Although gastric adenocarcinoma is associated with the presence of Helicobacter pylori in the stomach, only a small fraction of colonized individuals develop this common malignancy. H. pylori strain and host genotypes probably influence the risk of carcinogenesis by differentially affecting host inflammatory responses and epithelial-cell physiology. Understanding the host-microbial interactions that lead to neoplasia will improve cancer-targeted therapeutics and diagnostics, and provide mechanistic insights into other malignancies that arise within the context of microbially initiated inflammatory states.

SUMMARY Helicobacter pylori is a gastric pathogen that colonizes approximately 50% of the world's population. Infection with H. pylori causes chronic inflammation and significantly increases the risk of developing duodenal and gastric ulcer disease and gastric cancer. Infection with H. pylori is the strongest known risk factor for gastric cancer, which is the second leading cause of cancer-related deaths worldwide. Once H. pylori colonizes the gastric environment, it persists for the lifetime of the host, suggesting that the host immune response is ineffective in clearing this bacterium. In this review, we discuss the host immune response and examine other host factors that increase the pathogenic potential of this bacterium, including host polymorphisms, alterations to the apical-junctional complex, and the effects of environmental factors. In addition to host effects and responses, H. pylori strains are genetically diverse. We discuss the main virulence determinants in H. pylori strains and the correlation between these and the diverse clinical outcomes following H. pylori infection. Since H. pylori inhibits the gastric epithelium of half of the world, it is crucial that we continue to gain understanding of host and microbial factors that increase the risk of developing more severe clinical outcomes.

The Arabidopsis hyperpolarization-activated (inward-rectifying) K+ channel KAT1 is structurally more similar to animal depolarization-activated (outward-rectifying) K+ channels than to animal hyperpolarization-activated K+ channels. To gain insight into the structural basis for the opposite voltage dependences of plant inward-rectifying and animal outward-rectifying K+ channels, we constructed recombinant chimeric channels between the hyperpolarization-activated K+ channel KAT1 and a Xenopus depolarization-activated K+ channel. We report here that two of the chimeric constructs, which contain the first third of the KAT1 sequence, including the first four membrane-spanning segments (S1-S4) and the linker sequence between the fourth and fifth membrane-spanning segments, express functional channels that retain activation by hyperpolarization, but not depolarization. These two chimeric channels are no longer selective for K+. The chimeras are selective for cations over anions and are permeable to Ca2+. Therefore, unlike animal hyperpolarization-activated K+ channels, in which the carboxyl terminus is important for inward rectification induced by Mg2+ and polyamine block, the plant KAT1 channel has its major determinants for inward rectification in the amino-terminal region, which ends at the end of the S4-S5 linker.

Helicobacter pylori is the dominant species of the human gastric microbiome, and colonization causes a persistent inflammatory response. H. pylori-induced gastritis is the strongest singular risk factor for cancers of the stomach; however, only a small proportion of infected individuals develop malignancy. Carcinogenic risk is modified by strain-specific bacterial components, host responses and/or specific host-microbe interactions. Delineation of bacterial and host mediators that augment gastric cancer risk has profound ramifications for both physicians and biomedical researchers as such findings will not only focus the 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.Gastric adenocarcinoma is the second leading cause of cancer-related death in the world. Approximately 700,000 people succumb to this malignancy each year and 5-year survival rates in the United States are <15% 1 . Two histologically distinct variants of gastric adeno-carcinoma have been described, each with different pathophysiological features. Diffuse-type gastric adeno-carcinoma more commonly affects younger people and consists of individually infiltrating neoplastic cells that do not form glandular structures. The more prevalent form of gastric adenocarcinoma, intestinal-type adeno-carcinoma, progresses through a series of histological steps that are initiated by the transition from normal mucosa to chronic superficial gastritis, which then leads to atrophic gastritis and intestinal metaplasia, and finally to dysplasia and adenocarcinoma 2 . Helicobacter pylori is a microbial species that specifically colonizes gastric epithelium and it is the most common bacterial infection worldwide. Everyone infected by this organism develops coexisting gastritis, which typically persists for decades, coupling

Persistent gastritis induced by Helicobacter pylori is the strongest known risk factor for adenocarcinoma of the distal stomach, yet only a fraction of colonized persons ever develop gastric cancer. The H. pylori cytotoxin-associated gene (cag) pathogenicity island encodes a type IV secretion system that delivers the bacterial effector CagA into host cells after bacterial attachment, and cag ؉ strains augment gastric cancer risk. A host effector that is aberrantly activated in gastric cancer precursor lesions is ␤-catenin, and activation of ␤-catenin leads to targeted transcriptional up-regulation of genes implicated in carcinogenesis. We report that in vivo adaptation endowed an H. pylori strain with the ability to rapidly and reproducibly induce gastric dysplasia and adenocarcinoma in a rodent model of gastritis. Compared with its parental noncarcinogenic isolate, the oncogenic H. pylori strain selectively activates ␤-catenin in model gastric epithelia, which is dependent on translocation of CagA into host epithelial cells. ␤-Catenin nuclear accumulation is increased in gastric epithelium harvested from gerbils infected with the H. pylori carcinogenic strain as well as from persons carrying cag ؉ vs. cag ؊ strains or uninfected persons. These results indicate that H. pylori-induced dysregulation of ␤-catenindependent pathways may explain in part the augmentation in the risk of gastric cancer conferred by this pathogen.bacteria ͉ cancer ͉ inflammation

Colonization of the human stomach by Helicobacter pylori and its role in causing gastric cancer is one of the richest examples of complex relationship among human cells, microbes, and their environment. It is also a puzzle of enormous medical importance given the incidence and lethality of gastric cancer worldwide. We review recent findings that have changed how we view these relationships and affected the direction of gastric cancer research. For example, recent data indicate that subtle mismatches between host and microbe genetic traits greatly affect risk of gastric cancer. The ability of H pylori and its oncoprotein CagA to reprogram epithelial cells and activate properties of stemness demonstrates the sophisticated relationship among H pylori and progenitor cells in the gastric mucosa. The observation that cell-associated H pylori can colonize the gastric glands and directly affect precursor and stem cells supports these observations. The ability to mimic these interactions in human gastric organoid cultures as well as animal models will allow investigators to more fully unravel the extent of H pylori control on the renewing gastric epithelium. Finally, our realization that external environmental factors, such as dietary components and essential micronutrients, as well as the gastrointestinal microbiota, can change the balance between H pylori’s activity as a commensal or a pathogen has provided direction to studies aimed at defining the full carcinogenic potential of this organism.

Atrophic gastritis, intestinal metaplasia, and epithelial dysplasia of the stomach are common and are associated with an increased risk for gastric cancer. In the absence of guidelines, there is wide disparity in the management of patients with these premalignant conditions. The European Society of Gastrointestinal Endoscopy (ESGE), the European Helicobacter Study Group (EHSG), the European Society of Pathology (ESP) and the Sociedade Portuguesa de Endoscopia Digestiva (SPED) have therefore combined efforts to develop evidence-based guidelines on the management of patients with precancerous conditions and lesions of the stomach (termed MAPS). A multidisciplinary group of 63 experts from 24 countries developed these recommendations by means of repeat online voting and a meeting in June 2011 in Porto, Portugal. The recommendations emphasize the increased cancer risk in patients with gastric atrophy and metaplasia, and the need for adequate staging in the case of high grade dysplasia, and they focus on treatment and surveillance indications and methods.

Background & Aims-Gastroesophageal reflux causes inflammation, intestinal metaplasia and its downstream sequelum adenocarcinoma in the distal esophagus. The incidence of esophageal adenocarcinoma has increased approximately 6-fold in the U.S. since the 1970s, accompanied with a significant increase in prevalence of gastroesophageal reflux disease (GERD). Despite extensive epidemiological study, the cause for GERD and the unexpected increases remain unexplainable. Microbes are among the environmental factors that may contribute to the etiology of GERD but very little research has been done on the esophageal microbiome, particularly in its relation to GERD. This is the first reported correlation between a change in the esophageal microbiome and esophageal diseases.