Gastric cancer (GC) is a globally prevalent malignancy with a particularly heavy burden in China. Helicobacter pylori ( H. pylori ) is a Group I carcinogen for GC, with a higher seroprevalence rate indicating a higher GC incidence. However, only approximately 3% of the individuals with H. pylori infection eventually develop GC, and about 2.6% still progress to GC even 10-20 years after the eradication of H. pylori . Thus, the pathogenic mechanism of H. pylori for GC must be elucidated, and high-risk individuals precisely identified. Furthermore, GC can occur even in individuals who have never been infected with H. pylori . As H. pylori infection rates decline, the proportion of H. pylori -negative GC cases is increasing annually, gaining significant research attention. In this review, potential pathogenic mechanisms of H. pylori infection are explored from the aspects of H. pylori virulence factors and host factors (genetic susceptibility and immune microenvironment). Possible risk factors for H. pylori -negative GC include infections by other microorganisms (e.g., bacteria, fungi, and viruses), autoimmune gastritis, bile reflux, genetic mutations, and environmental factors. We aim to review the potential mechanisms for GC with varying H. pylori infection statuses, identify the high-risk individuals, and pose questions that need to be addressed. In the future, as the prevalence of H. pylori infection gradually decreases, GC prevention and management must evolve to address host-specific factors and the growing challenge of H. pylori -negative GC by integrating multidisciplinary perspectives.
Stomach Neoplasms/genetics* ; Humans ; Helicobacter Infections/complications* ; Helicobacter pylori/pathogenicity* ; Risk Factors

Objective: To investigate the characteristics of duodenal bulbar microbiota in children with duodenal ulcer and Helicobacter pylori (Hp) infection. Methods: This prospective cohort study enrolled 23 children with duodenal ulcers diagnosed by gastroscopy who were admitted to the Children's Hospital of Zhejiang University School of Medicine due to abdominal pain, abdominal distension, and vomiting from January 2018 to August 2018. They were divided into Hp-positive and Hp-negative groups according to the presence or absence of Hp infection. Duodenal bulbar mucosa was sampled to detect the bacterial DNA by high-throughput sequencing. The statistical difference in α diversity and β diversity, and the relative abundance in taxonomic level between the two groups were compared. Microbial functions were predicted using the software PICRUSt. T-test, Rank sum test or χ² test were used for comparison between the two groups. Results: A total of 23 children diagnosed with duodenal ulcer were enrolled in this study, including 15 cases with Hp infection ((11.2±3.3) years of age, 11 males and 4 females) and 8 cases without Hp infection ((10.1±4.4) years of age, 6 males and 2 females). Compared with Hp-negative group, the Hp-positive group had higher Helicobacter abundance (0.551% (0.258%, 5.368%) vs. 0.143% (0.039%, 0.762%), Z=2.00, P=0.045) and lower abundance of Fusobacterium, Streptococcus and unclassified- Comamonadaceae (0.010% (0.001%, 0.031%) vs. 0.049% (0.011%, 0.310%), Z=-2.24, P=0.025; 0.031% (0.015%, 0.092%) vs. 0.118% (0.046%, 0.410%), Z=-2.10, P=0.036; 0.046% (0.036%, 0.062%) vs. 0.110% (0.045%, 0.176%), Z=-2.01, P=0.045). Linear discriminant analysis (LDA) effect sized showed that at the genus level, only Helicobacter was significantly enriched in Hp-positive group (LDA=4.89, P=0.045), while Streptococcus and Fusobacterium significantly enriched in Hp-negative group (LDA=3.28, 3.11;P=0.036,0.025, respectively). PICRUSt microbial function prediction showed that the expression of oxidative phosphorylation and disease-related pathways (pathways in cancer, renal cell carcinoma, amoebiasis, type 1 diabetes mellitus) in Hp-positive group were significantly higher than that in Hp-negative group (all P<0.05), while the expression of pathways such as energy metabolism and phosphotransferase system pathways were significantly lower than that in Hp-negative group (all P<0.05). Conclusion: In children with Hp-infected duodenal ulcers, the mucosal microbiota of the duodenal bulb is altered, characterized by an increased abundance of Helicobacter and a decreased abundance of Clostridium and Streptococcus, and possibly alters the biological function of the commensal microbiota through specific metabolic pathways.
Male ; Female ; Humans ; Child ; Duodenal Ulcer/diagnosis* ; Helicobacter Infections/complications* ; Helicobacter pylori/genetics* ; Prospective Studies ; Microbiota

OBJECTIVE: To investigate the correlation between Helicobacter pylori (H. Pylori) infection and polymorphism of adiponectin gene promoter -11391G/A, extracellular superoxide dismutase (EC-SOD) gene in nonalcoholic fatty liver disease (NAFLD).
 METHODS: From June, 2010 to July, 2014, a hospital-based 1:1 matched case-control study was carried out, with 600 cases of NAFLD and 600 healthy people in the First Affiliated Hospital of Xinxiang Medical University. The genetic polymorphisms of adiponectin gene promoter -11391G/A and EC-SOD were analyzed by polymorphism-polymerase chain reaction (PCR) technique in peripheral blood leukocytes of the subjects. 14C-urea breath test (14C-UBT) was used to test 14C disntegration per minute (DPM) for evaluating the infections status of H. Pylori. The synergistic effect between the two mutants and the gene-environment interaction of the genotypes with H. Pylori infection were analyzed.
 RESULTS: The frequencies of -11391G/A (AA) and EC-SOD (CG+GG) were 50.67% and 50.33% in NAFLD cases, 23.83% and 24.17% in healthy controls, respectively. Statistical tests showed significantly higher frequencies of -11391G/A (AA) and EC-SOD (CG+GG) in the NAFLD group (-11391G/A: P=0.0051; EC-SOD: P=0.0057). The risk of NAFLD with -11391G/A (AA) was significantly higher than those with -11391G/A(GG+GA) (OR=3.2822, 95% CI 1.9170 to 5.2039). The individuals who carried EC-SOD (CG+GG) had a high risk of NAFLD (OR=3.1800, 95% CI 1.7974 to 5.2391). Combined analysis of the polymorphisms showed that percentage of -11391G/A (AA)/EC-SOD (CG+GG) in the NAFLD group was significantly higher than that in the control groups (25.50% vs 5.83%, P=0.0039). The people who carried with -11391G/A (AA)/EC-SOD (CG+GG) had a high risk of NAFLD (OR=10.3190, 95% CI 8.1869 to 20.5102). The H. Pylori infection rate in the NAFLD group was significantly higher than that in the control group (OR=3.1667, 95% CI 1.9139 to 5.7443, P=0.0062), and statistical analysis suggested a positive correlation between H. Pylori infection and NAFLD with -11391G/A (AA) and EC-SOD (CG+GG) (-11391G/A: γ=1.8532; EC-SOD: γ=1.7899).
 CONCLUSION These carriers of -11391G/A(AA) and EC-SOD (CG+GG) genotypes may have a high risk of NAFLD, and the gene genotypes can interact with H. Pylori infection in the pathogenesis of NAFLD. Therefore, effective prevention measures for NAFLD should consider eradicating H. Pylori or regulating gene expression.
Adiponectin ; genetics ; Case-Control Studies ; Gene-Environment Interaction ; Genotype ; Helicobacter Infections ; complications ; genetics ; Helicobacter pylori ; Humans ; Non-alcoholic Fatty Liver Disease ; complications ; genetics ; Polymerase Chain Reaction ; Polymorphism, Genetic ; Promoter Regions, Genetic ; Risk Factors ; Superoxide Dismutase ; genetics

BACKGROUND/AIMS: Helicobacter pylori cytotoxin-associated gene A (CagA) has been suggested to be involved in the inactivation of Runt-related transcription factor 3 (RUNX3), a known gastric carcinoma tumor suppressor gene. It remains unclear how H. pylori CagA initiates or maintains RUNX3 promoter methylation and inactivates its protein expression in gastric carcinoma. METHODS: RUNX3 promoter methylation status, RUNX3 expression, and H. pylori CagA were investigated in 76 sample pairs of gastric carcinoma tissue. The patients' medical records were reviewed. The association between RUNX3 methylation or loss of RUNX3 expression and clinicopathologic variables according to H. pylori CagA status were investigated. RESULTS: In gastric carcinoma patients with H. pylori CagA-positive infection, RUNX3 methylation did not show association with lymphatic invasion, venous invasion, and TNM stages. However RUNX3 methylation was observed more frequently in poorly differentiated adenocarcinoma and signet ring cell carcinoma (77.8% vs. 20.0%, p=0.023) in early stage. In gastric carcinoma patients with H. pylori CagA-positive infection, loss of RUNX3 expression did not show association with lymphatic invasion, venous invasion, and TNM stages. However loss of RUNX3 expression was observed more frequently in early gastric carcinoma than in advanced gastric carcinoma (84.2% vs. 75.0%, p=0.51), but this difference was not significant. CONCLUSIONS: In gastric carcinoma patients with H. pylori CagA-positive infection, RUNX3 methylation or loss of RUNX3 expression did not show correlation with lymphovascular invasion and TNM stages. In early gastric carcinoma patients with H. pylori CagA-positive infection, RUNX3 methylation was observed more in poorly differentiated adenocarcinoma and signet ring cell carcinoma.
Adult ; Aged ; Aged, 80 and over ; Antigens, Bacterial/*metabolism ; Bacterial Proteins/*metabolism ; Cell Line, Tumor ; Core Binding Factor Alpha 3 Subunit/genetics/*metabolism ; Female ; *Gene Expression Regulation, Neoplastic ; Helicobacter Infections/complications/microbiology ; Helicobacter pylori/isolation & purification/*metabolism ; Humans ; Immunohistochemistry ; Lymphatic Metastasis ; Male ; Methylation ; Middle Aged ; Neoplasm Staging ; Promoter Regions, Genetic ; Retrospective Studies ; Stomach Neoplasms/complications/microbiology/*pathology

BACKGROUND/AIMS: This 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. METHODS: Total 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. RESULTS: A 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. CONCLUSIONS: miRNA 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.
Aged ; Female ; Gene Expression Profiling ; *Gene Expression Regulation, Neoplastic ; Helicobacter Infections/complications/*genetics ; *Helicobacter pylori ; Humans ; Intestines/metabolism ; Male ; MicroRNAs/*metabolism ; Middle Aged ; RNA, Neoplasm/metabolism ; Stomach Neoplasms/complications/*genetics

BACKGROUND/AIMS: This 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. METHODS: Total 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. RESULTS: A 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. CONCLUSIONS: miRNA 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.
Aged ; Female ; Gene Expression Profiling ; *Gene Expression Regulation, Neoplastic ; Helicobacter Infections/complications/*genetics ; *Helicobacter pylori ; Humans ; Intestines/metabolism ; Male ; MicroRNAs/*metabolism ; Middle Aged ; RNA, Neoplasm/metabolism ; Stomach Neoplasms/complications/*genetics

Gastric cancer is the second leading cause of cancer-related mortality and the fourth most common cancer globally. There are, however, distinct differences in incidence rates in different geographic regions. While the incidence rate of gastric cancer has been falling, that of gastric cardia cancers is reportedly on the rise in some regions. Helicobacter pylori (H. pylori) infection is a major risk factor of non-cardia gastric cancer, and data has emerged concerning the role of H. pylori eradication for primary prevention of gastric cancer. Dietary, lifestyle and metabolic factors have also been implicated. Although addressing these other factors may contribute to health, the actual impact in terms of cancer prevention is unclear. Once irreversible histological changes have occurred, endoscopic surveillance would be necessary. A molecular classification system offers hope for molecularly tailored, personalised therapies for gastric cancer, which may improve the prognosis for patients.
Female ; Global Health ; Helicobacter Infections ; complications ; prevention & control ; Helicobacter pylori ; Humans ; Incidence ; Male ; Obesity ; complications ; Risk Factors ; Stomach Neoplasms ; epidemiology ; genetics ; microbiology ; prevention & control

OBJECTIVETo establish an animal model of gastric cancer by long-term infection of Helicobacter pylori (H.pylori) and to elucidate the pathogenesis by proteomics analysis.

METHODSFifty male Mongolian gerbils (4-5 week-old and weighted 60-100 g) were infected with H.pylori and the gastric tissues were obtained after the infection at 3, 6, 12 and 24 months. Histological changes were evaluated by H-E staining of the gastric tissue sections. Detection of H.pylori was performed by in-vitro culture of fresh gastric tissue samples, PCR amplification of H.pylori 16s rRNA and localization by silver staining. In addition, proteins extracted from gastric tissue samples were subjected to two-dimensional electrophoresis (2-DE) at various infection time points. Protein spots with increased quantity over the course of H.pylori infection were selected and analyzed by LC-MS/MS. Finally, differentially expressed proteins between human gastric cancer tissue samples and lymph nodes were analyzed by real-time RT-PCR.

RESULTSColonization of H.pylori was observed in gastric tissue of gerbils as early as 3 months after H.pylori infection, and persisted till 24 months. Pathological examination of infected animals showed various histological changes including acute gastritis, atrophic gastritis, intestinal metaplasia and gastric carcinoma. Seventy-eight differentially expressed proteins were identified by proteomics analysis, among which 36 proteins were up-regulated and 42 were down-regulated. Analyzed by LC-MS/MS, ten proteins were identified, including lactate dehydrogenase, ATP synthase, fatty acid-binding protein, COX5B, peroxiredoxin-4, peroxide reductase, transgelin, succinyl-CoA ligase, keratin and protein disulfide-isomerase A2, among which transgelin, ATP synthase and lactate dehydrogenase were highly expressed in human gastric carcinoma and lymph nodes.

CONCLUSIONSH.pylori infection induces the expression of transgelin, ATP synthase and lactate dehydrogenase, implying possible roles in the pathogenesis of gastric diseases including cancer.

Animals ; Disease Models, Animal ; Gastritis ; microbiology ; pathology ; Gerbillinae ; Helicobacter Infections ; complications ; metabolism ; Helicobacter pylori ; genetics ; Humans ; L-Lactate Dehydrogenase ; metabolism ; Male ; Metaplasia ; Microfilament Proteins ; metabolism ; Muscle Proteins ; metabolism ; Proteomics ; Proton-Translocating ATPases ; metabolism ; RNA, Ribosomal, 16S ; analysis ; Stomach Neoplasms ; metabolism ; microbiology ; Tandem Mass Spectrometry

Helicobacter pylori (Hp) is a high prevalence of chronic infectious pathogens, though not necessarily lead to symptoms, but it can affect the immune system. More than of the world's population harbors the bacterium, and most adult Hp infection was obtained in childhood. Hp infection is a major cause of peptic ulcer, although children rarely suffer from peptic ulcer disease. Hp infection is closely related to chronic gastritis, dyspepsia, chronic diarrhea and recurrent abdominal pain in children. In recent years, Hp infection may also participate in some of non-digestive diseases, such as children's nutritional iron deficiency anemia, growth retardation, malnutrition, autoimmune idiopathic thrombocytopenic purpura, chronic urticaria, as well as the development of adult atherosclerosis-related cardiovascular diseases and some nervous system diseases. Hp infection can be a lifetime issues of children. Hp infection of children will bring many socio-economic problems. In this paper, the correlation of Hp infection in stomach and oral cavity, and diagnostic technology, prevention as well as treatment strategies for Hp infection will be discussed.
Helicobacter Infections ; complications ; diagnosis ; epidemiology ; genetics ; Helicobacter pylori ; Humans ; Mouth ; microbiology ; Stomach ; microbiology

BACKGROUND/AIMS: Tumor necrosis factor alpha (TNF-alpha) encoded by TNFA is a key mediator in inflammation, a precursor condition for peptic ulceration. Promoter polymorphisms of TNFA that influence its transcriptional activity and TNF-alpha production are known. TNFA-308G>A (rs1800629) and TNFA-1031T>C (rs1799964), which are responsible for increased TNFA transcription, could influence the risk of peptic ulceration. This study aimed to investigate these polymorphisms and to evaluate their association with peptic ulcer disease and Helicobacter pylori infection in the Polish population. METHODS: Gastric mucosa specimens obtained from 177 Polish peptic ulcer patients were used to conduct rapid urease tests and to assess the investigated polymorphisms by polymerase chain reaction-restriction fragment length polymorphism. Genotyping data were compared with the results obtained from healthy individuals of Polish origin. RESULTS: There were no significant differences in genotype and allele frequency of the investigated polymorphisms between peptic ulcer patients and healthy individuals. No associations between the frequencies of particular genotypes and alleles for both single-nucleotide polymorphisms (SNPs) and the presence of H. pylori infection in peptic ulcer patients and in subgroups of men and women with peptic ulcer disease were found. CONCLUSIONS: The investigated SNPs are not risk factors for either peptic ulcer or H. pylori infection development in the Polish population. The results require verification in a larger cohort.
Adolescent ; Adult ; Aged ; Aged, 80 and over ; Case-Control Studies ; European Continental Ancestry Group/genetics ; Female ; Gastric Mucosa/*metabolism/microbiology ; Genetic Predisposition to Disease ; Genotype ; Helicobacter Infections/complications/*genetics ; Helicobacter pylori ; Humans ; Male ; Middle Aged ; Peptic Ulcer/complications/*genetics ; Poland ; Polymorphism, Restriction Fragment Length ; Polymorphism, Single Nucleotide ; *Promoter Regions, Genetic ; Tumor Necrosis Factor-alpha/*genetics ; Young Adult