially when accompanied by hyperproliferation, could lead to a heightened retention of mutagenized cells, which might also predispose certain colonized individuals towards development of gastric cancer. On the basis of the available data, it seems that apoptosis within mucosa colonized by H. pylori is regulated by host inflammatory mediators that modify the direct effect of the organism on epithelial cells, and the types and/or levels of mediator present (that is, TH1 cytokines versus prostaglandins) might differentially alter cancer risk.

Host–bacterial equilibrium

H. pylori is able to send and receive signals from the gastric epithelium, allowing host and bacteria to become linked in a dynamic equilibrium137. The equilibrium is different for each colonized individual, based on both host and bacterial characteristics40, which might explain why certain H. pylori strains augment the risk of carcinogenesis. For example, cag+ strains induce an intense inflammatory response that involves production of IL-8. This leads to increased production of IL-1β and TNF-α, which inhibit acid production (Fig. 4) — especially in hosts with polymorphisms that promote high expression levels of these factors (Table 2). This combination of strain and host factors results in lower gastric acidity (higher gastric pH) than would occur in a person infected with a cag strain or with polymorphisms that do not permit high expression levels of IL-1β or TNF-α. However, cagA transcription is reduced as pH rises138,139, and the bacterial stimulus to the host diminishes, creating a negative-feedback loop that leads towards equilibrium. As cag+ and cag strains can coexist and recombine within the same host, the percentage of cag+ strains is likely to vary over time, which will affect this equilibrium (Fig. 4).

Figure 4: Equilibrium of interactions between H. pylori and its host.
figure 4

H. pylori cells signal the host and the host signals the bacterial population. H. pylori cag+ strains promote production of the cytokine interleukin (IL)-8 by host cells, which amplifies the inflammatory response by recruiting neutrophils and monocytes. These cells release pro-inflammatory cytokines such as IL-1β and tumour necrosis factor (TNF)-α, which reduce acid production by parietal cells, causing a decrease in gastric acidity and hypochlorhydria. This increases the risk of atrophic gastritis, a pre-malignant condition. By contrast, cag H. pylori strains do not induce an intense host response, and do not promote IL-8 production. The exact equilibrium between cag+ and cag cells in a population will be determined by their relative fitness under each set of local conditions. Host genotype affects this equilibrium, as individuals possessing mutations that allow for high IL-1β (−31 C/C allele, −511 T/T allele) and TNF-α (−308 A/A allele) expression levels have a higher gastric pH, which downregulates cagA transcription, and provides selective pressure for cag cells. Individuals colonized with cag+ bacterial cells and who express high levels of IL-1β and TNF-α are more likely to develop atrophic gastritis and consequent hypochlorhydria, which increases risk of distal gastric cancer.

Levels of mucosal proliferation are directly related to the intensity of inflammation, that is augmented by cag+ strains. The ability of H. pylori in conjunction with inflammatory mediators to induce or attenuate apoptosis might also contribute to altered cellular turnover. An augmented inflammatory response induced by cag+ strains in the gastric body, leading to decreased acid production, permits overgrowth of pH-sensitive bacteria, conversion of ingested N-nitrosamines to nitrites, and an increased risk of gastric cancer.

So, cancer risk is the summation of the polymorphic nature of the bacterial population in that host, the host genotype and environmental exposures (ingested nitrates), each affecting the level of the equilibrium. This deterministic model of the mucosal events related to carcinogenesis also has clinical and epidemiological ramifications. For example, people with polymorphisms associated with high levels of IL-1β expression and who are colonized by cag+ strains might be most likely to derive benefit from H. pylori eradication, as such treatment could result in substantially reduced cancer risk.

GERD and oesophageal adenocarcinoma

The falling incidences of H. pylori carriage and gastric cancer in developed countries over the past century have been diametrically opposed by a rapidly increasing incidence of GERD and its sequelae. GERD is the strongest known risk factor for developing Barrett's oesophagus — a metaplasia of the distal oesophagus associated with an increased risk of oesophageal adenocarcinoma140. Among white males, the incidence of oesophageal adenocarcinoma has increased more than 350% since 1975 and its incidence is rising more rapidly than any other malignancy in the United States141. The relatively short (three-decade) timeframe over which the frequency of this cancer has increased indicates that an environmental factor might be involved. Could this factor be the falling incidence of H. pylori?

GERD is uncommon in geographical regions of the world in which most people are colonized by H. pylori (particularly cag+ strains)142. GERD and its sequelae are increasing in incidence in Western countries143, whereas the prevalence of H. pylori is falling23. In patients with duodenal ulcer disease (virtually always colonized with cag+ strains), successful H. pylori eradication was associated with a doubling in the development of new-onset reflux oesophagitis over a 3-year period, compared with individuals who remained persistently colonized144. Carriage of H. pylori is associated with a significantly reduced risk of developing GERD, Barrett's oesophagus, and oesophageal adenocarcinoma, and the entire protective effect seems to be attributable to the presence of cag+ strains11,12,145,146,147,148,149,150.

How can the ability of cag+ strains to enhance the risk of distal gastric cancer be reconciled with a presumed protective effect against GERD, Barrett's oesophagus and oesophageal adenocarcinoma? The location of inflammation within the gastric niche probably contributes to this dichotomy. By inhibiting parietal-cell function (Fig. 4) and/or inducing the development of atrophic gastritis, the severe inflammation in the acid-secreting gastric body (Fig. 2) induced by cag+ strains (especially in patients with polymorphisms that cause increased expression levels of IL-1β and/or TNF-α) can blunt the high-level acid secretion necessary for the development of GERD and its sequelae. Recent clinical studies have shown that severe gastritis, atrophic gastritis and reduced acid production associated with H. pylori colonization significantly reduce the risk of GERD11,151,152. So, the interaction of cag+ strains with their hosts has opposing effects on the risk of distal cancers (increases the risk of gastric adenocarcinoma) and proximal cancers (decreases the risk of oesophageal adenocarcinoma).


Analytical tools now exist — including genome sequences (H. pylori and human), measurable phenotypes (CagA seropositivity), and practical animal models — to discern the fundamental biological basis of H. pylori-associated neoplasia, which should have direct clinical applications. For example, elucidating the role of specific proteins (CagA, VacA) secreted by H. pylori in the pathogenesis of gastric adenocarcinoma might aid in vaccine development in high-risk populations. It is important to gain more insight into the pathogenesis of gastric adenocarcinoma induced by H. pylori, not only to develop more effective treatments for this common cancer, but also because it might serve as a model for the role of chronic inflammation in the genesis of other malignancies, such as ulcerative colitis-associated colon cancer.