SUMMARY: Helicobacter pyloriis a gastric pathogen that colonizes approximately 50% of the world's population. Infection withH. pyloricauses chronic inflammation and significantly increases the risk of developing duodenal and gastric ulcer disease and gastric cancer. Infection withH. pyloriis the strongest known risk factor for gastric cancer, which is the second leading cause of cancer-related deaths worldwide. OnceH. pyloricolonizes 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. pyloristrains are genetically diverse. We discuss the main virulence determinants inH. pyloristrains and the correlation between these and the diverse clinical outcomes followingH. pyloriinfection. SinceH. pyloriinhibits 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 antimicrobial effect of nitric oxide (NO) is an essential part of innate immunity. The vigorous host response to the human gastric pathogenHelicobacter pylorifails to eradicate the organism, despite up-regulation of inducible NO synthase (iNOS) in the gastric mucosa. Here we report that wild-type strains ofH. pyloriinhibit NO production by activated macrophages at physiologic concentrations ofl-arginine, the common substrate for iNOS and arginase. Inactivation of the generocF, encoding constitutively expressed arginase inH. pylori, restored high-output NO production by macrophages. By using HPLC analysis, we show thatl-arginine is effectively consumed in the culture medium by wild-type but not arginase-deficientH. pylori. The substantially higher levels of NO generated by macrophages cocultured withrocF-deficientH. pyloriresulted in efficient killing of the bacteria, whereas wild-typeH. pyloriexhibited no loss of survival under these conditions. Killing of the arginase-deficientH. pyloriwas NO-dependent, because peritoneal macrophages from iNOS^−/−mice failed to affect the survival of therocFmutant. Thus, bacterial arginase allowsH. pylorito evade the immune response by down-regulating eukaryotic NO production.

Probiotic bacteria can potentially have beneficial effects on the clinical course of several intestinal disorders, but our understanding of probiotic action is limited. We have identified a probiotic bacteria–derived soluble protein, p40, from Lactobacillus rhamnosus GG (LGG), which prevents cytokine-induced apoptosis in intestinal epithelial cells. In the current study, we analyzed the mechanisms by which p40 regulates cellular responses in intestinal epithelial cells and p40’s effects on experimental colitis using mouse models. We show that the recombinant p40 protein activated EGFR, leading to Akt activation. Activation of EGFR by p40 was required for inhibition of cytokine-induced apoptosis in intestinal epithelial cells in vitro and ex vivo. Furthermore, we developed a pectin/zein hydrogel bead system to specifically deliver p40 to the mouse colon, which activated EGFR in colon epithelial cells. Administration of p40-containing beads reduced intestinal epithelial apoptosis and disruption of barrier function in the colon epithelium in an EGFR-dependent manner, thereby preventing and treating DSS-induced intestinal injury and acute colitis. Furthermore, p40 activation of EGFR was required for ameliorating colon epithelial cell apoptosis and chronic inflammation in oxazolone-induced colitis. These data define what we believe to be a previously unrecognized mechanism of probiotic-derived soluble proteins in protecting the intestine from injury and inflammation.

Background: E (epithelial)-cadherin, the cell adhesion molecule also considered a potential invasion/metastasis suppressor, is mutationally inactivated in nearly half of all undifferentiated-scattered (diffuse-type) gastric carcinomas. In addition, silencing of E-cadherin by CpG methylation within its promoter region has been reported in several gastric carcinoma cell lines. We investigated the methylation status of the E-cadherin promoter region in 53 primary human gastric carcinomas. Methods: Hypermethylation of the E-cadherin promoter was determined by utilizing methylation-specific polymerase chain reaction (PCR)–single-strand conformation polymorphism (MSP–SSCP) analysis followed by direct sequencing of PCR products. Expression of E-cadherin was studied by western blot analysis. All statistical tests were two-sided. Results: Hypermethylation of the E-cadherin promoter was evident in 27 (51%) of 53 primary gastric carcinomas examined by MSP–SSCP. It occurred more frequently in carcinomas of the undifferentiated-scattered type (in 15 [83%] of 18) than in other histologic subtypes (in 12 [34%] of 35) (P = .0011, Fisher's exact test), and it was present at similar rates in early (in six [60%] of 10) versus advanced (in 21 [49%] of 43) carcinomas (P = .73, Fisher's exact test). Methylation occurring at all cytosine–guanosine sequences (CpGs) near the transcriptional start site was confirmed in six of six tumors examined by bisulfite–DNA sequencing, including two early gastric carcinomas. In addition, loss or diminished expression of E-cadherin was confirmed by western blotting in four of the six tumor tissues demonstrating hypermethylation. Conclusions: The E-cadherin promoter frequently undergoes hypermethylation in human gastric cancers, particularly those of the undifferentiated-scattered histologic subtype. E-cadherin promoter hypermethylation is associated with decreased expression and may occur early in gastric carcinogenesis.