Evolutionary History of the Helicobacter pylori Genome: Implications for Gastric Carcinogenesis

The genome of the bacterium Helicobacter pylori has evolved over the millennia since its migration out of Africa along with its human host approximately 60,000 years ago. Human migrations, after thousands of years of permanent settlement in those lands, resulted in seven prototypes of genetic populations of H. pylori with distinct geographical distributions. In all continents, present day isolates of H. pylori have molecular markers that reflect population migrations. The colonization of the Americas as well as the slave trade introduced European and African strains to the New World. The relationship between H. pylori genome and gastric cancer rates is linked to the presence of the cagA gene, but the knowledge on this subject is incomplete because other genes may be involved in certain populations. A new situation for Homo sapiens is the absence of H. pylori colonization in certain, mostly affluent, populations, apparently brought about by improved home sanitation and widespread use of antibiotics during the last decades. The disappearance of H. pylori from the human microbiota may be linked to emerging epidemics of esophageal adenocarcinoma, some allergic diseases such as asthma and some autoimmune disorders.     

Helicobacter pylori Seropositivity Is Associated with Gastric Cancer Regardless of Tumor Subtype in Korea

Background/Aims

To evaluate the association between Helicobacter pylori (H. pylori) infection and gastric cancer (GC) according to tumor subtype in Korea.

Methods

H. pylori status was determined serologically using the enzyme-linked immunosorbent assay. In total, 2,819 patients with GC and 562 healthy controls were studied. A logistic regression method was used after adjusting for possible confounders.

Results

The prevalence of H. pylori infection was significantly higher in the GC patients (84.7%) than in the controls (66.7%) (odds ratio [OR], 3.13; 95% confidence interval [CI], 2.46-3.97). The adjusted OR was significantly higher in H. pylori-infected patients aged <60 years (OR, 4.69; 95% CI, 3.44-6.38) than in those aged ≥60 years (OR, 1.48; 95% CI, 0.88-2.46; p<0.001). Subgroup analyses revealed no differences in seroprevalence between early gastric cancer (84.8%; OR, 3.01; 95% CI, 2.27-4.01) and advanced gastric cancer (84.6%; OR, 2.94; 95% CI, 2.24-3.85), cardia cancer (83.8%; OR, 2.98; 95% CI, 2.16-4.02) and noncardia cancer (84.8%; OR, 3.17; 95% CI, 2.48-4.04), and differentiated carcinoma (82.7%; OR, 2.99; 95% CI, 2.21-4.04) and undifferentiated carcinoma (86.8%; OR, 3.05; 95% CI, 2.32-4.00).

Conclusions

The seroprevalence of H. pylori was higher in GC patients than in healthy controls, especially in younger patients. H. pylori infection is associated with GC, regardless of the tumor location, stage, or differentiation.     

Detection of Helicobacter pylori in Gastric Aspirates Using a Monoclonal Antibody-Based Test

Background/Aims

The objective of this study was to evaluate a monoclonal antibody-based test to detect Helicobacter pylori-specific antigen in gastric aspirates from humans.

Methods

Sixty-one volunteers were enrolled in the study. All of the subjects underwent a ¹³C-urea breath test (UBT) before esophagogastroduodenoscopy. Gastric aspirates were analyzed for pH and ammonia and used for polymerase chain reaction (PCR), culture, and monoclonal antibody-based detection of H. pylori. Multiple biopsies of the gastric antrum and body were obtained for a rapid urease test (RUT) and histological evaluation.

Results

Thirty-six subjects were H. pylori-positive and 25 were H. pylori-negative according to the UBT results. Compared with the H. pylori-negative subjects, H. pylori-positive subjects had a higher pH (4.77±1.77 vs 3.49±1.30, p<0.05) and ammonia level (1,130.9±767.4 vs 184.2±126.3, p<0.0001). The sensitivities and specificities of the PCR test, RUT, culture test, and monoclonal antibody-based test were 100% and 72%, 89% and 100%, 47% and 100%, and 78% and 100%, respectively.

Conclusions

The monoclonal antibody-based test for diagnosing H. pylori infection in gastric aspirates has increased sensitivity compared with the culture test and specificity as high as that of the RUT. The test may be useful as an additive test for examining gastric aspirates.     

The Effects of Broccoli Sprout Extract Containing Sulforaphane on Lipid Peroxidation and Helicobacter pylori Infection in the Gastric Mucosa

Background/Aims

The aims of this study were to investigate whether a broccoli sprout extract containing sulforaphane (BSES) inhibited the Helicobacter pylori infection density and exerted an antioxidative effect on gastric mucosal damage.

Methods

The enrolled subjects were randomized in a double-blinded manner into three groups. Finally, 33 H. pylori (+) BSES treatment subjects (group A), 28 H. pylori (+) placebo subjects (group B), and 28 H. pylori (−) BSES treatment subjects (group C) were studied. H. pylori infection density was indirectly quantified by a ¹³C-urea breath test (UBT), and the ammonia concentration in gastric juice aspirates was measured through gastroscopic examination. Malondialdehyde (MDA), an oxidative damage biomarker, and reduced glutathione (GSH), an antioxidant biomarker, were measured in the gastric mucosa by an enzyme-linked immunosorbent assay.

Results

BSES treatment did not significantly affect the UBT values or ammonia concentration in group A (p=0.634 and p=0.505, respectively). BSES treatment did significantly reduce mucosal MDA concentrations in group A (p<0.05) and group C (p<0.001), whereas the gastric mucosal GSH concentrations did not differ before and after treatment in any of the groups.

Conclusions

BSES did not inhibit the H. pylori infection density. However, BSES prevented lipid peroxidation in the gastric mucosa and may play a cytoprotective role in H. pylori-induced gastritis.     

An Inverse Relationship between the Expression of the Gastric Tumor Suppressor RUNX3 and Infection with Helicobacter pylori in Gastric Epithelial Dysplasia

Background/Aims

This study was performed to determine the association between RUNX3 expression and Helicobacter pylori infection in premalignant gastric lesions.

Methods

We examined 107 patients with gastric epithelial dysplasia who had undergone endoscopic mucosal resection or submucosal dissection. All tissue samples were evaluated by RUNX3 staining and subclassified by immunophenotype. H. pylori infection in dysplastic lesions and the normal surrounding tissue was examined by silver staining, and cagA status was assessed by polymerase chain reaction.

Results

The loss of RUNX3 expression was observed in 62 cases (57.9%), and an association with H. pylori infection was found in 54 cases (50.5%). The infection rate with the cagA-positive H. pylori strain was 63.0%. In RUNX3-negative lesions, the rate of H. pylori infection (p=0.03) and the frequency of category 4 lesions (according to the revised Vienna classification) were high (p=0.02). In addition, the gastric mucin phenotype was predominant. In RUNX3-negative category 4 lesions, the rate of cagA-positive H. pylori infection rate was high but not significantly increased (p=0.08).

Conclusions

Infection with H. pylori is associated with inactivation of RUNX3 in early gastric carcinogenesis. This mechanism was prominent in gastric cancer with a gastric mucin phenotype.     

Seroprevalence of Helicobacter pylori Infection in Korean Health Personnel

Background/Aims

The aims of this study were to evaluate whether doctors and nurses in a single hospital were at an increased risk of acquiring Helicobacter pylori infection in 2011 and to identify risk factors for H. pylori seroprevalence.

Methods

Nurses (n=362), doctors (n=110), health personnel without patient contact (medical control, n=179), and nonhospital controls (n=359) responded to a questionnaire during a health check-up, which included questions on socioeconomic status, education level, working years, and occupation in 2011. The prevalence of H. pylori was measured by serology.

Results

The seroprevalence rate was 29.8% (nurses), 34.5% (doctors), 30.7% (medical control), and 52.9% (nonhospital control). Among younger subjects (<40 years of age), the nonhospital control had a higher seropositivity rate (48.1%) than nurses (29.2%), doctors (29.8%), and the medical control (24.8%), which was not observable in subjects ≥40 years of age. The risk factors for H. pylori seroprevalence were not different for health and nonhealth personnel. A multivariate analysis indicated that seropositivity significantly increased with age, the province of residence, and a gastroscopic finding of a peptic ulcer.

Conclusions

The medical occupation was not associated with H. pylori infection. The seroprevalence of H. pylori in one hospital in 2011 was found to be 38.7%, most likely due to the improvement in socioeconomic status and hospital hygiene policy in Korea.     

Mass Eradication of Helicobacter pylori to Prevent Gastric Cancer: Theoretical and Practical Considerations

Although the age-adjusted incidence of gastric cancer is declining, the absolute number of new cases of gastric cancer is increasing due to population growth and aging. An effective strategy is needed to prevent this deadly cancer. Among the available strategies, screen-and-treat for Helicobacter pylori infection appears to be the best approach to decrease cancer risk; however, implementation of this strategy on the population level requires a systematic approach. The program also must be integrated into national healthcare priorities to allow the limited resources to be most effectively allocated. Implementation will require adoption of an appropriate screening strategy, an efficient delivery system with a timely referral for a positive test, and standardized treatment regimens based on clinical efficacy, side effects, simplicity, duration, and cost. Within the population, there are subpopulations that vary in risk such that a “one size fits all” approach is unlikely to be ideal. Sensitivity analyses will be required to identify whether the programs can be utilized by heterogeneous populations and will likely require adjustments to accommodate the needs of subpopulations.     

Helicobacter pylori eradication for preventing gastric cancer

Helicobacter pylori(H.pylori)infection is a major riskfactor for gastric cancer(GC)development,which isone of the most challenging malignant diseases worldwide with limited treatments.In the multistep pathogenesis of GC,H.pylori infection slowly induces chronicactive gastritis,which progresses through the premalignant stages of atrophic gastritis,intestinal metaplasia,and dysplasia,and then finally to GC.Although eradication of H.pylori is a reasonable approach for the prevention of GC,there have been some contradictory reports,with only some long-term follow-up data showingefficacy of this approach.The inconsistencies are likely due to the insufficient number of participants,relatively short follow-up periods,poor quality of study designs,and the degree and extent of preneoplastic changes atthe time of H.pylori eradication.This review analyzesrecent high-quality studies to resolve the discrepancies regarding the eradication of H.pylori for GC prevention.The relationship between H.pylori eradication and GC/precancerous lesions/metachronous GC is examined,and the cost-effectiveness of this strategy in the prevention of GC is assessed.Although it is assumed that eradication of H.pylori has the potential to prevent GC,the feasibility and appropriate timing of this strategy for cancer prevention remain to be determined.As a result,additional well-designed trials with longer followup periods are needed to clarify this issue.     

Gastric Juice Levels of Lactoferrin and Helicobacter pylori Infection

Background: Recently, in vitro studies suggested that lactoferrin (Lf) might play an important role in the physiopathology of Helicobacter pylori-associated gastritis. However, whether Lf is present in the gastric juice and its relationship with H. pylori infection have not as yet been reported. In the present investigation the presence of Lf in gastric juice and its correlation with H. pylori infection were assessed. Methods: This study comprised 30 H. pylori-positive and 14 -negative patients with chronic gastritis. Gastric juice levels of Lf were measured with enzyme-linked immunoassays. Gastric juice concentration of Lf was also investigated in accordance with the histologic findings of biopsy specimens in the gastric body and antrum. Results: Lf concentration in gastric juice was significantly higher in H. pylori-positive than in -negative patients (P=0.033). The pH values are known to influence the levels of Lf. However, intragastric Lf levels were also significantly increased in H. pylori-positive patients as compared with H. pylori-negative patients after correcting the Lf levels for pH values (P = 0.029) or after adjusting the pH values of the gastric juice with NaHCO₃ solution in both groups of patients (P = 0.0007). in addition, the gastric juice levels of Lf correlated significantly with the gastric mucosal concentrations of Lf in the gastric body (P < 0.005, r=0.568) and the antrum (P < 0.05, r=0.401). Conclusions: This study showed for the first time that Lf is present in gastric juice and that it correlates with H. pylori infection. Lf may constitute a good marker for H. pylori-associated gastritis. Although correlation does not prove causation, this study suggests that Lf might play an important role in the physiopathology of H. pylori-associated gastritis.     

Helicobacter pylori infection following partial gastrectomy for gastric cancer

Gastric remnants are an inevitable consequence of partial gastrectomy following resection for gastric cancer.The presence of gastric stumps is itself a risk factor for redevelopment of gastric cancer.Helicobacter pylori(H.pylori)infection is also a well-known characteristic of gastric carcinogenesis.H.pylori colonization in the remnant stomach therefore draws special interest from clinicians in terms of stomach cancer development and pathogenesis;however,the H.pylori-infected gastric remnant is quite different from the intact organ in several aspects and researchers have expressed conflicting opinions with respect to its role in pathogenesis.For instance,H.pylori infection of the gastric stump produced controversial results in several recent studies.The prevalence of H.pylori infection in the gastric stump has varied among recent reports.Gastritis developing in the remnant stomach presents with a unique pattern of inflammation that is different from the pattern seen in ordinary gastritis of the intact organ.Bilerefluxate also has a significant influence on the colonization of the stomach stump,with several studies reporting mixed results as well.In contrast,the elimination of H.pylori from the gastric stump has shown a dramatic impact on eradication rate.H.pylori elimination is recognized to be important for cancer prevention and considerable agreement of opinion is seen among researchers.To overcome the current discrepancies in the literature regarding the role of H.pylori in the gastric stump,further research is required.     

Gastric precancerous lesions are associated with gene variants in Helicobacter pylori -susceptible ethnic Malays

AIM: To identify genes associated with gastric pre-cancerous lesions in Helicobacter pylori (H. pylori )susceptible ethnic Malays. METHODS: Twenty-three Malay subjects with H. pylori infection and gastric precancerous lesions identified during endoscopy were included as "cases". Thirtyseven Malay subjects who were H. pylori negative and had no precancerous lesions were included as "controls". Venous blood was collected for genotyping with Affymetrix 50K Xba1 kit. Genotypes with call rates < 90% for autosomal single nucleotide polymorphisms (SNPs) were excluded. For each precancerous lesion, associated SNPs were identified from Manhattan plots, and only SNPs with a χ2 P value < 0.05 and Hardy Weinberg Equilibrium P value > 0.5 was considered as significant markers. RESULTS: Of the 23 H. pylori -positive subjects recruited, one sample was excluded from further analysis due to a low genotyping call rate. Of the 22 H. pylori positive samples, atrophic gastritis only was present in 50.0%, complete intestinal metaplasia was present in 18.25%, both incomplete intestinal metaplasia and dysplasia was present in 22.7%, and dysplasia only was present in 9.1%. SNPs rs9315542 (UFM1 gene), rs6878265 (THBS4 gene), rs1042194 (CYP2C19 gene) and rs10505799 (MGST1 gene) were significantly associated with atrophic gastritis, complete intestinal metaplasia, incomplete metaplasia with foci of dysplasia and dysplasia, respectively. Allele frequencies in "cases" vs "controls" for rs9315542, rs6878265, rs1042194 and rs10505799 were 0.4 vs 0.06, 0.6 vs 0.01, 0.6 vs 0.01 and 0.5 vs 0.02, respectively. CONCLUSION: Genetic variants possibly related to gastric precancerous lesions in ethnic Malays susceptible to H. pylori infection were identified for testing in subsequent trials.     

The Effect of Helicobacter pylori on Epidermal Growth Factor Receptor-Induced Signal Transduction and the Preventive Effect of Celecoxib in Gastric Cancer Cells

Background/Aims

Helicobacter pylori infection induces cyclooxygenase-2 (COX-2) and epidermal growth factor receptor (EGFR) overexpression, and these factors may engage in cross-talk. The aim of the present study was to evaluate the effect of H. pylori on EGFR signaling pathways and to determine whether celecoxib has an inhibitory effect on this pathway.

Methods

The AGS cell line was cocultured with H. pylori G27 and the isogenic cagE- mutant. The expression of COX-2, EGFR, heparin binding-epidermal growth factor (HB-EGF), and transforming growth factor-β (TGF-β) was measured by real time-polymerase chain reaction (RT-PCR). Next, Western blot analyses of COX-2, EGFR, total Akt, phosphorylated Akt (pAkt), and phosphorylated glycogen synthase kinase-3β (pGSK3β) were performed after incubating H. pylori-treated AGS cells for 24 hours with various concentrations of celecoxib (0, 10, 20, and 30 µmol/L).

Results

H. pylori infection upregulated the mRNA levels of COX-2, EGFR, HB-EGF, and TGF-β, as detected by RT-PCR. However, AGS cells treated with cagE- mutants, which have a defective type IV secretion system, did not exhibit EGFR upregulation. Celecoxib had inhibitory effects on the H. pylori-induced overexpression of COX-2 (p=0.015), EGFR (p=0.025), pAkt (p=0.025), and pGSK3β (p=0.029) by Western blot analysis.

Conclusions

H. pylori with an intact type IV secretion system activated the COX-2 and EGFR-Akt pathways in the AGS cell line. As celecoxib exhibited inhibitory effects on the EGFR signaling pathway, the cross-talk of COX-2 and EGFR likely mediates H. pylori-induced gastric cancer.     

Sequential Therapy for Helicobacter pylori Infection in Korea: Systematic Review and Meta-Analysis

Background/Aims

Sequential therapy (ST) for Helicobacter pylori infection in countries other than Korea has shown higher eradication rates than triple therapy (TT). The aim of this study was to evaluate the efficacy of ST in Korea by performing a meta-analysis.

Methods

We performed a comprehensive literature search on the efficacy of ST as a first-line therapy. The odds ratios (ORs) of eradicating H. pylori infection after ST compared with TT were pooled. Pooled estimates of the eradication rates of ST and TT were also calculated.

Results

A total of six studies provided data on 1,759 adult patients. The ORs for the intention to treat (ITT) and the per-protocol (PP) eradication rate were 1.761 (95% confidence interval [CI], 1.403 to 2.209) and 1.966 (95% CI, 1.489 to 2.595). Pooled estimates of the ITT and PP eradication rate were 79.4% (95% CI, 76.3% to 82.2%) and 86.4% (95% CI, 83.5% to 88.8%), respectively, for the ST group, and 68.2% (95% CI, 62.1% to 73.8%) and 78.9% (95% CI, 68.9% to 81.7%), respectively, for the TT group.

Conclusions

Although ST presented a higher eradication rate than TT in Korea, the pooled eradication rates were lower than expected. Further studies are needed to validate ST as a first-line treatment for H. pylori in Korea.     

Additive Effect of Pronase on the Eradication Rate of First-Line Therapy for Helicobacter pylori Infection

Background/Aims

Helicobacter pylori colonizes on the apical surface of gastric surface mucosal cells and the surface mucous gel layer. Pronase is a premedication enzyme for endoscopy that can disrupt the gastric mucus layer. We evaluated the additive effects of pronase combined with standard triple therapy for H. pylori eradication.

Methods

This prospective, single-blinded, randomized, controlled study was conducted between June and October 2012. A total of 116 patients with H. pylori infection were enrolled in the study (n=112 patients, excluding four patients who failed to meet the inclusion criteria) and were assigned to receive either the standard triple therapy, which consists of a proton pump inhibitor with amoxicillin and clarithromycin twice a day for 7 days (PAC), or pronase (20,000 tyrosine units) combined with the standard triple therapy twice a day for 7 days (PACE).

Results

In the intention-to-treat analysis, the eradication rates of PAC versus PACE were 76.4% versus 56.1% (p=0.029). In the per-protocol analysis, the eradication rates were 87.5% versus 68.1% (p=0.027). There were no significant differences concerning adverse reactions between the two groups.

Conclusions

According to the interim analysis of the trial, pronase does not have an additive effect on the eradication of H. pylori infection (ClinicalTrial.gov: {"type":"clinical-trial","attrs":{"text":"NCT01645761","term_id":"NCT01645761"}}NCT01645761).     

Accuracy of Rapid Urease Test in Diagnosing Helicobacter pylori Infection in Patients using NSAIDs

Background/Aim:

This study aimed to determine the effect of nonsteroidal anti-inflammatory drugs (NSAIDs) on the results of rapid urease test (RUT).

Patients and Methods:

The study evaluated 210 consecutive patients for the diagnosis of Helicobacter pylori (H. pylori) infection. They were divided into case and control groups based on history of NSAID use (n=70 each). Two biopsy specimens were collected from antrum and corpus of stomach during endoscopy and sent for rapid urease testing and histopathology. Sensitivity, specificity, and accuracy rate of RUT test were compared against histology.

Results:

The average age was 55.2±12.9 and 43.3±12.1 years in the case and control groups, respectively. Among NSAID users, RUT sensitivity, specificity and accuracy rate were all 100%. The sensitivity, specificity and accuracy rate of RUT in patients without history of NSAID use were 97.37, 98.57 and 98.14%, respectively. The overall sensitivity, specificity and accuracy rate of RUT were 98.57, 99.29, and 99.04%, respectively.

Conclusion:

Our study shows that sensitivity, specificity and accuracy rate of RUT are not affected by NSAID use. Rapid urease test remains a reliable test for diagnosis of H. pylori in patients on NSAIDs.     

Helicobacter pylori Infection Enhances Gastric Mucosal Inflammation in Individuals Carrying the 260-T Allele of the CD14 Gene

Background/Aims

We aim to evaluate the association between promoter polymorphism of the clusters of differentiation 14 (CD14) gene and Helicobacter pylori-induced gastric mucosal inflammation in a healthy Korean population.

Methods

The study population consisted of 267 healthy subjects who visited our hospital for free nationwide gastric cancer screening. Promoter polymorphism at -260 C/T of the CD14 gene was determined by polymerase chain reaction and restriction fragment length polymorphism analysis. The severity of gastric mucosal inflammation was estimated by a gastritis score based on the sum of the values of the grade and activity of the gastritis. Expression of soluble CD14 (sCD14) was assessed by quantitative sandwich ELISA.

Results

CD14 polymorphism was not associated with H. pylori infection. There were no significant differences in gastritis scores among the genotype subgroups, but subjects carrying the CD14 -260 CT/TT genotype had significantly higher sCD14 levels than those carrying the CC genotype. Subjects with the 260-T allele of the CD14 gene and H. pylori infection had significantly higher sCD14 levels than those with the same genotype but without infection.

Conclusions

In individuals with the T allele at the -260 site of the promoter region of the CD14 gene, H. pylori infection accentuates gastric mucosal inflammation.     

Treatment for Eradication of Helicobacter pylori Infection among Chronic Hepatitis C Patients

Background/Aims

Helicobacter pylori infection causes gastritis, peptic ulcers and gastric malignancies, and its eradication has been advocated by many groups. We determined the H. pylori carrier status and eradication rates of patients with chronic hepatitis C virus (HCV) infection.

Methods

In total, 76 chronically HCV-infected patients were enrolled for comparison with 228 HCV-noninfected, age- and sex-matched controls. H. pylori infection was confirmed by H. pylori antibody and urea breath testing.

Results

The H. pylori infection rate was significantly higher for HCV-infected patients (67 of 76, 88.2%) than for HCV-noninfected controls (158 of 228, 69.3%). Endoscopic findings showed that the rates of gastric ulcers and gastritis were significantly higher for the 67 HCV-infected patients with H. pylori infection (34.3% and 77.6%) than for the 158 HCV-noninfected controls with H. pylori infection (15.2% and 57.6%). Treatment to eradicate H. pylori had a significantly higher success rate for HCV-infected patients (61 of 67, 91.0%) than for HCV-noninfected controls (115 of 158, 72.8%).

Conclusions

The markedly high H. pylori eradication rate observed in this study shows that eradication of H. pylori holds promise for the improvement of the long-term health condition of patients with chronic HCV infection.     

Helicobacter pylori and interleukin-8 in gastric cancer

Helicobacter pylori(H.pylori)is a major etiological factor in the development of gastric cancer.Large-scale epidemiological studies have confirmed the strong association between H.pylori infection and both cancer development and progression.Interleukin-8(IL-8)is overexpressed in gastric mucosa exposed to H.pylori.The expression of IL-8 directly correlates with a poor prognosis in gastric cancer.IL-8 is multifunctional.In addition to its potent chemotactic activity,it can induce proliferation and migration of cancer cells.In this review,we focus on recent insights into the mechanisms of IL-8 signaling associated with gastric cancer.The relationship between IL-8 and H.pylori is discussed.We also summarize the current therapeutics against IL-8 in gastric cancer.