Helicobacters are indigenous to the human stomach: duodenal ulceration is due to changes in gastric microecology in the modern era.
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Duodenal Ulcer↗
Biomedical subjects
M J Blaser
Publications and source records attributed to M J Blaser.
Insensitivity of the CLOtest for H. pylori, especially in the elderly.
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Adult↗
Apoptosis in gastric epithelial cells is induced by Helicobacter pylori and accompanied by increased expression of BAK.
Carriage of the bacterium H. pylori in the human stomach is associated with evidence of increased epithelial cell apoptosis. This may be of significance in the etiology of gastritis, peptic ulcers, and neoplasia. The ability of H. pylori to directly induce epithelial apoptosis was examined in vitro by fluorescence and electron microscopy, flow cytometry, and DNA fragmentation ELISA. The induction of apoptosis by H. pylori was time and concentration-dependent and inhibited by preventing direct bacterial-epithelial cell contact. Apoptosis was accompanied by increased expression of Bak, with little change in expression of other Bcl-2 family proteins. The expression of Bak was also increased in gastric biopsies from patients colonized by H. pylori. Thus, H. pylori induces gastric epithelial cell apoptosis, by a Bak-dependent pathway.
Apoptosis↗
Ecology of Helicobacter pylori in the human stomach.
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Helicobacter pylori↗
Country-specific constancy by age in cagA+ proportion of Helicobacter pylori infections.
Helicobacter pylori strains may be either cagA+ or cagA-, and in logitudinal studies, infection with a cagA+ strain has been associated with increased risk for the development of atrophic gastritis and cancer of the distal stomach. We sought to determine the relative proportion of strains producing CagA in different geographic locales, and the extent to which CagA seroprevalence varied in countries with different gastric and esophageal cancer rates. Using an enzyme-linked immunosorbent assay (ELISA) to detect serum IgG to CagA, we examined sera from 468 asymptomatic H. pylori-infected adults from Canada, Peru, China, Thailand, The Netherlands and 3 different ethnic groups in New Zealand. The CagA seroprevalence in Peru and Thailand (82.2% and 78.8%, respectively) were each substantially higher than for the Chinese (37.9%), Canadian (41.9%), Dutch (39.0%) and New Zealand (28.2%) subjects, but within each population, rates were relatively constant across gender and age groups. Reported gastric but not esophageal cancer rates for the 8 studied populations were significantly associated with H. pylori seroprevalence. Variation in CagA positivity rates was not significantly associated with variation in either gastric or esophageal cancer rates. Our data suggest that CagA seroprevalence is not the major factor influencing gastric cancer rates.
Adult↗
Helicobacter pylori cagA+ strains and dissociation of gastric epithelial cell proliferation from apoptosis.
BACKGROUND: Infection with Helicobacter pylori induces chronic gastritis in virtually all infected persons, and such gastritis has been associated with an increased risk of developing gastric cancer. This risk is further enhanced with cagA+ (positive for cytotoxin-associated gene A) H. pylori strains and may be a consequence of induced gastric cell proliferation and/or alteration in apoptosis (programmed cell death) in the gastric epithelium. PURPOSE: To determine whether the H. pylori cagA genotype and another virulence-related characteristic, the vacA (vacuolating cytotoxin A) s1a genotype, differentially affect epithelial cell proliferation, apoptosis, and the histologic parameters of inflammation and injury, we quantitated these characteristics in infected and uninfected persons. METHODS: Fifty patients underwent upper gastrointestinal endoscopy, and biopsy specimens were taken. Apoptotic cells in the specimens were quantitated after terminal deoxynucleotidyl transferase labeling of DNA fragments with digoxigenin-deoxyuridine triphosphate; epithelial cell proliferation was scored by immunohistochemical analysis of the proliferation-associated antigen Ki-67. Antibodies directed against H. pylori and CagA protein were measured in the serum of patients by means of enzyme-linked immunosorbent assays. Analysis of H. pylori genomic DNA, by use of the polymerase chain reaction, was performed to determine the cagA and vacA genotypes. Acute and chronic inflammation, epithelial cell degeneration, mucin depletion, intestinal metaplasia, glandular atrophy, and vacuolation were each scored in a blinded manner. Reported P values are two-sided. RESULTS: Persons harboring cagA+ strains (n = 20) had significantly higher gastric epithelial proliferation scores than persons infected with cagA-strains (n = 9) or uninfected persons (n = 21) (P = .025 and P<.001, respectively), but the difference in cell proliferation between the latter two groups was not statistically significant. The number of apoptotic cells per 100 epithelial cells (apoptotic index) in persons infected with cagA+ strains was lower than in persons infected with cagA-strains (P = .05). Apoptotic indices in the cagA+ group were similar to those in the uninfected group (P = .2). Epithelial cell proliferation was significantly correlated with acute gastric inflammation, but only in the cagA+ group (r = .44; P = .006). The cagA+ and vacA s1a genotypes were found to be concordant, confirming the close relationship between these virulence-related genotypes. CONCLUSIONS: Gastric mucosal proliferation was significantly correlated with the severity of acute gastritis in persons infected with cagA+ vacA s1a strains of H. pylori. This increased proliferation was not accompanied by a parallel increase in apoptosis. IMPLICATIONS: Increased cell proliferation in the absence of a corresponding increase in apoptosis may explain the heightened risk for gastric carcinoma that is associated with infection by cagA+ vacA s1a strains of H. pylori.
Antigens, Bacterial↗
Not all Helicobacter pylori strains are created equal: should all be eliminated?
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Anti-Bacterial Agents↗
Nested DNA inversion as a paradigm of programmed gene rearrangement.
Programmed gene rearrangements are employed by a variety of microorganisms, including viruses, prokaryotes, and simple eukaryotes, to control gene expression. In most instances in which organisms mediate host evasion by large families of homologous gene cassettes, the mechanism of variation is not thought to involve DNA inversion. Here we report that Campylobacter fetus, a pathogenic Gram-negative bacterium, reassorts a single promoter, controlling surface-layer protein expression, and one or more complete ORFs strictly by DNA inversion. Rearrangements were independent of the distance between sites of inversion. These rearrangements permit variation in protein expression from the large surface-layer protein gene family and suggest an expanding paradigm of programmed DNA rearrangements among microorganisms.
Bacterial Outer Membrane Proteins↗
Lack of serologic evidence for Helicobacter pylori infection in head and neck cancer.
BACKGROUND: Several epidemiologic investigations have established a link between Helicobacter pylori infection and gastric malignancies. Because the stomach is in continuity with the oral cavity and the bacterium has been isolated from dental plaque and saliva, we hypothesized that H. pylori infection of the upper aerodigestive tract might result in mucosal disruption, allowing for subsequent transformation by known carcinogens such as tobacco and alcohol. METHODS: To test this hypothesis, we assayed for the presence of IgG antibodies to H. pylori in the serum of 21 patients with squamous cell carcinoma of the head and neck (SCCHN) and 21 matched controls without a history of head and neck cancer. RESULTS: The incidence of seropositivity in the SCCHN patients was 57% and in the controls, 62% (p > 0.05). CONCLUSIONS: These data do not support an etiologic role for H. pylori infection in head and neck cancer.
Antibodies, Bacterial↗
Heterogeneity of Helicobacter pylori.
Although many physicians view Helicobacter pylori strains as a homogenous group of organisms, it has become increasingly clear that populations in humans are highly diverse. This heterogeneity can be analyzed at two different levels: genotypic variation among strains and variations in H. pylori populations within an individual host. Genotypic variation includes point mutations in conserved genes (e.g. ureC), variation in the gene order on physical maps, mosaicism in conserved genes (e.g. vacAs1a), non-conserved genes (e.g. cagA) and extragenetic elements (e.g. IS605). Population differences include the observations that humans can be simultaneously infected with two or more H. pylori strains and that a single strain may represent a cluster of closely related organisms (a 'quasispecies'). The presence of multiple organisms within a host may occur as a result of recombination events leading to genetic shift, whereas ongoing mutation within a strain can lead to the formation of quasispecies by genetic drift. Over recent years it has become increasingly clear that observations on the fundamental biology of H. pylori have considerable clinical relevance. Several genotypic markers (e.g. cagA, vacA, sIa and iceA1) are associated with an increased risk of disease. Also, the multiplicity of infection and quasispecies indicates that analysis of a single H. pylori isolate is inaccurate for defining the genotype of H. pylori strains present in a patient. Global assays, such as serology, are more suitable. The aim of this paper is to review the general phenomenon of diversity in H. pylori and to describe particular heterogeneities that are related to clinical outcome.
Genetic Variation↗
Pathophysiology of Helicobacter pylori-induced gastritis and peptic ulcer disease.
Helicobacter pylori causes persistent infection and inflammation in the human stomach, yet only a small fraction of persons harboring this organism develop peptic ulcer disease. An important question is why this variation in infection outcome exists. Recent studies have demonstrated that H pylori isolates possess substantial phenotypic and genotypic diversity that may engender differential host inflammatory responses that influence clinical outcome. Further investigation in this field may help to define which H pylori-infected persons bear the highest risk for subsequent development of peptic ulcer disease, and thus enable physicians to focus eradication therapy.
Gastric Acid↗
Clinical and pathological importance of heterogeneity in vacA, the vacuolating cytotoxin gene of Helicobacter pylori.
BACKGROUND & AIMS: vacA encodes the vacuolating cytotoxin of Helicobacter pylori and exhibits marked variation in signal sequence and midgene coding regions. The implications for gastroduodenal pathology are unknown. The aim of this study was to define the association of vacA genotype with gastric inflammation and injury, in vitro cytotoxin activity, and peptic ulceration. METHODS: Sixty-one consecutive dyspeptic patients underwent endoscopy and gastric biopsy. The biopsy specimens were processed for H. pylori culture, and 52 specimens were also processed for histology. H. pylori vacA was typed by polymerase chain reaction and colony hybridization. Cytotoxin activity was assessed by a HeLa cell vacuolation assay. RESULTS: vacA signal sequence type s1a strains were associated with greater antral mucosal neutrophil and lymphocyte infiltration than s1b or s2 strains (P < 0.05). vacA midregion type m1 strains were associated with greater gastric epithelial damage than m2 strains (P < 0.05). Both midregion and signal sequence were associated with cytotoxin activity in vitro. Duodenal ulcer disease occurred in 89% of 18 patients with s1a strains vs. 29% of 14 with s1b strains (P < 0.01), 20% of 10 with s2 strains (P < 0.001), and 16% of 19 uninfected patients (P < 0.001). CONCLUSIONS: H. pylori strains of vacA signal sequence type s1a are associated with enhanced gastric inflammation and duodenal ulceration. vacA s2 strains are associated with less inflammation and lower ulcer prevalence.
Adult↗
Helicobacter pylori eradication and its implications for the future.
It has become evident that at least some strains of Helicobacter pylori are pathogenic for humans. However, H. pylori are highly diverse and at least part of this variation involves characteristics related to pathogenicity. A large amount of evidence suggests that H. pylori infection of humans is ancient, and in general, the interaction is not terribly destructive. However, we should try to understand better the risks associated with infection with particular H. pylori strains, and limit treatment to those situations in which the indications for eradicating H. pylori are clear-cut. It is entirely possible that some H. pylori strains are commensals, and that others are symbionts. Eradicating those infections could ultimately cause more harm than good. It is too early to reach firm conclusions about whether all H. pylori infections need to be eradicated.
Anti-Bacterial Agents↗
Molecular mechanisms of Campylobacter fetus surface layer protein expression.
Cells of the Gram-negative bacteria Campylobacter fetus are covered by monomolecular arrays of surface layer proteins (SLPs) critical for both persistence in their natural hosts and for virulence. For C. fetus cells, expression of SLPs essentially eliminates C3b binding and their antigenic variation thwarts host immunological defences. Each cell possesses multiple partially homologous and highly conserved SLP gene cassettes, tightly clustered in the genome, that encode SLPs of 97-149 kDa. These attach non-covalently via a conserved N-terminus to the cell wall lipopolysaccharide. Recent studies indicate that C. fetus reassorts a single promoter, controlling SLP expression, and one, or more, complete open reading frame strictly by DNA inversion, and that rearrangement is independent of the distance between sites of inversion. In contrast to previously reported programmed DNA inversion systems, inversion in C. fetus is recA-dependent. These rearrangements permit variation in protein expression from the family of SLP genes and suggest an expanding paradigm of programmed DNA rearrangements among microorganisms.
Animals↗
Effect of Helicobacter pylori products and recombinant cytokines on gastrin release from cultured canine G cells.
BACKGROUND & AIMS: The pathophysiology of hypergastrinemia in Helicobacter pylori infection is undefined, but the infected antrum shows a marked inflammatory response with local production of cytokines. Hypergastrinemia and inflammatory infiltrate clear with successful eradication. The aim of this study was to examine whether the cytokines tumor necrosis factor alpha or interleukin 8 (IL-8), which are produced in the gastric mucosa of patients with H. pylori-induced peptic disease or H. pylori products, can stimulate gastrin release from isolated cultured canine G cells. METHODS: Canine G cells were isolated by collagenase digestion, enriched by centrifugal elutriation, incubated with cytokines, bacterial components, or both, and gastrin release was measured by radioimmunoassay. RESULTS: IL-8 (1 and 10 nmol/L) stimulated gastrin release by 34% +/- 13% and 43% +/- 23% (P < 0.05) above basal, respectively. H. pylori sonicates, water extract preparations, and lipopolysaccharide had no stimulatory actions, but the sonicates from two of four strains potentiated the effects of IL-8, leading to maximal gastrin release of 230% +/- 130% and 232% +/- 33% above basal, respectively (P < 0.05). CONCLUSIONS: IL-8 stimulated gastrin release from isolated G cells, and the effect was potentiated by H. pylori products. The interaction of cytokines and H. pylori may contribute to the hypergastrinemia seen in vivo.
Animals↗
Helicobacter pylori Lewis expression is related to the host Lewis phenotype.
BACKGROUND & AIMS: Lewis antigens occur in human gastric epithelium and in Helicobacter pylori lipopolysaccharide; their expression is polymorphic in both. Autoimmune mechanisms induced by bacterial Lewis expression have been proposed to cause gastritis. The aim of this study was to examine the relationship between bacterial and host gastric Lewis expression, as determined by the erythrocyte Lewis(a/b) phenotype, and between gastric histopathology and bacterial Lewis expression. METHODS: H. pylori Lewis expression was determined by enzyme immunoassays, erythrocyte Lewis phenotype was assessed by agglutination tests, and gastric histopathology was scored blindly. RESULTS: The host Lewis phenotype was (a+b-) in 15, (a-b+) in 34, and (a-b-) in 17 patients, therefore expressing Lewis x, y, or neither as their major gastric epithelial Lewis type 2 antigen. H. pylori from patients with Lewis(a+b-) expressed Lewis x more than y (1147 +/- 143 vs. 467 +/- 128 optical density units [ODU]; P = 0.006), isolates from patients with Lewis(a-b+) expressed Lewis x less than y (359 +/- 81 vs. 838 +/- 96 ODU; P = 0.0001), and isolates from Lewis(a-b-) patients expressed Lewis x and y approximately equally. Gastritis was unrelated to H. pylori Lewis expression. CONCLUSIONS: In mimicking host gastric epithelium, H. pylori cells not only express Lewis x and y, but the relative proportion of expression corresponds to the host Lewis phenotype, suggesting selection for host-adapted organisms.
Adult↗
Helicobacter pylori lipopolysaccharide stimulates histamine release and DNA synthesis in rat enterochromaffin-like cells.
BACKGROUND & AIMS: Helicobacter pylori alterations in gastric acid output and mucosal proliferation may involve the enterochromaffin-like (ECL) cell. To test whether H. pylori affects ECL cell histamine secretion and proliferation, the effect of lipopolysaccharide (LPS) on ECL cell function in vitro was investigated. METHODS: Using a rat ECL cell preparation of high purity (+/-95%), basal and stimulated histamine secretion and DNA synthesis were measured by enzyme immunoassay and bromodeoxyuridine (BrdU) uptake, respectively. RESULTS: Escherichia coli LPS (10(-12) to 10(-6) mol/L) had no effect on basal and stimulated histamine secretion at concentrations of > 10(-6) mol/L. H. pylori LPS stimulated basal and gastrin-stimulated histamine secretion. These effects were completely inhibited by somatostatin (10(-10) mol/L) but not by the gastrin receptor antagonist L365,260 at 10(-6) mol/L. E. coli LPS had a weak stimulatory effect on ECL cell BrdU uptake at 10(-6) mol/L but had no effect on gastrin-stimulated BrdU uptake. H. pylori LPS did not stimulate basal synthesis but significantly increased (1.5-fold) gastrin-stimulated BrdU uptake. CONCLUSIONS: H. pylori influences both ECL cell proliferation and secretion in vitro. An interaction between H. pylori LPS and ECL cells may contribute to the reported abnormalities in acid secretion and gastric pathobiology noted in H. pylori infections.
Animals↗