The gastric microbial community,Helicobacter pylori colonization,and disease

Long thought to be a sterile habitat, the stomach contains a diverse and unique community of bacteria. One particular inhabitant, Helicobacter pylori, colonizes half of the world’s human population and establishes a decades-long infection that can be asymptomatic, pathogenic, or even beneficial for the host. Many host and bacterial factors are known to influence an individual’s risk of gastric disease, but another potentially important determinant has recently come to light: the host microbiota. Although it is unclear to what extent H. pylori infection perturbs the established gastric microbial community, and H. pylori colonization seems generally resistant to disturbances in the host microbiota, it can modulate H. pylori pathogenicity. Interactions between H. pylori and bacteria at non-gastric sites are likely indirect—via programming of the pro-inflammatory vs. regulatory T lymphocytes—which may have a significant impact on human health.     

Different MicroRNA Expression Levels in Gastric Cancer Depending on Helicobacter pylori Infection

Background/AimsThis study was conducted to identify microRNAs (miRNAs) that are differentially expressed in Helicobacter pylori-infected patients with an intestinal type of gastric cancer using miRNA microarray and to confirm the candidate miRNA expression levels.MethodsTotal RNA was extracted from the cancerous and noncancerous regions of formalin-fixed, paraffin-embedded tissues of H. pylori-positive (n=8) or H. pylori-negative (n=8) patients with an intestinal type of gastric cancer. RNA expression was analyzed using a 3,523 miRNA profiling microarray based on the Sanger miRBase. Validation analysis was performed using TaqMan miRNA assays.ResultsA total of 219 miRNAs in the aberrant miRNA profiles across the miRNA microarray showed at least a 2-fold change differential expression in H. pylori-positive and H. pylori-negative cancer tissues. After candidate miRNAs were selected using online miRNA databases, TaqMan miRNA assays confirmed that three miRNAs (miR-99b-3p, miR-564, and miR-638) were significantly increased in three H. pylori-positive cancer tissues compared to the H. pylori-negative cancer tissues. Additionally, four miRNAs (miR-204-5p, miR-338-5p, miR-375, and miR-548c-3p) were significantly increased in H. pylori-negative cancer tissues compared to H. pylori-positive cancer tissues.ConclusionsmiRNA expression in the intestinal type of H. pylori infection-dependent gastric cancer suggests that different gastric cancer pathogenesis mechanisms could exist between H. pylori-positive and H. pylori-negative gastric cancer. Additional functional studies are required.     

Bacterial flora concurrent with Helicobacter pylori in the stomach of patients with upper gastrointestinal diseases

AIM: To investigate the non-Helicobacter pylori (H. pylori) bacterial flora concurrent with H. pylori infection.METHODS: A total of 103 gastric biopsy specimens from H. pylori positive patients were selected for bacterial culture. All the non-H. pylori bacterial isolates were identified by matrix-assisted laser desorption ionization time-of-flight mass spectrometry (MALDI-TOF MS).RESULTS: A total of 201 non-H. pylori bacterial isolates were cultivated from 67 (65.0%) of the 103 gastric samples, including 153 isolates identified successfully at species level and 48 at genus level by MALDI-TOF MS. The dominant species were Streptococcus, Neisseria, Rothia and Staphylococcus, which differed from the predominantly acid resistant species reported previously in healthy volunteers. The prevalence of non-H. pylori bacteria was higher in non-ulcer dyspepsia group than in gastric ulcer group (100% vs 42.9%, P < 0.001). Six bacterial species with urease activity (Staphylococcus epidermidis, Staphylococcus warneri, Staphylococcus capitis, Staphylococcus aureus, Brevibacterium spp. and Klebsiella pneumoniae) were also isolated.CONCLUSION: There is a high prevalence of the non-H. pylori bacteria concurrent with H. pylori infection, and the non-H. pylori bacteria may also play important as-yet-undiscovered roles in the pathogenesis of stomach disorders.     

Efficacy of Helicobacter pylori eradication for the prevention of metachronous gastric cancer after endoscopic resection for early gastric cancer

Helicobacter pylori(H.pylori)plays an important role in gastric carcinogenesis,as the majority of gastric cancers develop from H.pylori-infected gastric mucosa.The rate of early gastric cancer diagnosis has increased in Japan and Korea,where H.pylori infection and gastric cancer are highly prevalent.Early intestinal-type gastric cancer without concomitant lymph node metastasis is usually treated by endoscopic resection.Secondary metachronous gastric cancers often develop because atrophic mucosa left untreated after endoscopic treatment confers a high risk of gastric cancer.The efficacy of H.pylori eradication for the prevention of metachronous gastric cancer remains controversial.However,in patients who undergo endoscopic resection of early gastric cancer,H.pylori eradication is recommended to suppress or delay metachronous gastric cancer.Careful and regularly scheduled endoscopy should be performed to detect minute metachronous gastric cancer after endoscopic resection.     

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.     

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.     

Helicobacter heilmannii sensu stricto-related gastric ulcers:A case report

A spiral bacterium(SH9),morphologically different from Helicobacter pylori(H.pylori),was found in a 62-yearold woman’s gastric mucosa.Gastroscopic examination revealed multiple gastric ulcers near the pyloric ring;mapping gastric biopsy showed mild mononuclear infiltration with large lymphoid follicles in the antrum,without corpus atrophy.Urea breath test and H.pylori culture were negative,but Giemsa staining of biopsies revealed tightly coiled bacteria that immunostained with anti-H.pylori antibody.Sequencing of SH9 16S rRNA and the partial urease A and B subunit genes showed that the former sequence had highest similarity(99%;1302/1315 bp)to Helicobacter heilmannii(H.heilmannii)sensu stricto(H.heilmannii s.s.)BC1 obtained from a bobcat,while the latter sequence confirmed highest similarity(98.3%;1467/1493 bp)to H.heilmannii s.s.HU2 obtained from a human.The patient was diagnosed with multiple gastric ulcers associated with H.heilmannii s.s.infection.After triple therapy(amoxicillin,clarithromycin,and lansoprazole)with regimen for eradicating H.pylori,gastroscopy showed ulcer improvement and no H.heilmannii s.s.upon biopsy.     

Management of Helicobacter pylori infection after gastric surgery

The Maastricht IV/Florence Consensus Report and the Second Asia-Pacific Consensus Guidelines strongly recommend eradication of Helicobacter pylori(H.pylori)in patients with previous gastric neoplasia who have undergone gastric surgery.However,the guidelines do not mention optimal timing,eradication regimens,diagnostic tools,and follow-up strategies for patients undergoing gastrectomy and do not indicate if eradication of H.pylori reduces the risk of marginal ulcer or stump cancer in the residual stomach after gastrectomy.The purpose of this review is to provide an update which may help physicians to properly manage H.pylori infection in patients who have undergone gastric surgery.This review focuses on(1)the microenvironment change in the stomach after gastrectomy;(2)the phenomenon of spontaneous clearance of H.pylori after gastrectomy;(3)the effects of H.pylori on gastric atrophy and intestinal metaplasia after gastrectomy;(4)incidence and clinical features of ulcers developing after gastrectomy;(5)does eradication of H.pylori reduce the risk of gastric stump cancer in the residual stomach?(6)does eradication of H.pylori reduce the risk of secondary metachronous gastric cancer in the residual stomach?and(7)optimal timing and regimens for H.pylori eradication,diagnostic tools and follow-up strategies for patients undergoing gastrectomy.     

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.     

Carcinogenic Helicobacter pylori in gastric pre-cancer and cancer lesions: Association with tobacco-chewing

AIM:To investigate the low gastric cancer incidence rate relative to the highly prevalent Helicobacter pylori(H.pylori)infection;data relevant to H.pylori infection during gastric carcinogenesis in Indian patients is currently lacking.METHODS:The present study examines the prevalence of H.pylori infection in DNA derived from 156endoscopic gastric biopsies of different disease groups that represent gastric pre-cancer[intestinal metaplasia(n=15),dysplasia(n=15)],cancer[diffuse adenocarcinoma(n=44),intestinal adenocarcinoma(n=21)],and symptomatic but histopathologically-normal controls(n=61).This was done by generic ureC polymerase chain reaction(PCR)and cagA-specific PCR that could specifically identify the carcinogenic H.pylori strain.RESULTS:Our analysis showed the presence of H.pylori infection in 61%of symptomatic histopathologically-normal individuals,however only 34%of control tissues were harboring the cagA+H.pylori strain.A similar proportion of H.pylori infection(52%)and cagA(26%)positivity was observed in the tumor tissue of the gastric cancer group.In comparison,H.pylori infection(90%)and cagA positivity(73%)were the highest in gastric pre-cancer lesions.In relation to tobacco and alcohol abuse,H.pylori infection showed an association with tobacco chewing,whereas we did not observe any association between tobacco smoking or alcohol abuse with prevalence of H.pylori infection in the tissue of any of the patient groups studied.CONCLUSION:High incidence of H.pylori infection and carcinogenic cagA positive strain in pre-cancer lesions during gastric carcinogenesis may be associated     

Factors that mediate colonization of the human stomach by Helicobacter pylori

Helicobacter pylori(H.pylori)colonizes the stomach of humans and causes chronic infection.The majority of bacteria live in the mucus layer overlying the gastric epithelial cells and only a small proportion of bacteria are found interacting with the epithelial cells.The bacteria living in the gastric mucus may act as a reservoir of infection for the underlying cells which is essential for the development of disease.Colonization of gastric mucus is likely to be key to the establishment of chronic infection.How H.pylori manages to colonise and survive in the hostile environment of the human stomach and avoid removal by mucus flow and killing by gastric acid is the subject of this review.We also discuss how bacterial and host factors may together go some way to explaining the susceptibility to colonization and the outcome of infection in different individuals.H.pylori infection of the gastric mucosa has become a paradigm for chronic infection.Understanding of why H.pylori is such a successful pathogen may help us understand how other bacterial species colonise mucosal surfaces and cause disease.     

Immune evasion strategies used by Helicobacter pylori

Helicobacter pylori (H. pylori) is perhaps the most ubiquitous and successful human pathogen, since it colonizes the stomach of more than half of humankind. Infection with this bacterium is commonly acquired during childhood. Once infected, people carry the bacteria for decades or even for life, if not treated. Persistent infection with this pathogen causes gastritis, peptic ulcer disease and is also strongly associated with the development of gastric cancer. Despite induction of innate and adaptive immune responses in the infected individual, the host is unable to clear the bacteria. One widely accepted hallmark of H. pylori is that it successfully and stealthily evades host defense mechanisms. Though the gastric mucosa is well protected against infection, H. pylori is able to reside under the mucus, attach to gastric epithelial cells and cause persistent infection by evading immune responses mediated by host. In this review, we discuss how H. pylori avoids innate and acquired immune response elements, uses gastric epithelial cells as mediators to manipulate host T cell responses and uses virulence factors to avoid adaptive immune responses by T cells to establish a persistent infection. We also discuss in this review how the genetic diversity of this pathogen helps for its survival.     

Helicobacter pylori-negative gastric mucosa-associated lymphoid tissue lymphomas: A review

Since Isaacson and Wright first reported on the extranodal marginal zone B-cell lymphoma of the stomach in 1983,following studies have clarified many aspects of this disease.We now know that the stomach is the most affected organ by this disease,and approximately90% of gastric mucosa-associated lymphoid tissue(MALT) lymphomas are related to Helicobacter pylori(H.pylori) infection.This implies that approximately 10% of gastric MALT lymphomas occur independent of H.pylori infection.The pathogenesis of these H.pylori-negative gastric MALT lymphomas remains unclear.To date,there have been several speculations.One possibility is that genetic alterations result in nuclear factor-kappa B(NF-κB) activation.Among these alterations,t(11;18)(q21;q21) is more frequently observed in H.pylori-negative gastric MALT lymphomas,and such translocation results in the synthesis of fusion protein API2-MALT1,which causes canonical and noncanonical NF-κB activation.Another possibility is infection with bacteria other than H.pylori.This could explain why H.pylori eradication therapy can cure some proportions of H.pylori-negative gastric MALT lymphoma patients,although the bacteria responsible for MALT lymphomagenesis are yet to be defined.Recent advances in endoscopy suggest magnifying endoscopy with narrow band imaging as a useful tool for both detecting gastric MALT lymphoma lesions and judging the response to treatment.A certain proportion of H.pylori-negative gastric MALT lymphoma patients respond to eradication therapy; hence,H.pylori eradication therapy could be considered as a first-line treatment for gastric MALT lymphomas regardless of their H.pylori infection status.     

Relatedness of Helicobacter pylori populations to gastric carcinogenesis

Helicobacter pylori (H. pylori) is a Gram-negative bacterium that infects half of the human population. The infection is associated with chronic inflammation of the gastric mucosa and peptic ulcers. It is also a major risk factor for gastric cancer. Phylogenetic analysis of global strains reveals there are seven populations of H. pylori, including hpAfrica1, hpAfrica2, hpEastAsia, hpEurope, hpNEAfrica, hpAsia2 and hpSahul. These populations are consistent with their geographical origins, and possibly result from geographical separation of the bacterium leading to reduced bacterial recombination in some populations. For each population, H. pylori has evolved to possess genomic contents distinguishable from others. The hpEurope population is distinct in that it has the largest genome of 1.65 mbp on average, and the highest number of coding sequences. This confers its competitive advantage over other populations but at the cost of a lower infection rate. The large genomic size could be a cause of the frequent occurrence of the deletion of the cag pathogenicity island in H. pylori strains from hpEurope. The incidence of gastric cancer varies among different geographical regions. This can be attributed in part to different rates of infection of H. pylori. Recent studies found that different populations of H. pylori vary in their carcinogenic potential and contribute to the variation in incidence of gastric cancer among geographical regions. This could be related to the ancestral origin of H. pylori. Further studies are indicated to investigate the bacterial factors contributing to differential virulence and their influence on the clinical features in infected individuals.     

Vacuoles of Candida yeast as a specialized niche for Helicobacter pylori

Helicobacter pylori(H.pylori)are resistant to hostile gastric environments and antibiotic therapy,reflecting the possibility that they are protected by an ecological niche,such as inside the vacuoles of human epithelial and immune cells.Candida yeast may also provide such an alternative niche,as fluorescently labeled H.pylori were observed as fast-moving and viable bacterium-like bodies inside the vacuoles of gastric,oral,vaginal and foodborne Candida yeasts.In addition,H.pylori-specific genes and proteins were detected in samples extracted from these yeasts.The H.pylori present within these yeasts produce peroxiredoxin and thiol peroxidase,providing the ability to detoxify oxygen metabolites formed in immune cells.Furthermore,these bacteria produce urease and VacA,two virulence determinants of H.pylori that influence phago-lysosome fusion and bacterial survival in macrophages.Microscopic observations of H.pylori cells in new generations of yeasts along with amplification of H.pylori-specific genes from consecutive generations indicate that new yeasts can inherit the intracellular H.pylori as part of their vacuolar content.Accordingly,it is proposed that yeast vacuoles serve as a sophisticated niche that protects H.pylori against the environmental stresses and provides essential nutrients,including ergosterol,for its growth and multiplication.This intracellular establishment inside the yeast vacuole likely occurred long ago,leading to the adaptation of H.pylori to persist in phagocytic cells.The presence of these bacteria within yeasts,including foodborne yeasts,along with the vertical transmission of yeasts from mother to neonate,provide explanations for the persistence and propagation of H.pylori in the human population.This Topic Highlight reviews and discusses recent evidence regarding the evolutionary adaptation of H.pylori to thrive in host cell vacuoles.     

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 associated chronic gastritis,clinical syndromes,precancerous lesions,and pathogenesis of gastric cancer development

Helicobacter pylori(H.pylori)infection is well known to be associated with the development of precancerous lesions such as chronic atrophic gastritis(AG),or gastric intestinal metaplasia(GIM),and cancer.Various molecular alterations are identified not only in gastric cancer(GC)but also in precancerous lesions.H.pylori treatment seems to improve AG and GIM,but still remains controversial.In contrast,many studies,including meta-analysis,show that H.pylori eradication reduces GC.Molecular markers detected by genetic and epigenetic alterations related to carcinogenesis reverse following H.pylori eradication.This indicates that these changes may be an important factor in the identification of high risk patients for cancer development.Patients who underwent endoscopic treatment of GC are at high risk for development of metachronous GC.A randomized controlled trial from Japan concluded that prophylactic eradication of H.pylori after endoscopic resection should be used to prevent the development of metachronous GC,but recent retrospective studies did not show the tendency.Patients with precancerous lesions(molecular alterations)that do not reverse after H.pylori treatment,represent the"point of no return"and may be at high risk for the development of GC.Therefore,earlier H.pylori eradication should be considered for preventing GC development prior to the appearance of precancerous lesions.     

Helicobacter pylori infection,gastrin and cyclooxygenase-2 in gastric carcinogenesis

Gastric cancer is one of the most frequent neoplasms and a main cause of death worldwide, especially in China and Japan. Numerous epidemiological, animal and experimental studies support a positive association between chronic Helicobacter pylori(H. pylori) infec-tion and the development of gastric cancer. However, the exact mechanism whereby H. pylori causes gastric carcinogenesis remains unclear. It has been demon-strated that expression of cyclooxygenase-2(COX-2) is elevated in gastric carcinomas and in their precursor le-sions. In this review, we present the latest clinical and experimental evidence showing the role of gastrin and COX-2 in H. pylori-infected patients and their possible association with gastric cancer risk.     

Comparison between Resectable Helicobacter pylori-Negative and -Positive Gastric Cancers

Background/Aims

Controversy exists regarding the characteristics of Helicobacter pylori infection-negative gastric cancer (HPIN-GC). The aim of this study was to evaluate clinicopathologic features of HPIN-GC compared to H. pylori infection-positive gastric cancer (HPIP-GC) using a comprehensive analysis that included genetic and environmental factors.

Methods

H. pylori infection status of 705 resectable gastric cancer patients was determined by the rapid urease test, testing for anti-H. pylori antibodies, histologic analysis and culture of gastric cancer tissue samples, and history of H. pylori eradication. HPIN-GC was defined as gastric cancer that was negative for H. pylori infection based on all five methods and that had no evidence of atrophy in histology or serology.

Results

The prevalence of HPIN-GC was 4% (28/705). No significant differences with respect to age, sex, smoking, drinking, family history of gastric cancer or obesity were observed between the two groups. HPIN-GC tumors were marginally more likely to involve the cardia (14.3% for HPIN-GC vs 5.3% for HPIP-GC, p=0.068). The Lauren classification, histology, and TNM stage did not differ according to H. pylori infection status. Microsatellite instability was not different between the two groups, but p53 overexpression in HPIN-GC was marginally higher than in HPIP-GC (56.0% for HPIN-GC vs 37.0% for HPIP-GC, p=0.055).

Conclusions

The prevalence of HPIN-GC was extremely low, and its clinicopathologic characteristics were similar to HPIP-GC.