Assessment of atrophic gastritis using the OLGA system

Background: An international group of gastroenterologists and pathologists (Operative Link for Gastritis Assessment (OLGA)) proposed the staging system of atrophy. The aim of this study was to assess the severity of atrophic gastritis using the OLGA system. Materials and Methods: The subjects comprised 163 H. pylori‐positive patients: 18 with early gastric cancers of the intestinal type (GC), 55 with atrophic gastritis (AG), 49 with gastric ulcers or scars (GU), and 41 with duodenal ulcers or scars (DU). Biopsies were taken from the lesser and greater curvatures of the antrum and middle body. The OLGA gastritis stage (0–IV) (the severity and topography of atrophy) was obtained by combining antral with body atrophy scores. The gastritis grade (the severity and topography of inflammation) was obtained by combining antral and body inflammation scores. Results: Most (84%) of patients with GC showed stage III or IV. Gastritis stages were significantly higher in patients with GC than in those with AG, GU, and DU. Gastritis stage became higher with age. Gastritis grades were slightly higher in patients with AG than in others. Conclusions: Our results indicate that higher stages are found in patients with GC using the OLGA staging system and that the high risk of GC can be recognized. It is simple to use and useful for the assessment of the severity of atrophic gastritis.     

Helicobacter pylori infection‐induced H3Ser10 phosphorylation in stepwise gastric carcinogenesis and its clinical implications

Background

Our previous works have demonstrated that Helicobacter pylori (Hp) infection can alter histone H3 serine 10 phosphorylation status in gastric epithelial cells. However, whether Helicobacter pylori‐induced histone H3 serine 10 phosphorylation participates in gastric carcinogenesis is unknown. We investigate the expression of histone H3 serine 10 phosphorylation in various stages of gastric disease and explore its clinical implication.

Materials and Methods

Stomach biopsy samples from 129 patients were collected and stained with histone H3 serine 10 phosphorylation, Ki67, and Helicobacter pylori by immunohistochemistry staining, expressed as labeling index. They were categorized into nonatrophic gastritis, chronic atrophic gastritis, intestinal metaplasia, low‐grade intraepithelial neoplasia, high‐grade intraepithelial neoplasia, and intestinal‐type gastric cancer groups. Helicobacter pylori infection was determined by either ¹³C‐urea breath test or immunohistochemistry staining.

Results

In Helicobacter pylori‐negative patients, labeling index of histone H3 serine 10 phosphorylation was gradually increased in nonatrophic gastritis, chronic atrophic gastritis, intestinal metaplasia groups, peaked at low‐grade intraepithelial neoplasia, and declined in high‐grade intraepithelial neoplasia and gastric cancer groups. In Helicobacter pylori‐infected patients, labeling index of histone H3 serine 10 phosphorylation followed the similar pattern as above, with increased expression over the corresponding Helicobacter pylori‐negative controls except in nonatrophic gastritis patient whose labeling index was decreased when compared with Helicobacter pylori‐negative control. Labeling index of Ki67 in Helicobacter pylori‐negative groups was higher in gastric cancer than chronic atrophic gastritis and low‐grade intraepithelial neoplasia groups, and higher in intestinal metaplasia group compared with chronic atrophic gastritis group. In Helicobacter pylori‐positive groups, Ki67 labeling index was increased stepwise from nonatrophic gastritis to gastric cancer except slightly decrease in chronic atrophic gastritis group. In addition, we noted that histone H3 serine 10 phosphorylation staining is accompanied with its location changes from gastric gland bottom expanded to whole gland as disease stage progress.

Conclusions

These results indicate that stepwise gastric carcinogenesis is associated with altered histone H3 serine 10 phosphorylation, Helicobacter pylori infection enhances histone H3 serine 10 phosphorylation expression in these processes; it is also accompanied with histone H3 serine 10 phosphorylation location change from gland bottom staining expand to whole gland expression. The results suggest that epigenetic dysregulation may play important roles in Helicobacter pylori‐induced gastric cancer.     

Previous Helicobacter pylori infection–induced atrophic gastritis: A distinct disease entity in an understudied population without a history of eradication

Individuals with chronic atrophic gastritis who are negative for active H. pylori infection with no history of eradication therapy have been identified in clinical practice. By excluding false‐negative and autoimmune gastritis cases, it can be surmised that most of these patients have experienced unintentional eradication of H. pylori after antibiotic treatment for other infectious disease, unreported successful eradication, or H. pylori that spontaneously disappeared. These patients are considered to have previous H. pylori infection–induced atrophic gastritis. In this work, we define these cases based on the following criteria: absence of previous H. pylori eradication; atrophic changes on endoscopy or histologic confirmation of glandular atrophy; negative for a current H. pylori infection diagnosed in the absence of proton‐pump inhibitors or antibiotics; and absence of localized corpus atrophy, positivity for autoantibodies, or characteristic histologic findings suggestive of autoimmune gastritis. The risk of developing gastric cancer depends on the atrophic grade. The reported rate of developing gastric cancer is 0.31%‐0.62% per year for successfully eradicated severely atrophic cases (pathophysiologically equal to unintentionally eradicated cases and unreported eradicated cases), and 0.53%‐0.87% per year for spontaneously resolved cases due to severe atrophy. Therefore, for previous H. pylori infection–induced atrophic gastritis cases, we recommend endoscopic surveillance every 3 years for high‐risk patients, including those with endoscopically severe atrophy or intestinal metaplasia. Because of the difficulty involved in the endoscopic diagnosis of gastric cancer in cases of previous infection, appropriate monitoring of the high‐risk subgroup of this understudied population is especially important.     

A lucid review of Helicobacter pylori‐induced DNA damage in gastric cancer

Helicobacter pylori (H pylori) is the main risk factor for gastric cancer (GC). In recent years, many studies have addressed the effects of H pylori itself and of H pylori‐induced chronic inflammation on DNA damage. Unrepaired or inappropriately repaired DNA damage is one possible carcinogenic mechanism. We may conclude that H pylori‐induced DNA damage is one of the carcinogenic mechanisms of GC. In this review, we summarize the interactions between H pylori and DNA damage and the effects of H pylori‐induced DNA damage on GC. Then, focusing on oxidative stress, we introduce the application of antioxidants in GC. At the end of this review, we discuss the outlook for further research on H pylori‐induced DNA damage.     

Impact factors that modulate gastric cancer risk in Helicobacter pylori‐infected rodent models

Gastric cancer causes a large social and economic burden to humans. Helicobacter pylori (H pylori) infection is a major risk factor for distal gastric cancer. Detailed elucidation of H pylori pathogenesis is significant for the prevention and treatment of gastric cancer. Animal models of H pylori‐induced gastric cancer have provided an invaluable resource to help elucidate the mechanisms of H pylori‐induced carcinogenesis as well as the interaction between host and the bacterium. Rodent models are commonly used to study H pylori infection because H pylori‐induced pathological processes in the stomachs of rodents are similar to those in the stomachs of humans. The risk of gastric cancer in H pylori‐infected animal models is greatly dependent on host factors, bacterial determinants, environmental factors, and microbiota. However, the related mechanisms and the effects of the interactions among these impact factors on gastric carcinogenesis remain unclear. In this review, we summarize the impact factors mediating gastric cancer risk when establishing H pylori‐infected animal models. Clarifying these factors and their potential interactions will provide insights to construct animal models of gastric cancer and investigate the in‐depth mechanisms of H pylori pathogenesis, which might contribute to the management of H pylori‐associated gastric diseases.     

Helicobacter pylori-negative gastric cancer in South Korea: incidence and clinicopathologic characteristics

Background and Aim: It is difficult to determine the exact incidence rate of Helicobacter pylori (H. pylori) infection‐negative gastric cancer (HPIN‐GC) because H. pylori detection rates decrease with the progression of gastric atrophy and intestinal metaplasia. The aim of this study was to evaluate the incidence and clinicopathologic characteristics of HPIN‐GC in South Korea. Methods: Helicobacter pylori infection status was evaluated by histology, a rapid urease test (CLO test), culturing, serology, and history of H. pylori eradication for 627 patients with gastric cancer. Current H. pylori infection was defined as positive results from histology, the CLO test, and culturing. Previous H. pylori infection was defined as negative in all three biopsy‐based tests and positive serology or history of H. pylori eradication. Patients were considered to be negative for H. pylori infection if all results from five methods were negative. However, patients who were found to have severe gastric atrophy by the serum pepsinogen test or metaplastic gastric atrophy by histology were assumed to have had a previous H. pylori infection even if results from other tests for H. pylori infection were all negative. Results: The number of patients with gastric cancer with current or previous H. pylori infection was 439 (70.0%) and 154 (24.6%), respectively. The rate of HPIN‐GC occurrence was 5.4% (n = 34). Sex, age, Lauren type, location of the tumor, and treatment modalities were not different according to H. pylori infection status. However, HPIN‐GC had a more advanced pT classification (T3/T4; 51.9 vs 31.1%, p = .025) and a more advanced stage (more than stage I; 63 vs 41.3%, p = .027) than H. pylori‐positive gastric cancer. Conclusion: At least 5.4% cases of gastric cancer were H. pylori negative among South Korean patients. HPIN‐GC looks like to have a poorer prognosis than H. pylori‐positive cases.     

Helicobacter pylori infection,mucosal atrophy and intestinal metaplasia in Asian populations: a comparative study in age-, gender- and endoscopic diagnosis-matched subjects

Background. It is known that the incidence and mortality rate of gastric cancer is high among Japanese and Chinese populations, but extremely low in Thai and Vietnamese populations. The aim of this study was to investigate the prevalence of Helicobacter pylori infection and the differences in the glandular atrophy and intestinal metaplasia scores in stomach specimens of Asian adult subjects of different races. Materials and Methods. Chinese, Thai, Vietnamese and Japanese patients were matched by age, gender and endoscopic diagnosis, in order to compare the differences in incidence of H. pylori‐related peptic ulcer disease and the prevalence of H. pylori infection among four Asian populations (n = 700). Glandular atrophy scores and intestinal metaplasia scores were also compared among four Asian populations divided into H. pylori‐positive cases (n = 120, 109, 145, 80, respectively) and H. pylori‐negative cases (n = 55, 66, 30, 95, respectively). Results. Among peptic ulcers, gastric ulcer was more frequently seen in Japanese subjects than in the other Asian populations examined. On the other hand, duodenal ulcer was more frequently seen in other Asian populations than in Japanese subjects. The prevalence of H. pylori infection was similar in the Japanese (Tokyo) and Chinese (Beijing and Fuzhou) populations. It was higher in Thai (Chiang Mai) subjects compared with Japanese subjects. On the other hand, Vietnamese (Ho Chi Minh) subjects had significantly lower rates of H. pylori infection than Japanese subjects. The glandular atrophy and intestinal metaplasia scores in the stomach were significantly higher in the H. pylori‐positive Japanese subjects than in H. pylori‐positive subjects belonging to other Asian populations, except for the higher glandular atrophy scores in Chinese rather than Japanese subjects. On the other hand, there were no significant differences in the glandular atrophy and intestinal metaplasia scores in the angulus of the stomach among H. pylori‐negative subjects belonging to the different Asian populations examined. Conclusions. Gastric ulcer was more common among Japanese subjects, while duodenal ulcer was more common among the other Asian populations examined. Japanese subjects with H. pylori infection showed more severe atrophic and metaplastic gastritis compared with that in other Asian subjects with H. pylori infection. These results may be related to the higher incidence of gastric cancer noted in Japanese subjects and the lower incidence of the cancer seen in Thai and Vietnamese patients.     

Helicobacter pylori CagA Status,Mucosal Oxidative Damage and Gastritis Phenotype: A Potential Pathway to Cancer?

Background. Oxidative DNA damage is associated with Helicobacter pylori infection, atrophy and intestinal metaplasia. H. pylori‐cagA‐positive strains are associated with the highest risk of gastric cancer. Aims. To ascertain whether cagA‐positive H. pylori infection correlates with higher concentrations of 8OHdG and the presence of precancerous changes. Patients and Methods. 118 patients were studied (65M/53F, age 61 ± 14 years). Twelve were H. pylori‐negative. Among the H. pylori‐positive patients, 34 were cagA‐positive and 40 were cagA negative. In 32 patients H. pylori had been eradicated at least 6 months before endoscopic sampling. The phenotype of the gastritis (atrophic compared with nonatrophic, with and without intestinal metaplasia) was scored in biopsy samples obtained from the antrum, corpus, and angularis incisura. In antral biopsy samples, 8‐hydroxydeoxyguanosine was assessed by HPLC (electrochemical detector). CagA status was determined by PCR. Results. The highest scores for both mononuclear inflammation and activity of gastritis were significantly associated with cagA status (p = 0.036 antrum and p = 0.02 corpus). cagA‐positive infection significantly correlated with a higher prevalence of atrophic‐metaplastic lesions (p = 0.04). cagA‐positive patients had higher 8‐hydroxydeoxyguanosine levels than both cagA‐negative and H. pylori‐negative cases (p = 0.01). The 8‐hydroxydeoxyguanosine levels were significantly higher in multifocal atrophic gastritis (p = 0.04). The odds ratio for cagA‐positive patients having 8OHdG levels above a cut‐off calculated on the basis of the ROC curves were 7.12, overall, reaching 11.25 when only patients younger than 50 were considered. Conclusions. cagA‐positive patients were characterized: first, for higher scores for gastritis, activity and atrophic and metaplastic lesions; and second for greater oxidative DNA damage overall, at younger age and in the presence of multifocal atrophy. This setting may represent a cancer‐prone biological context.     

Review: Prevention and management of gastric cancer

Gastric cancer (GC) is still the fifth most frequently diagnosed cancer and the third leading cause of cancer deaths in both sexes worldwide. Although the incidence of GC is predicted to continue declining in a growing number of countries in the future, on a global scale the number of newly diagnosed GC cases will remain high, or increase even further, due to changes in population size and increasing risks observed in younger generations. In a retrospective cohort study, collecting data from the Veterans Health Administration, treatment of Helicobacter pylori infection decreased GC risk only if eradication was successful. In a German case‐control study, among GC patients with autoimmune gastritis, pernicious anemia was associated with earlier detection of GC, which translated into a significantly better 5‐year survival. In an updated meta‐analysis, H. pylori eradication therapy in healthy individuals significantly reduced both GC incidence and mortality from GC with a number needed to treat of 72 and 135, respectively. In Korea, successful H. pylori eradication substantially reduced GC incidence in first‐degree relatives of GC patients as well. A meta‐analysis of four trials including 1,556 patients with resectable GC reported that the patient subgroup tumors with high microsatellite instability undergoing surgery did not benefit from perioperative or adjuvant chemotherapy.     

Preventive effects of Cladosiphon fucoidan against Helicobacter pylori infection in Mongolian gerbils

Background. Recently, the acquisition by Helicobacter pylori of resistance to antibiotics has become a serious problem. Therefore, nonantibiotic substances are required to diminish H. pylori‐induced gastric lesions. In the present study, the effects of Cladosiphon fucoidan were examined in terms of H. pylori attachment to porcine gastric mucin in vitro and Helicobacter pylori‐induced gastritis in vivo. Methods. The inhibitory effect of Cladosiphon fucoidan and other polysaccharides on H. pylori attachment to porcine gastric mucin was assayed in vitro with mucin‐coated microtiter plates. The effect of Cladosiphon fucoidan on H. pylori‐induced gastritis was examined in vivo using Mongolian gerbils. H. pylori‐inoculated gerbils were given fucoidan in drinking water. Six weeks after H. pylori‐inoculation, gerbils were sacrificed for macroscopic and microscopic examination of gastric lesions and counting of viable H. pylori in the gastric mucosa. Results. Cladosiphon fucoidan inhibited the H. pylori attachment to porcine gastric mucin at pH 2.0 and 4.0. Two other sulfated polysaccharides, Fucus fucoidan and dextran sulfate sodium, also inhibited the attachment but only at pH 2.0. Inhibitory effects of these three sulfated polysaccharides were not observed at pH 7.2 and nonsulfated polysaccharides, such as mannan and dextran, exerted no influence at any pH. In the in vivo experiment, the H. pylori‐induced gastritis and the prevalence of H. pylori infected animals were markedly reduced by fucoidan in a dose‐dependent manner, at doses of 0.05 and 0.5% in the drinking water. Conclusion. Cladosiphon fucoidan may deserve particular attention as a safe agent that can prevent H. pylori infection and reduce the risk of associated gastric cancer.     

Effects of aspirin on the development of Helicobacter pylori-induced gastric inflammation and heterotopic proliferative glands in Mongolian gerbils

Background: Helicobacter pylori infection is a major cause of gastritis and gastric carcinoma. Aspirin has anti‐inflammatory and antineoplastic activity. The aim of the present study was to determine the effects of aspirin on H. pylori‐induced gastritis and the development of heterotopic proliferative glands. Methods: H. pylori strain SS1 was inoculated into the stomachs of Mongolian gerbils. Two weeks after inoculation, the animals were fed with the powder diets containing 0 p.p.m. (n = 10), 150 p.p.m. (n = 10), or 500 p.p.m. (n = 10) aspirin. Mongolian gerbils were killed after 36 weeks of infection. Uninfected Mongolian gerbils (n = 10) were used as controls. Histologic changes, epithelial cell proliferation and apoptosis, and prostaglandin E₂ (PGE₂) levels of gastric tissue were determined. Results: H. pylori infection induced gastric inflammation. Administration of aspirin did not change H. pylori‐induced gastritis, but alleviated H. pylori‐induced hyperplasia and the development of heterotopic proliferative glands. Administration of aspirin accelerated H. pylori‐associated apoptosis but decreased H. pylori‐associated cell proliferation. In addition, the increased gastric PGE₂ levels due to H. pylori infection were suppressed by treatment with aspirin, especially at the dose of 500 p.p.m. Conclusions: Aspirin alleviates H. pylori‐induced hyperplasia and the development of heterotopic proliferative glands. Moreover, aspirin increases H. pylori‐induced apoptosis. We demonstrated the antineoplastic activities of aspirin in H. pylori‐related gastric carcinogenesis.     

Gastric microbiota in gastric cancer and precancerous stages: Mechanisms of carcinogenesis and clinical value

Gastric cancer (GC) is a globally important disease. The discovery of Helicobacter pylori (H. pylori) demonstrated that the human stomach is not a sterile environment, and recent advances in molecular biology have led to the detection of large populations of microorganisms in the stomach. A growing number of studies have elucidated differences in the microbiota of patients at various stages of GC development. Evidence from insulin-gastrin transgenic (INS-GAS) and human gastric microbiota-transplanted mouse models have further demonstrated the potential causality of microbiota in the development of GC. To date, H. pylori is still thought to be the strongest risk factor for GC. H. pylori interacts with non-H. pylori commensals and affects the composition of the gastric microbiota. This review provides an overview of the relationship between the gastric microbiota and GC, including the mechanisms of microbe-associated carcinogenesis, the clinical value of the microbiota as a GC biomarker, and the potential of modulating the microbiota for GC prevention or therapy.     

Recruitment of CCR6+ Foxp3+ regulatory gastric infiltrating lymphocytes in Helicobacter pylori gastritis

Helicobacter pylori (H. pylori) infection is associated with an inflammatory response in the gastric mucosa, leading to chronic gastritis, peptic ulcers, and gastric cancer. Increased T‐cell infiltration is found at sites of H. pylori infection. The CCR6⁺ subset of CD4⁺ regulatory T cells (Tregs), a newly characterized subset of Tregs, has been reported to contribute to local immune inhibition. However, whether CCR6⁺ Tregs are present in H. pylori gastritis, and what their relationship is to disease prognosis, remains to be elucidated. In this study, gastric infiltrating lymphocytes were isolated from endoscopic biopsy specimens of H. pylori gastritis patients and analyzed. We found that in gastric infiltrating lymphocytes, CCR6⁺ CD4⁺ CD25^high Tregs, which express high levels of CD45RO, are positively associated with more severe inflammation in gastric mucosa during H. pylori infection. Furthermore, the frequency of CCR6⁺ Tregs in gastric infiltrating lymphocytes, but not CCR6^? Tregs, is significantly increased in inflamed gastric tissues, which is inversely correlated with significantly lower expression of IFN‐γ⁺ CD8⁺ T cells. We also found that the frequency of CCR6⁺ Tregs is positively correlated with the frequency of CD4⁺ IFN‐γ⁺ T cells. In addition, the frequency of CCR6⁺ Tregs, but not that of CCR6^? Tregs, is significantly correlated with increased inflammation in H. pylori gastritis. This study demonstrates that immunosuppression in H. pylori gastritis might be related to the activity of CCR6⁺ Tregs, which could influence disease prognosis.     

Superoxide dismutase from Helicobacter pylori suppresses the production of pro‐inflammatory cytokines during in vivo infection

Background

Helicobacter pylori has undergone considerable adaptation to allow chronic persistence within the gastric environment. While H. pylori‐associated diseases are driven by an excessive inflammation, severe gastritis is detrimental to colonization by this pathogen. Hence, H. pylori has developed strategies to minimize the severity of gastritis it triggers in its host. Superoxide dismutase (SOD) is well known for its role in protecting against oxidative attack; less recognized is its ability to inhibit immunity, shown for SOD from mammalian sources and those of some bacterial species. This study examined whether H. pylori SOD (HpSOD) has the ability to inhibit the host immune response to these bacteria.

Materials and Methods

The ability of recombinant HpSOD to modify the response to LPS was measured using mouse macrophages. A monoclonal antibody against HpSOD was generated and injected into H. pylori‐infected mice.

Results

Addition of HpSOD to cultures of mouse macrophages significantly inhibited the pro‐inflammatory cytokine response to LPS stimulation. A monoclonal antibody was generated that was specific for SOD from H. pylori. When injected into mice infected with H. pylori for 3 months, this antibody was readily detected in both sera and gastric tissues 5 days later. While treatment with anti‐HpSOD had no effect on H. pylori colonization at this time point, it significantly increased the levels of a range of pro‐inflammatory cytokines in the gastric tissues. This did not occur with antibodies against other antioxidant enzymes.

Conclusions

SOD from H. pylori can inhibit the production of pro‐inflammatory cytokine during in vivo infection.     

Helicobacter pylori strain and the pattern of gastritis among first-degree relatives of patients with gastric carcinoma

Background. Relatives of gastric cancer patients have an increased risk of gastric cancer, possibly related to genetically‐related strains of Helicobacter pylori or a common environment. Methods. The pattern of gastritis and H. pylori from gastric cancer patients and their first‐degree relatives were compared using detailed DNA fingerprints and vacA, cagA, and iceA genotyping. Results. Sixteen index cases from Korea, the US, or Colombia and their 38 first‐degree relatives (brothers, sisters, sons and daughters) were studied. No definite, or consistent, relationship between the pattern of gastritis and the relatedness of the H. pylori strain was observed (i.e. relatives could have an identical or a totally different pattern of gastritis regardless if they were infected with identical or highly similar organisms). For example, three elderly siblings of an index case with atrophic pangastritis had identical H. pylori isolates and environments in childhood and yet two had antral predominant nonatrophic gastritis, which is typically associated with duodenal ulcer instead of gastric cancer. Conclusions. The results of this study are not consistent with the hypothesis that specific virulence factors or similar H. pylori strains correlate with a specific histologic pattern or outcome even among those sharing the same environment in childhood.     

Analysis of key genes and signaling pathways involved in Helicobacter pylori‐associated gastric cancer based on The Cancer Genome Atlas database and RNA sequencing data

Background

Helicobacter pylori (H. pylori) infection is associated with the development of gastric cancer, although the mechanism is unclear. Herein, this study aimed to clarify the key genes and signaling pathways involved in H. pylori pathogenesis based on The Cancer Genome Atlas (TCGA) database and RNA sequencing analysis.

Materials and Methods

Forty‐nine gastric cancer samples (16 with H. pylori and 33 without H. pylori) and 35 cancer‐adjacent normal samples from TCGA database were analyzed by bioinformatics. The differentially expressed genes between H. pylori‐positive and H. pylori‐negative patients were verified in 18 gastric cancer (GC) samples (9 with H. pylori and 9 without H. pylori), which were analyzed using RNA sequencing. Survival analysis was carried out to explore associations between the differentially expressed genes and prognosis. Bioinformatics analysis was performed to determine the signaling pathways associated with H. pylori.

Results

The baseline level of clinical features from TCGA database and RNA sequencing showed no differences between the H. pylori‐positive and H. pylori‐negative GC groups (P > 0.05). TP53 was shown to be upregulated in the H. pylori‐positive group in both TCGA database and RNA sequencing data, which also showed higher expression in the GC tissues than in adjacent normal tissues (P < 0.05). CCDC151, CHRNB2, GMPR2, HDGFRP2, and VSTM2L were shown to be downregulated in the H. pylori‐positive group by both TCGA database and RNA sequencing, which also showed lower expression in the GC tissues than in adjacent normal tissues (P < 0.05). GC patients with low expression levels of HDGFRP2 had a poor prognosis (P < 0.05). Thirty‐three signaling pathways and 10 biological processes were found to be positively associated with H. pylori infection (P < 0.05, FDR < 0.05).

Conclusions

These results indicate that some genes (TP53, CCDC151, CHRNB2, GMPR2, HDGFRP2, VSTM2L) and previously unidentified signaling pathways (eg, the Hippo signaling pathway) might play an important role in H. pylori‐associated GC.     

Helicobacter pylori modulation of gastric acid

Helicobacter pylori plays major causative roles in peptic ulcer disease and gastric cancer. Elevated acid secretion in patients with duodenal ulcers (DUs) contributes to duodenal injury, and diminished acid secretion in patients with gastric cancer allows carcinogen-producing bacteria to colonize the stomach. Eradication of H. pylori normalizes acid secretion both in hyper-secreting DU patients and hypo-secreting relatives of gastric cancer patients. Therefore, we and others have asked how H. pylori causes these disparate changes in acid secretion. H. pylori gastritis more or less restricted to the gastric antrum in DU patients is associated with increased acid secretion. This is probably because gastritis increases release of the antral acid-stimulating hormone gastrin and diminished mucosal expression of the inhibitory peptide somatostatin. Bacterial products and inflammatory cytokines including TNFalpha may cause these changes in endocrine function. Gastritis involving the gastric corpus tends to diminish acid secretion, probably because bacterial products and cytokines including IL-1 inhibit parietal cells. Pharmacological inhibition of acid secretion increases corpus gastritis in H. pylori-infected subjects, so it is envisaged that gastric hypo-secretion of any cause might become self-perpetuating. H. pylori-associated mucosal atrophy will also contribute to acid hypo-secretion and is more likely in when the diet is high in salt or lacking in antioxidant vitamins. Data on gastric acid secretion in patients with esophagitis are limited but suggest that acid secretion is normal or slightly diminished. Nevertheless, H. pylori infection may be relevant to the management of esophagitis because: (i) H. pylori infection increases the pH-elevating effect of acid inhibiting drugs; (ii) proton pump inhibitors may increase the tendency of H. pylori to cause atrophic gastritis; and (iii) successful eradication of H. pylori is reported to increase the likelihood of esophagitis developing in patients who had DU disease. Points (ii) and (iii) remain controversial and more work is clearly required to elucidate the relationship between H. pylori, acid secretion, gastric mucosa atrophy and esophagitis.     

Effects of selective cyclooxygenase-2 inhibitor and non-selective NSAIDs on Helicobacter pylori-induced gastritis in Mongolian gerbils

Background. It is still a point of controversy whether Helicobacter pylori‐infected patients are more likely to develop mucosal damage while taking NSADIs. Selective cyclooxygenase (COX‐2) inhibitors may be associated with less severe gastric mucosal damage than conventional NSAIDs, but this association is undefined in H. pylori‐induced gastritis. The aim of this study was to evaluate the effects of selective COX‐2 and nonselective NSAIDs on H. pylori‐induced gastritis. Methods. After intragastric administration of indomethacin, NS‐398 or vehicle alone, once daily for 5 days in H. pylori‐infected and uninfected Mongolian gerbils, we evaluated gastric mucosal damage, inflammatory cell infiltration and prostaglandin E₂ (PGE₂) concentration. We investigated whether H. pylori infection induced the COX‐2 expression. Results. In H. pylori‐uninfected groups, the indomethacin‐treated group showed the highest mucosal damage score and the lowest PGE₂ concentration. There was no difference in mucosal damage scores and PGE₂ concentration between NS‐398 and vehicle‐alone treated group. In H. pylori‐infected groups, there was no difference in mucosal damage scores, irrespective of the type of drugs administered. The indomethacin‐treated group showed the lowest PGE₂ concentration, similar to that of the NS‐398 and vehicle‐alone treated groups, both without H. pylori infection. Gastric neutrophil and monocyte infiltration scores were higher in H. pylori‐infected groups than in uninfected groups. However, there was no difference in these scores according to the type of drugs administered, within H. pylori‐infected or uninfected groups. COX‐2 protein expression was observed in H. pylori‐infected Mongolian gerbils but not in uninfected ones. Conclusions. Our animal study showed that H. pylori infection induced COX‐2 expression and increased prostaglandin concentration. Administration of NSAIDs decreased the prostaglandin concentration, but did not increase mucosal damage in H. pylori‐induced gastritis. Selective COX‐2 inhibitors, instead of conventional NSIADs, had no beneficial effect on preventing mucosal damage in H. pylori‐induced gastritis.     

Case Report: Helicobacter suis Infection in a Pig Veterinarian

This study describes a non‐Helicobacter (H.) pylori Helicobacter (NHPH) infection in a pig veterinarian. The patient suffered from reflux esophagitis and general dyspeptic symptoms and was referred to the hospital for upper gastrointestinal endoscopy. Histologic examination of corpus and antrum biopsies revealed a chronic gastritis. Large spiral‐shaped non‐H. pylori helicobacters could be visualized and were identified as H. suis by PCR. The patient was treated with a triple therapy, consisting of amoxicillin, clarithromycin, and pantoprazole for 10 days. Successful eradication was confirmed after a follow‐up gastrointestinal endoscopy and PCR 10 weeks after treatment. A mild chronic gastritis was, however, still observed at this point in time. This case report associates porcine H. suis strains with gastric disease in humans, thus emphasizing the zoonotic importance of H. suis bacteria from pigs.