The role of the gastrointestinal microbiome in Helicobacter pylori pathogenesis

The discovery of Helicobacter pylori overturned the conventional dogma that the stomach was a sterile organ and that pH values < 4 were capable of sterilizing the stomach. H. pylori are an etiological agent associated with gastritis, hypochlorhydria, duodenal ulcers, and gastric cancer. It is now appreciated that the human stomach supports a bacterial community with possibly 100s of bacterial species that influence stomach homeostasis. Other bacteria colonizing the stomach may also influence H. pylori-associated gastric pathogenesis by creating reactive oxygen and nitrogen species and modulating inflammatory responses. In this review, we summarize the available literature concerning the gastric microbiota in humans, mice, and Mongolian gerbils. We also discuss the gastric perturbations, many involving H. pylori, that facilitate the colonization by bacteria from other compartments of the gastrointestinal tract, and identify risk factors known to affect gastric homeostasis that contribute to changes in the microbiota.     

Risk of gastric cancer in Helicobacter pylori infection in a 15-year follow-up

Objective: We investigated the risk of gastric cancer among men with Helicobacter pylori (H. pylori) infection or atrophic gastritis (AG) in a 15-year follow-up.

Materials and methods: Study population consists of 12,016 men aged 50–65 years at the beginning of the follow-up in 1994–1996. Serum levels of pepsinogen I (SPGI) and antibodies (IgG) to H. pylori (HpAb) were assayed from serums collected in 1994–1996. Incidence of gastric cancer in the study population was assessed in follow-up from 1994 to 2011 by data from the nationwide cancer registry. Based on SPGI and HpAb values, standardized incidence ratios (SIRs) of gastric cancer were calculated in three subgroups, that is, in those with a healthy stomach, those with H. pylori infection but without AG and those with AG. Risk ratios (RR) of gastric cancer were calculated using SIR of subgroups.

Results: During 15 years, seven gastric cancers appeared per 79,928 person years among men with healthy stomachs, 50 cancers per 92,533 person years in men with H. pylori infection but without AG, and 8 per 8658 person years in men with AG. Risk ratio (RR) of stomach cancer in men with H. pylori infection was 5.8 (95%CI: 2.7–15.3) compared to men with healthy stomachs, and 9.1 (95%CI: 2.9–30.0) in men with AG. There were no differences in cancer risk between cardia and distal stomach.

Conclusions: Risk of gastric cancer is low in men with healthy stomachs. It is significantly increased in those with H. pylori infection and more in those with AG.     

Association of the interleukin-1 β genetic polymorphism and gastric cancer risk in Japanese

Background. Helicobacter pylori infection is associated not only with gastroduodenal ulcers but with the development of gastric cancer. Interleukin-1 β (IL-1 β) is a potent inhibitor of gastric secretion. The −31 C-to-T base transition in the intron of this gene has been reported to be involved in carcinogenic changes within the stomach, especially in H. pylori-infected individuals. Methods. In this study, the −511 T-to-C polymorphism in the IL-1 β gene was investigated in 669 patients with gastric diseases. Results. The allelic frequencies of the C allele, which indicates low acid secretion and is a component of a supposedly high-risk genotype for gastric cancer, were 0.48 in H. pylori-negative noncancer controls, 0.52 in H. pylori-positive noncancer controls, 0.57 in subjects with chronic active gastritis (CAG) with H. pylori, 0.58 in subjects with intestinal metaplasia (IM) or CAG without H. pylori, and 0.52 in gastric cancer patients. Significant differences among the groups were observed between the IM or CAG without H. pylori group and the gastric cancer group and between the IM or CAG without H. pylori group and the H. pylori-negative noncancer control group (P < 0.05). Conclusions. The IL-1 β−511 genetic polymorphism was not associated with gastric cancer in a multistep carcinogenesis model. However, in view of the results for the IM or CAG without H. pylori group, the presence of the C allele may also indicate a risk of mucosal atrophy of the stomach in the Japanese population. Received: February 20, 2001 / Accepted: July 6, 2001     

Participation of microbiota in the development of gastric cancer

There are a large number of bacteria inhabiting the human body,which provide benefits for the health.Alterations of microbiota participate in the pathogenesis of diseases.The gastric microbiota consists of bacteria from seven to eleven phyla,predominantly Proteobacteria,Firmicutes,Bacteroidetes,Actinobacteria and Fusobacteria.Intrusion by Helicobacter pylori(H.pylori)does not remarkably interrupt the composition and structure of the gastric microbiota.Absence of bacterial commensal from the stomach delays the onset of H.pylori-induced gastric cancer,while presence of artificial microbiota accelerates the carcinogenesis.Altered gastric microbiota may increase the production of N-nitroso compounds,promoting the development of gastric cancer.Further investigation of the carcinogenic mechanisms of microbiota would benefit for the prevention and management of gastric cancer.     

Epidemiology of gastric cancer in relation to diet and Helicobacter pylori infection

Abstract Gastric cancer is the second most common fatal malignancy in the world. In China, gastric cancer is now the second most common malignancy, while in Hong Kong, the mortality rate ranked fourth among all cancers in 1995. Dietary factors in gastric carcinogenesis came mostly from case-control studies. N-Nitroso compounds from dietary sources such as preserved, smoked and salted foods were found to be associated with gastric cancer. ß-Carotene, selenium and α-tocopherol have been shown in an intervention study to be favourable in the reduction of stomach cancer mortality. Fruits and vegetables showed the most consistent results of inverse association with gastric cancer. Dietary salt intake in preserved or salted foods is also shown to be associated with gastric cancer. Tea drinking, especially green tea, has a protective effect against gastric cancer as shown in some studies. Prospective case-control studies of the association between Helicobacter pylori infection and the subsequent development of gastric cancer showed that the odds ratio ranged from 2.8 to 6.0. However, results of similar case-control studies in countries with a high frequency of gastric cancer are controversial. Infection with H. pylori leads to changes in the vitamin C content of gastric juice, reactive oxygen metabolites, epithelial cell proliferation and apoptosis. Recently, CagA-positive strains were found to be associated with gastric cancer and also duodenal ulcers. The exact role of H. pylori in gastric carcinogenesis is still under investigation. Large-scale intervention studies are underway to examine dietary supplementation, H. pylori infection and gastric cancer. Helicobacter pylori eradication for gastric cancer prevention is being conducted in China and other parts of the world. In high-risk areas, for example in China, a combination approach including H. pylori eradication and dietary supplementation may be necessary.     

Association between Helicobacter pylori infection and the risk of gastric cancer in the Korean population: prospective case-controlled study

Background. Gastric cancer is still the most common malignant tumor in Koreans. Although many reports have supported the association of Helicobacter pylori infection and the development of gastric cancer, few studies have been adjusted by variable factors such as age, sex, education, and economic status. Furthermore, most results from areas with a high incidence of gastric cancer, such as China and Korea, have failed to document any relationship between H. pylori infection and gastric cancer. We conducted a prospective case-controlled study, with controls matched for and adjusted by age, sex, education, and economic status, to evaluate the causal relationship between H. pylori infection and gastric cancer in Korean people. Methods. From March 1997 to October 1998, 136 consecutive patients with gastric cancer, diagnosed by endoscopic histology, and 136 age- and sex-matched control subjects, confirmed to be free of gastric cancer by endoscopy during the same period, were enrolled in the study. The presence of H. pylori infection was determined by enzyme immunoassay (EIA) serology test. Results. Seventy-two of the 136 gastric cancer patients (53%) were positive for H. pylori infection and 54 of the 136 control subjects (40%) were positive for H. pylori infection. The odds ratio (OR), adjusted by variable risk factors, such as age, sex, education, and economic status, for gastric cancer in H. pylori-infected patients was 1.82 (95% confidence internal [CI], 1.10–3.00; P = 0.019). The age- and sex-matched OR by conditional logistic regression was 1.6 (95% CI, 1.01–2.53; P = 0.043). Conclusions. H. pylori infection may be one of the important risk factors for the development of gastric cancer in Korea, an area of high prevalence of H. pylori infection and a high incidence of gastric cancer. Received: September 27, 2000 / Accepted: May 25, 2001     

Association between peroxisome proliferator-activated receptor-γ gene polymorphism (Pro12Ala) and Helicobacter pylori infection in gastric carcinogenesis

Abstract

Objective. Helicobacter pylori infection is accompanied by inflammatory processes leading to peptic ulcer and gastric cancer in the minority of infected individuals. The interaction between H. pylori virulence factors, host defense mechanisms and environmental factors determine the outcome of clinical manifestations. One of the host factors involved in the processes of inflammation and carcinogenesis is the peroxisome proliferator-activated receptor-γ (PPAR-γ) molecule. The present case–control study aimed to determine polymorphism of PPAR-γ gene and its association with H. pylori infection and gastrointestinal diseases (peptic ulcer and non-cardia gastric cancer) in Iranian patients. Materials and methods. One hundred and fifty-five patients with upper gastrointestinal diseases (76 peptic ulcer and 79 non-cardia gastric cancer) and 152 matched controls were genotyped for PPAR-γ gene polymorphism (Pro12Ala) by the PCR–RFLP method. Infection with H. pylori was confirmed by histology, the rapid urease test (RUT) and ELISA assay (IgG anti-H. pylori). Results. The frequency of PPAR-γ G (Ala 12) allele was significantly higher in H. pylori positive patients with non-cardia gastric cancer than in controls (22.8% vs. 3.9%, p = 0.027; OR = 3.28; 95% CI = 1.21–8.89), But there was no significant difference without infection (p = 0.7). Moreover, the PPAR-γ polymorphism was not associated with peptic ulcer in the presence or absence of H. pylori infection. Conclusion. Our results indicated PPAR-γ G allele may be an important contributor to non-cardia gastric cancer in Iranian H. pylori infected patients.     

Helicobacter pylori and the gastric microbiota

The human microbiota along the gastrointestinal tract is currently extensively studied and a number of studies focuses on elucidating the association between a more or less diverse intestinal microbial community and health and disease. The human stomach is considered to be exclusively inhabited by Helicobacter pylori and further lacks a colonizing non-H. pylori bacterial flora due to the acidic environment. However, recently a limited number of studies using molecular-based methods have provided a broader picture of the stomach microbiota. The question is whether changes in gastric pH or antibiotic treatment can lead to significant shifts in the stomach microbiota that may be involved in disease development such as gastric cancer.     

The relationship between gastric microbiota and gastric disease

Traditionally, the stomach was believed to be a sterile organ unsuitable for microbiota growth. However, the discovery of H. pylori subverted this conception. With the development of molecular techniques, an abundance of microbiota of great diversity was found in the stomach. In addition, various lines of evidence suggest that the gastric microbiota plays a critical role in the development and progression of the gastric disease.The gastrointestinal microbiome plays an important role in various physiologic and pathologic processes.     

Helicobacter pylori and gastric cancer: Indian enigma

Helicobacter pylori(H. pylori) is a gram negative microaerophilic bacterium which resides in the mucous linings of the stomach. It has been implicated in the causation of various gastric disorders including gastric cancer. The geographical distribution and etiology of gastric cancer differ widely in different geographical regions and H. pylori, despite being labeled as a grade Ⅰ carcinogen, has not been found to be associated with gastric cancer in many areas. Studies in Asian countries such as Thailand, India, Bangladesh, Pakistan, Iran, Saudi Arabian countries, Israel and Malaysia, have reported a high frequency of H. pylori infection co-existing with a low incidence of gastric cancer. In India, a difference in the prevalence of H. pylori infection and gastric cancer has been noted even in different regions of the country leading to a puzzle when attempting to find the causes of these variations. This puzzle of H. pylori distribution and gastric cancer epidemiology is known as the Indian enigma. In this review we have attempted to explain the Indian enigma using evidence from various Indian studies and from around the globe. This review covers aspects of epidemiology, the various biological strains present in different parts of the country and within individuals, the status of different H. pylori-related diseases and the molecular pathogenesis of the bacterium.     

The expression level of TRAF1 in human gastric mucosa is related to virulence genotypes of Helicobacter pylori

Abstract

Objective. To investigate the expression level of tumor necrosis factor receptor-associated factor 1 (TRAF1) in gastric mucosa tissue in patients infected with Helicobacter pylori (H. pylori) and to analyze the relationship between TRAF1 expression and H. pylori virulence. Methods. Gastric tissue samples were collected from patients with gastritis, atrophic gastritis, intestinal metaplasia with atypical hyperplasia, and gastric cancer. The expression level of TRAF1 in each group was analyzed by real-time polymerase chain reaction (PCR) and Western blot analysis. Virulence genotypes of H. pylori were determined by PCR. Results. Significant differences in TRAF1 mRNA levels were observed between the gastritis and gastric cancer groups, and the atrophic gastritis and gastric cancer groups (p < 0.05). Moreover, significant differences in TRAF1 protein levels were observed between the gastritis and intestinal metaplasia with atypical hyperplasia groups, between the gastritis and gastric cancer groups, and between the atrophic gastritis and gastric cancer groups (all p < 0.05). The virulence genotypes of cytotoxin-associated gene A (cagA), vacAs1, and vacAm1 were more frequent in the TRAF1 high-level group than in the TRAF1 low-level group (p < 0.05). Conclusion. Higher TARF1 expression level is associated with infection by CagA⁺/vacAs1⁺/m1⁺ virulent H. pylori strains and may promote the proliferation of gastric mucosal cells and induce gastric cancer.     

Novel role of toll-like receptors in Helicobacter pylori-induced gastric malignancy

Helicobacter pylori(H.pylori)infects the human stomach during infancy and develops into chronic activeinflammation.The majority of H.pylori tend to colonize within the mucous gel layer of the stomach.Thestomach lacks its own immune function,thus innateimmunity as the first line of defense is vital for specificimmunity against H.pylori.We review recent discoveries in the pathophysiologic roles of toll-like receptors(TLRs),mainly TLR2 and TLR4,in H.pylori-induced inflammation.In addition,the TLR pathways activated byH.pylori-induced inflammation have been shown to beclosely associated not only with gastric carcinogenesis,but also with formation of the tumor microenvironmentthrough the production of pro-inflammatory cytokines,chemokines,and reactive oxygen species.Althoughthe correlation between single nucleotide polymorphisms of TLRs and gastric cancer risk remains unclear,a recent study demonstrated that STAT3-driven upregulation of TLR2 might promote gastric tumorigenesis independent of inflammation.Further research onthe regulation of TLRs in H.pylori-associated gastriccarcinogenesis will uncover diagnostic/predictive biomarkers and therapeutic targets for gastric cancer.     

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.     

Relationship of Helicobacter pylori to Bcl-2 family expression, DNA content, and pathological characteristics of gastric cancer

Background. Despite the fact that the association of Helicobacter pylori with an increased risk of gastric cancer has been well documented, the exact mechanisms of this association have not been fully elucidated. Scarce data on H. pylori infection and its relationship with the different pathological characteristics are available in Egypt. Aim of the Study. The rationale of the present study was to determine the prevalence of H. pylori in a group of gastric cancer patients and to analyze the relationship between H. pylori infection with the different pathological characteristics including the types of gastric cancer and tumor location within the stomach, in addition, to investigate the Bcl-2 and Bax expressions along with DNA flow cytometric analysis in the gastric cancer patients with and without H. pylori infection. Methods. Samples were obtained from 66 consecutive patients with gastric cancer (46 males and 20 females). The youngest patient was 20 yr old, the oldest 76 yr with mean age of 52.8 yr. The samples were subjected for histopathological characterization, H. pylori detection, DNA flow cytometric analysis, and Bcl-2 and Bax expressions detection, in addition to apoptosis analysis. Results. The obtained results showed that the H. pylori infection was found in 38/66 (57.6%) [Odds ratio=1.357 with 95% confidence interval (CI) 0.84–2.2]. There was a statistical significance for Bcl-2, Bax, and apoptosis with H. pylori status (p=0.009, 0.008, 0.032, respectively). On the other hand, There was a statistical significance for H. pylori infection with the disease grade (p=0.015) and lymph node metastasis (p=0.05). No statistical significance was found between H. pylori status with the patients’ age, gender, tumor site, tumor type, depth of invasion, and stromal reaction. Conclusions. These data may indicate that the H. pylori infection not only contributes in the disease formation through the apoptosis dysregulation but also takes a part in the disease dissemination and progression. In addition, it may reflect a biologic, pathogenic, and ethnic background affecting the relationship of H. pylori infection to gastric cancer in the Egyptian patients. A high rate of smoking in Egypt and the diet are important factors that may affect such background. Further studies are warranted.     

The eradication of Helicobacter pylori to prevent gastric cancer: a critical appraisal

Introduction: Gastric cancer is one of the top causes of cancer-related death worldwide. How to eliminate gastric cancer is an urgent public-health issue.

Areas covered: In this review, we present up-to-date results of studies on gastric cancer prevention through the eradication of Helicobacter pylori and discuss strategies and obstacles for the implementation of population-wide screening and treatment of this pathogen to prevent gastric cancer.

Expert commentary: Gastric cancer is an inflammation-associated cancer with multistep carcinogenesis. The process consists of H. pylori infection, ongoing inflammation, development of metaplastic epithelia and genetic instability eventuating in gastric cancer. H. pylori infection is critical for development of the disease and studies have consistently shown that H. pylori eradication results in a reduction in (a) gastric mucosal inflammation, (b) progression of histologic damage, (c) risk of peptic ulcers and ulcer recurrence, and (d) risk of gastric cancer. Compared with a large number of clinical trials evaluating chemopreventive approaches, studies of population-wide screening, and eradication of H. pylori have only recently begun and only in high-risk populations. To eliminate gastric cancer requires information on how to implement an effective program for screening and treatment of H. pylori taking into consideration the other health priorities in any specific population.     

Meta-analysis of the relationship between Helicobacter pylori seropositivity and gastric cancer

Background & Aims: Reports in the literature regarding the relationship of Helicobacter pylori infection to gastric cancer are conflicting. The aim of this study was to identify the source of heterogeneity between studies. Methods: Meta-analysis of cohort or case-control studies with age- and/or sex-matched controls, providing raw data on H. pylori infection detected by serology, was used. Results: A fully recursive literature search identified 19 qualified studies with 2491 patients and 3959 controls. Test for homogeneity found a significant difference in odds ratio between patients with early and advanced gastric cancer (6.35 vs. 2.13; P = 0.01), patients with cardiac and noncardiac gastric cancer (1.23 vs. 3.08; P = 0.003), and population- and hospital-based controls (2.11 vs. 1.49; P < 0.001). The summary odds ratio for gastric cancer in H. pylori–infected patients is 1.92 (95% confidence interval [CI], 1.32–2.78), 2.24 (95% CI, 1.15–4.4), and 1.81 (95% CI, 1.16–2.84) for all studies, cohort, and case-control studies, respectively. H. pylori–infected younger patients have a higher relative risk for gastric cancer than older patients with odds ratios decreasing from 9.29 at age ≤29 years to 1.05 at age ≥70 years. H. pylori infection is equally associated with the intestinal or diffuse type of gastric cancer. Conclusions:H. pylori infection is a risk factor for gastric cancer. The heterogeneity of reported results is caused by differences in the selection of controls, patient age, and the site and stage of gastric cancer.GASTROENTEROLOGY 1998;114:1169-1179     

H. pylori and its modulation of gastrointestinal microbiota

The discovery of Helicobacter pylori (H. pylori) changed the dogma of the stomach as a sterile organ. H. pylori is an obligate pathogen in the human stomach and recognized as a definite carcinogen. Extensive research on the interaction of this bacterium with the gastric mucosa has been performed over the past three decades. The development of new nucleotide sequencing techniques and new biocomputational tools has opened the field for studying the diversity and complexity of the microbiome in the gastrointestinal tract independently of cultural methods. These techniques allow to better characterize further gastric bacteria. However, the differentiation of alive resident and transient microbes requires an analysis beyond the pure detection of bacterial genomic material applying a combination with metabolomic analyses. Currently, the interaction of gastric microbiota with each other, with H. pylori and with the host is addressed by extensive research. This review gives a concise overview on current knowledge on this topic.     

Helicobacter pylori‐negative gastric cancer: Characteristics and endoscopic findings

Helicobacter pylori (H. pylori) leads to chronic gastritis and eventually causes gastric cancer. The prevalence of H. pylori infection is gradually decreasing with improvement of living conditions and eradication therapy. However, some reports have described cases of H. pylori‐negative gastric cancers (HpNGC), and the prevalence was 0.42–5.4% of all gastric cancers. Diagnostic criteria of HpNGC vary among the different reports; thus, they have not yet been definitively established. We recommend negative findings in two or more methods that include endoscopic or pathological findings or serum pepsinogen test, and negative urease breath test or serum immunoglobulin G test and no eradication history the minimum criteria for diagnosis of HpNGC. The etiology of gastric cancers, excluding H. pylori infection, is known to be associated with several factors including lifestyle, viral infection, autoimmune disorder and germline mutations, but the main causal factor of HpNGC is still unclear. Regarding the characteristics of HpNGC, the undifferentiated type (UD‐type) is more frequent than the differentiated type (D‐type). The UD‐type is mainly signet ring‐cell carcinoma that presents as a discolored lesion in the lower or middle part of the stomach in relatively young patients. The gross type is flat or depressed. The D‐type is mainly gastric adenocarcinoma of the fundic gland type that presents as a submucosal tumor‐like or flat or depressed lesion in the middle and upper part of the stomach in relatively older patients. Early detection of HpNGC enables minimally invasive treatment which preserves the patient's quality of life. Endoscopists should fully understand the characteristics and endoscopic findings of HpNGC.     

Helicobacter pylori infection and the risk of gastric cancer among the Korean population

Helicobacter pylori infection has been associated with chronic atrophic gastritis, a precursor of gastric cancer. We conducted a prospective, case-controlled study to investigate whether H. pylori infection increases the risk of gastric cancer in Korean people with a high risk of gastric cancer. We enrolled 160 gastric cancer patients who were confirmed by endoscopic biopsy during 1994 and 160 age-matched control subjects with non-ulcer dyspepsia were compared to document the relationship between H. pylori infection and gastric cancer. The presence of H. pylori infection was determined by the rapid urease test and/or histology by Wright-Giemsa staining. The overall presence of H. pylori infection was 60% in gastric cancer patients and 51.9% in age-matched control subjects (odds ratio 1.39; 95% confidence interval 0.894–2.17; P= 0.143). Carcinomas of cardia, body and antrum were not associated with H. pylori infection (odds ratio 1.43, 1.69 and 1.29, respectively; 95% confidence interval, 0.271–7.52, 0.787–3.62 and 0.689–2.43, respectively; P= 0.178, 0.177 and 0.642, respectively) nor was the intestinal or diffuse type of cancer (odds ratio 1.39 and 1.40, respectively; 95% confidence interval 0.791–2.45 and 0.681–2.87, respectively; P= 0.250 and 0.835, respectively). Gender was not a risk for gastric cancer. In contrast to previous studies, these results do not provide evidence of H. pylori infection for gastric carcinogenesis in Korea.