Characterization of Helicobacter pylori Bacteriophage KHP30

Helicobacter pylori inhabits the stomach mucosa and is a causative agent of stomach ulcer and cancer. In general, bacteriophages (phages) are strongly associated with bacterial evolution, including the development of pathogenicity. Several tailed phages have so far been reported in H. pylori. We have isolated an H. pylori phage, KHP30, and reported its genomic sequence. In this study, we examined the biological characteristics of phage KHP30. Phage KHP30 was found to be a spherical lipid-containing phage with a diameter of ca. 69 nm. Interestingly, it was stable from pH 2.5 to pH 10, suggesting that it is adapted to the highly acidic environment of the human stomach. Phage KHP30 multiplied on 63.6% of clinical H. pylori isolates. The latent period was ca. 140 min, shorter than the doubling time of H. pylori (ca. 180 min). The burst size was ca. 13, which was smaller than the burst sizes of other known tailed or spherical phages. Phage KHP30 seemed to be maintained as an episome in H. pylori strain NY43 cells, despite a predicted integrase gene in the KHP30 genomic sequence. Seven possible virion proteins of phage KHP30 were analyzed using N-terminal protein sequencing and mass spectrometry, and their genes were found to be located on its genomic DNA. The genomic organization of phage KHP30 differed from the genomic organizations in the known spherical phage families Corticoviridae and Tectiviridae. This evidence suggests that phage KHP30 is a new type of spherical phage that cannot be classified in any existing virus category.     

Comparative Genomics of a Helicobacter pylori Isolate from a Chinese Yunnan Naxi Ethnic Aborigine Suggests High Genetic Divergence and Phage Insertion

Helicobacter pylori is a common pathogen correlated with several severe digestive diseases. It has been reported that isolates associated with different geographic areas, different diseases and different individuals might have variable genomic features. Here, we describe draft genomic sequences of H. pylori strains YN4-84 and YN1-91 isolated from patients with gastritis from the Naxi and Han populations of Yunnan, China, respectively. The draft sequences were compared to 45 other publically available genomes, and a total of 1059 core genes were identified. Genes involved in restriction modification systems, type four secretion system three (TFS3) and type four secretion system four (TFS4), were identified as highly divergent. Both YN4-84 and YN1-91 harbor intact cag pathogenicity island (cagPAI) and have EPIYA-A/B/D type at the carboxyl terminal of cagA. The vacA gene type is s1m2i1. Another major finding was a 32.5-kb prophage integrated in the YN4-84 genome. The prophage shares most of its genes (30/33) with Helicobacter pylori prophage KHP30. Moreover, a 1,886 bp transposable sequence (IS605) was found in the prophage. Our results imply that the Naxi ethnic minority isolate YN4-84 and Han isolate YN1-91 belong to the hspEAsia subgroup and have diverse genome structure. The genome has been extensively modified in several regions involved in horizontal DNA transfer. The important roles played by phages in the ecology and microevolution of H. pylori were further emphasized. The current data will provide valuable information regarding the H. pylori genome based on historic human migrations and population structure.     

A Unique Feature of Iron Loss via Close Adhesion of Helicobacter pylori to Host Erythrocytes

Iron deficiency anemia is an extra-stomach disease experienced in H. pylori carriers. Individuals with type A blood are more prone to suffering from H. pylori infection than other individuals. To clarify the molecular mechanisms underlying H. pylori-associated anemia, we collected erythrocytes from A, B, O, and AB blood donors and analyzed morphology, the number of erythrocytes with H. pylori colonies attached to them, and iron contents in erythrocytes and H. pylori (NCTC11637 and SS1 strains) by means of optical microscopy, scanning electron microscopy, and synchrotron radiation soft X-ray imaging. The number of type A erythrocytes with H. pylori attached to them was significantly higher than that of other erythrocytes (P<0.05). Far more iron distribution was observed in H. pylori bacteria using dual energy analysis near the iron L2, 3 edges by soft X-ray imaging. Iron content was significantly reduced in host erythrocytes after 4 hours of exposure to H. pylori. H. pylori are able to adhere more strongly to type A erythrocytes, and this is related to iron shift from the host to the bacteria. This may explain the reasons for refractory iron deficiency anemia and elevated susceptibility to H. pylori infection in individuals with type A blood.     

Helicobacter pylori causes runx3 gene methylation and its loss of expression in gastric epithelial cells, which is mediated by nitric oxide produced by macrophages

Previous reports have indicated that Helicobacter pylori (H. pylori) causes epigenetic changes of certain genes such as cancer suppression genes, which may be associated with carcinogenesis. However, the mechanism by which it causes epigenetic changes in certain genes and not in others is unclear. Presently, we focused on a cancer suppression gene, runx3, and demonstrated the following: (1) H. pylori induces nitric oxide (NO) production in macrophages. (2) NO causes methylation of runx3 in epithelial cells. (3) H. pylori induces the methylation of epithelial cells in the presence of macrophages, which is reversed by an NO-specific inhibitor. These results indicate that H. pylori-induced methylation is mediated by NO, and suggest that NO may be a key to the mechanism of how H. pylori causes epigenetic changes in certain genes. Additionally, we demonstrated that lipopolysaccharide, as well as H. pylori, induces NO-mediated methylation, indicating that other inflammation inducers beside H. pylori might induce aberrant methylation of runx3.     

Quantitation of Helicobacter pylori ureC gene and its comparison with different diagnostic techniques and gastric histopathology

Numerous diagnostic assays for Helicobacter pylori detection are available. However, these techniques have their own advantages as well as limitations. Here we tried to develop a real-time quantitative (Q) PCR assay to measure ureC copy number to detect H. pylori, based on the fact that there is only one copy of the ureC gene per bacterium. We enrolled 120 adult patients [non-ulcer dyspepsia (NUD) 60, peptic ulcer disease (PUD) 20, gastric cancer (GC) 40] undergoing upper gastrointestinal endoscopies. During each endoscopic examination, antral biopsies from normal region of the antrum were obtained and subjected to the following tests: RUT, culture, histopathology, H. pylori-specific ureC PCR and ureC Q-PCR. Calculation of H. pylori copy number was based on the standard curve generated using 10-fold dilutions of DNA extracted from the H. pylori control strain varying from 10⁵ to 10¹ copies. The prevalence of H. pylori infection in our study population was 54% with no significant difference among disease and control population. The sensitivity of Q-PCR was found to be 100% which was highest among all diagnostic tests. The established Q-PCR is around 10 times more sensitive than the conventional PCR method. The copy number of H. pylori DNA was significantly increased when overall gastritis, H. pylori density, chronic inflammation and intestinal metaplasia were present. In summary, we developed a rapid and sensitive Q-PCR method for detecting H. pylori. This technique offers a significant improvement over other available methods for detecting H. pylori in clinical and research samples.     

Protection against Helicobacter pylori infection by a trivalent fusion vaccine based on a fragment of urease B-UreB414

A multivalent fusion vaccine is a promising option for protection against Helicobacter pylori infection. In this study, UreB414 was identified as an antigenic fragment of urease B subunit (UreB) and it induced an antibody inhibiting urease activity. Immunization with UreB414 partially protected mice from H. pylori infection. Furthermore, a trivalent fusion vaccine was constructed by genetically linking heat shock protein A (HspA), H. pylori adhesin A (HpaA), and UreB414, resulting in recombinant HspA-HpaA-UreB414 (rHHU). Its protective effect against H. pylori infection was tested in BALB/c mice. Oral administration of rHHU significantly protected mice from H. pylori infection, which was associated with H. pylori-specific antibody production and Th1/Th2-type immune responses. The results show that a trivalent fusion vaccine efficiently combats H. pylori infection, and that an antigenic fragment of the protein can be used instead of the whole protein to construct a multivalent vaccine.     

A stable shuttle vector system for efficient genetic complementation of Helicobacter pylori strains by transformation and conjugation

A versatile plasmid shuttle vector system was constructed, which is useful for genetic complementation of Helicobacter pylori strains or mutants with cloned genes of homologous or heterologous origin. The individual plasmid vectors consist of the minimal essential genetic elements, including an origin of replication for Escherichia coli, a H. pylori-specific replicon originally identified on a small cryptic H. pylori plasmid, an oriT sequence and a multiple cloning site. Shuttle plasmid pHel2 carries a chloramphenicol resistance cassette (cat _GC) and pHel3 contains a kanamycin resistance gene (aphA-3) as the selectable marker; both are functional in E. coli and H. pylori. The shuttle plasmids were introduced into the H. pylori strain P1 by natural transformation. A efficiency of 7.0?×?10^?7 and 4.7?×?10^?7 transformants per viable recipient was achieved with pHel2 and pHel3, respectively, and both vectors showed stable, autonomous replication in H. pylori. An approximately 100-fold higher H. pylori transformation rate was obtained when the shuttle vectors for transformation were isolated from the homologous H. pylori strain, rather than E. coli, indicating that DNA restriction and modification mechanisms play a crucial role in plasmid transformation. Interestingly, both shuttle vectors could also be mobilized efficiently from E. coli into different H.?pylori recipients, with pHel2 showing an efficiency of 2.0?×?10^?5 transconjugants per viable H. pylori P1 recipient. Thus, DNA restriction seems to be strongly reduced or absent during conjugal transfer. The functional complementation of a recA-deficient H. pylori mutant by the cloned H. pylorirecA ⁺ gene, and the expression of the heterologous green fluorescent protein (GFP) in H.?pylori demonstrate the general usefulness of?this system, which will significantly facilitate the molecular analysis of H. pylori virulence factors in the future.     

Age of the Association between Helicobacter pylori and Man

When modern humans left Africa ca. 60,000 years ago (60 kya), they were already infected with Helicobacter pylori, and these bacteria have subsequently diversified in parallel with their human hosts. But how long were humans infected by H. pylori prior to the out-of-Africa event? Did this co-evolution predate the emergence of modern humans, spanning the species divide? To answer these questions, we investigated the diversity of H. pylori in Africa, where both humans and H. pylori originated. Three distinct H. pylori populations are native to Africa: hpNEAfrica in Afro-Asiatic and Nilo-Saharan speakers, hpAfrica1 in Niger-Congo speakers and hpAfrica2 in South Africa. Rather than representing a sustained co-evolution over millions of years, we find that the coalescent for all H. pylori plus its closest relative H. acinonychis dates to 88–116 kya. At that time the phylogeny split into two primary super-lineages, one of which is associated with the former hunter-gatherers in southern Africa known as the San. H. acinonychis, which infects large felines, resulted from a later host jump from the San, 43–56 kya. These dating estimates, together with striking phylogenetic and quantitative human-bacterial similarities show that H. pylori is approximately as old as are anatomically modern humans. They also suggest that H. pylori may have been acquired via a single host jump from an unknown, non-human host. We also find evidence for a second Out of Africa migration in the last 52,000 years, because hpEurope is a hybrid population between hpAsia2 and hpNEAfrica, the latter of which arose in northeast Africa 36–52 kya, after the Out of Africa migrations around 60 kya.     

Recent Acquisition of Helicobacter pylori by Baka Pygmies

Both anatomically modern humans and the gastric pathogen Helicobacter pylori originated in Africa, and both species have been associated for at least 100,000 years. Seven geographically distinct H. pylori populations exist, three of which are indigenous to Africa: hpAfrica1, hpAfrica2, and hpNEAfrica. The oldest and most divergent population, hpAfrica2, evolved within San hunter-gatherers, who represent one of the deepest branches of the human population tree. Anticipating the presence of ancient H. pylori lineages within all hunter-gatherer populations, we investigated the prevalence and population structure of H. pylori within Baka Pygmies in Cameroon. Gastric biopsies were obtained by esophagogastroduodenoscopy from 77 Baka from two geographically separated populations, and from 101 non-Baka individuals from neighboring agriculturalist populations, and subsequently cultured for H. pylori. Unexpectedly, Baka Pygmies showed a significantly lower H. pylori infection rate (20.8%) than non-Baka (80.2%). We generated multilocus haplotypes for each H. pylori isolate by DNA sequencing, but were not able to identify Baka-specific lineages, and most isolates in our sample were assigned to hpNEAfrica or hpAfrica1. The population hpNEAfrica, a marker for the expansion of the Nilo-Saharan language family, was divided into East African and Central West African subpopulations. Similarly, a new hpAfrica1 subpopulation, identified mainly among Cameroonians, supports eastern and western expansions of Bantu languages. An age-structured transmission model shows that the low H. pylori prevalence among Baka Pygmies is achievable within the timeframe of a few hundred years and suggests that demographic factors such as small population size and unusually low life expectancy can lead to the eradication of H. pylori from individual human populations. The Baka were thus either H. pylori-free or lost their ancient lineages during past demographic fluctuations. Using coalescent simulations and phylogenetic inference, we show that Baka almost certainly acquired their extant H. pylori through secondary contact with their agriculturalist neighbors.     

Use of selected lactic acid bacteria in the eradication of Helicobacter pylori infection

Helicobacter pylori is among the major pathogenic bacteria that cause chronic gastritis and peptic ulcer disease and is related to the development of gastric cancer. Several chemicals, including antibiotics, have been used to eradicate H. pylori; however, they do not always curb the infection. Ten representative type strains of lactic acid bacteria (LAB) were screened for antagonism toward H. pylori via inhibition of urease activity. Strains inhibiting the binding of H. pylori to human gastric cell line cells and suppressing H. pylori-induced interleukin-8 (IL-8) production were also screened. Of these, Pediococcus pentosaseus (SL4), which inhibited the adhesion of H. pylori to MKN-45 gastric cancer cells, Bifidobacterium longum (BG7), with urease inhibiting activity, and Lactococcus lactis (SL3), and Enterococcus faecalis (SL5), which suppressed H. pylori-induced IL-8 production within MKN-45 and AGS cells, were selected. In mouse model, these LAB stains in combination significantly suppressed IL-8 levels in serum. Gastric pH also recovered to normal values after the administration of these LAB. These stains effectively suppressed H. pylori viability, although not to the extent of antibiotic treatment. When used as probiotics, LAB may help decrease the occurrence of gastritis and reduce the risk of H. pylori infection without, inducing side effects.     

A 500-year tale of co-evolution,adaptation, and virulence: Helicobacter pylori in the Americas

Helicobacter pylori is a common component of the human stomach microbiota, possibly dating back to the speciation of Homo sapiens. A history of pathogen evolution in allopatry has led to the development of genetically distinct H. pylori subpopulations, associated with different human populations, and more recent admixture among H. pylori subpopulations can provide information about human migrations. However, little is known about the degree to which some H. pylori genes are conserved in the face of admixture, potentially indicating host adaptation, or how virulence genes spread among different populations. We analyzed H. pylori genomes from 14 countries in the Americas, strains from the Iberian Peninsula, and public genomes from Europe, Africa, and Asia, to investigate how admixture varies across different regions and gene families. Whole-genome analyses of 723 H. pylori strains from around the world showed evidence of frequent admixture in the American strains with a complex mosaic of contributions from H. pylori populations originating in the Americas as well as other continents. Despite the complex admixture, distinctive genomic fingerprints were identified for each region, revealing novel American H. pylori subpopulations. A pan-genome Fst analysis showed that variation in virulence genes had the strongest fixation in America, compared with non-American populations, and that much of the variation constituted non-synonymous substitutions in functional domains. Network analyses suggest that these virulence genes have followed unique evolutionary paths in the American populations, spreading into different genetic backgrounds, potentially contributing to the high risk of gastric cancer in the region.Subject terms: Population genetics, Microbial genetics     

Compromised autophagy by MIR30B benefits the intracellular survival of Helicobacter pylori

Helicobacter pylori evade immune responses and achieve persistent colonization in the stomach. However, the mechanism by which H. pylori infections persist is not clear. In this study, we showed that MIR30B is upregulated during H. pylori infection of an AGS cell line and human gastric tissues. Upregulation of MIR30B benefited bacterial replication by compromising the process of autophagy during the H. pylori infection. As a potential mechanistic explanation for this observation, we demonstrate that MIR30B directly targets ATG12 and BECN1, which are important proteins involved in autophagy. These results suggest that compromise of autophagy by MIR30B allows intracellular H. pylori to evade autophagic clearance, thereby contributing to the persistence of H. pylori infections.     

Helicobacter pylori lipids can form ordered membrane domains (rafts)

Ordered lipid domains (rafts) are generally considered to be features of eukaryotic cells, but ordered lipid domains formed by cholesterol lipids have been identified in bacteria from the genus Borrelia, and similar cholesterol lipids exist in the bacterium Helicobacter pylori. To determine whether H. pylori lipids could form ordered membrane domains, we investigated domain formation in aqueous dispersions of H. pylori whole lipid extracts, individual H. pylori lipids, or defined mixtures of H. pylori lipids and other membrane-forming lipids. DPH (1,6-diphenyl-1,3,5-hexatriene) anisotropy measurements were used to assay membrane order and FRET (Förster resonance energy transfer) was used to detect the presence of co-existing ordered and disordered domains. We found that H. pylori membrane lipid extracts spontaneously formed lipid domains. Domain formation was more stable when lipids were extracted from H. pylori cells grown in the presence of cholesterol. Certain isolated H. pylori lipids (by themselves or when mixed with other lipids) also had the ability to form ordered domains. To be specific, H. pylori cholesteryl-6-O-tetradecanoyl-α-D-glucopyranoside (CAG) and cholesterol-6-O-phosphatidyl-α-D-glucopyranoside (CPG) had the ability to form and/or stabilize ordered domain formation, while H. pylori phosphatidylethanolamine did not, behaving similarly to unsaturated phosphatidylethanolamines. We conclude that specific H. pylori cholesterol lipids have a marked ability to form ordered lipid domains.     

Development of a Selective Medium for Isolation of Helicobacter pylori from Cattle and Beef Samples

Helicobacter pylori has been isolated from the human stomach with media containing only minimal selective agents. However, current research on the transmission and sources of infection requires more selective media due to the higher numbers of contaminants in environmental, oral, and fecal samples. The objective of this study was to develop and evaluate detection techniques that are sufficiently selective to isolate H. pylori from potential animal and food sources. Since H. pylori survives in the acidic environment of the stomach, low pH with added urea was studied as a potential selective combination. H. pylori grew fairly well on H. pylori Special Peptone plating medium supplemented with 10 mM urea at pH 4.5, but this pH did not sufficiently inhibit the growth of contaminants. Various antibiotic combinations were then compared, and a combination consisting of 10 mg of vancomycin per liter, 5 mg of amphotericin B per liter, 10 mg of cefsulodin per liter, 62,000 IU of polymyxin B sulfate per liter, 40 mg of trimethoprim per liter, and 20 mg of sulfamethoxazole per liter proved to be highly selective but still allowed robust colonies of H. pylori to grow. This medium was highly selective for recovering H. pylori from cattle and beef samples, and it is possible that it could be used to enhance the recovery of this bacterium from human and environmental samples, which may be contaminated with large numbers of competing microorganisms.     

Structure of the human gastric bacterial community in relation to Helicobacter pylori status

The human stomach is naturally colonized by Helicobacter pylori, which, when present, dominates the gastric bacterial community. In this study, we aimed to characterize the structure of the bacterial community in the stomach of patients of differing H. pylori status. We used a high-density 16S rRNA gene microarray (PhyloChip, Affymetrix, Inc.) to hybridize 16S rRNA gene amplicons from gastric biopsy DNA of 10 rural Amerindian patients from Amazonas, Venezuela, and of two immigrants to the United States (from South Asia and Africa, respectively). H. pylori status was determined by PCR amplification of H. pylori glmM from gastric biopsy samples. Of the 12 patients, 8 (6 of the 10 Amerindians and the 2 non-Amerindians) were H. pylori glmM positive. Regardless of H. pylori status, the PhyloChip detected Helicobacteriaceae DNA in all patients, although with lower relative abundance in patients who were glmM negative. The G2-chip taxonomy analysis of PhyloChip data indicated the presence of 44 bacterial phyla (of which 16 are unclassified by the Taxonomic Outline of the Bacteria and Archaea taxonomy) in a highly uneven community dominated by only four phyla: Proteobacteria, Firmicutes, Actinobacteria and Bacteroidetes. Positive H. pylori status was associated with increased relative abundance of non-Helicobacter bacteria from the Proteobacteria, Spirochetes and Acidobacteria, and with decreased abundance of Actinobacteria, Bacteroidetes and Firmicutes. The PhyloChip detected richness of low abundance phyla, and showed marked differences in the structure of the gastric bacterial community according to H. pylori status.     

Helicobacter pylori Lipopolysaccharide Is Synthesized via a Novel Pathway with an Evolutionary Connection to Protein N-Glycosylation

Lipopolysaccharide (LPS) is a major component on the surface of Gram negative bacteria and is composed of lipid A-core and the O antigen polysaccharide. O polysaccharides of the gastric pathogen Helicobacter pylori contain Lewis antigens, mimicking glycan structures produced by human cells. The interaction of Lewis antigens with human dendritic cells induces a modulation of the immune response, contributing to the H. pylori virulence. The amount and position of Lewis antigens in the LPS varies among H. pylori isolates, indicating an adaptation to the host. In contrast to most bacteria, the genes for H. pylori O antigen biosynthesis are spread throughout the chromosome, which likely contributed to the fact that the LPS assembly pathway remained uncharacterized. In this study, two enzymes typically involved in LPS biosynthesis were found encoded in the H. pylori genome; the initiating glycosyltransferase WecA, and the O antigen ligase WaaL. Fluorescence microscopy and analysis of LPS from H. pylori mutants revealed that WecA and WaaL are involved in LPS production. Activity of WecA was additionally demonstrated with complementation experiments in Escherichia coli. WaaL ligase activity was shown in vitro. Analysis of the H. pylori genome failed to detect a flippase typically involved in O antigen synthesis. Instead, we identified a homolog of a flippase involved in protein N-glycosylation in other bacteria, although this pathway is not present in H. pylori. This flippase named Wzk was essential for O antigen display in H. pylori and was able to transport various glycans in E. coli. Whereas the O antigen mutants showed normal swimming motility and injection of the toxin CagA into host cells, the uptake of DNA seemed to be affected. We conclude that H. pylori uses a novel LPS biosynthetic pathway, evolutionarily connected to bacterial protein N-glycosylation.     

Helicobacter pylori sensitizes TNF-related apoptosis-inducing ligand (TRAIL)-mediated apoptosis in human gastric epithelial cells through regulation of FLIP

Helicobacter pylori (H. pylori) infection is associated with chronic gastritis, peptic ulcer and gastric cancer. Apoptosis induced by microbial infections is implicated in the pathogenesis of H. pylori infection. Here we show that human gastric epithelial cells sensitized to H. pylori confer susceptibility to TRAIL-mediated apoptosis via modulation of death receptor signaling. Human gastric epithelial cells are intrinsically resistant to TRAIL-mediated apoptosis. The induction of TRAIL sensitivity by H. pylori is dependent on the activation of caspase-8 and its downstream pathway. H. pylori induces caspase-8 activation via enhanced assembly of the TRAIL death-inducing signaling complex (DISC) through downregulation of cellular FLICE-inhibitory protein (FLIP). Overexpression of FLIP abolished the H. pylori-induced TRAIL sensitivity in human gastric epithelial cells. Our study thus demonstrates that H. pylori induces sensitivity to TRAIL apoptosis by regulation of FLIP and assembly of DISC, which initiates caspase activation, resulting in the breakdown of resistance to apoptosis, and provides insight into the pathogenesis of gastric damage in Helicobacter infection. Modulation of host apoptosis signaling by bacterial interaction adds a new dimension to the pathogenesis of Helicobacter.     

Streptococcus mitis Induces Conversion of Helicobacter pylori to Coccoid Cells during Co-Culture In Vitro

Helicobacter pylori (H. pylori) is a major gastric pathogen that has been associated with humans for more than 60,000 years. H. pylori causes different gastric diseases including dyspepsia, ulcers and gastric cancers. Disease development depends on several factors including the infecting H. pylori strain, environmental and host factors. Another factor that might influence H. pylori colonization and diseases is the gastric microbiota that was overlooked for long because of the belief that human stomach was a hostile environment that cannot support microbial life. Once established, H. pylori mainly resides in the gastric mucosa and interacts with the resident bacteria. How these interactions impact on H. pylori-caused diseases has been poorly studied in human. In this study, we analyzed the interactions between H. pylori and two bacteria, Streptocccus mitis and Lactobacillus fermentum that are present in the stomach of both healthy and gastric disease human patients. We have found that S. mitis produced and released one or more diffusible factors that induce growth inhibition and coccoid conversion of H. pylori cells. In contrast, both H. pylori and L. fermentum secreted factors that promote survival of S. mitis during the stationary phase of growth. Using a metabolomics approach, we identified compounds that might be responsible for the conversion of H. pylori from spiral to coccoid cells. This study provide evidences that gastric bacteria influences H. pylori physiology and therefore possibly the diseases this bacterium causes.     

N-acetylcysteine prevents the development of gastritis induced by <Emphasis Type="Italic">Helicobacter pylori</Emphasis> infection

Helicobacter pylori (H. pylori) is a human gastric pathogen, causing various gastric diseases ranging from gastritis to gastric adenocarcinoma. It has been reported that combining N-acetylcysteine (NAC) with conventional antibiotic therapy increases the success rate of H. pylori eradication. We evaluated the effect of NAC itself on the growth and colonization of H. pylori, and development of gastritis, using in vitro liquid culture system and in vivo animal models. H. pylori growth was evaluated in broth culture containing NAC. The H. pylori load and histopathological scores of stomachs were measured in Mongolian gerbils infected with H. pylori strain 7.13, and fed with NAC-containing diet. In liquid culture, NAC inhibited H. pylori growth in a concentration-dependent manner. In the animal model, 3-day administration of NAC after 1 week from infection reduced the H. pylori load; 6-week administration of NAC after 1 week from infection prevented the development of gastritis and reduced H. pylori colonization. However, no reduction in the bacterial load or degree of gastritis was observed with a 6-week administration of NAC following 6-week infection period. Our results indicate that NAC may exert a beneficial effect on reduction of bacterial colonization, and prevents the development of severe inflammation, in people with initial asymptomatic or mild H. pylori infection.     

Genetic host factors in Helicobacter pylori-induced carcinogenesis: Emerging new paradigms

Helicobacter Pylori is a gram negative rod shaped microaerophilic bacterium that colonizes the stomach of approximately half the world's population. Infection with c may cause chronic gastritis which via a quite well described process known as Correas cascade can progress through sequential development of atrophic gastritis, intestinal metaplasia and dysplasia to gastric cancer. H. pylori is currently the only bacterium that is classified as a class 1 carcinogen by the WHO, although the exact mechanisms by which this bacterium contributes to gastric carcinogenesis are still poorly understood. Only a minority of H. pylori-infected patients will eventually develop gastric cancer, suggesting that host factors may be important in determining the outcome of H. pylori infection. This is supported by a growing body of evidence suggesting that the host genetic background contributes to risk of H. pylori infection and gastric carcinogenesis. In particular single nucleotide polymorphisms in genes that influence bacterial handling via pattern recognition receptors appear to be involved, further strengthening the link between host risk factors, H. pylori incidence and cancer. Many of these genes influence cellular pathways leading to inflammatory signaling, inflammasome formation and autophagy. In this review we summarize known carcinogenic effects of H. pylori, and discuss recent findings that implicate host genetic pattern recognition pathways in the development of gastric cancer and their relation with H. pylori.