Role of Bacterial Overgrowth in the Stomach as an Additional Risk Factor for Gastritis

Gastric bacteria can either be ingested or ascend from the distal bowel; however, their survival is usually limited by gastric acidity and motility. A reduction in gastric acid can result in bacterial overgrowth in the stomach and proximal small bowel, and the number of organisms rises as the intragastric pH rises.The increased risk of noncardia gastric cancer seen in patients with hypochlorhydria may be explained by an excess of nitrites and N-nitroso compounds (NOCs). These compounds are found in the diet of populations with a high gastric cancer risk, but can also be produced by the organisms that exist in the hypochlorhydria stomach. It has long been hypothsized that nitrites and NOCs act as one of the triggers in the atrophy-metaplasia-dysplasia-carcinoma path. However, although indirect data have linked the premalignant changes of metaplasia and dysplasia to NOCs, direct measurement of gastric nitrites and NOCs has not confirmed such a link.The role ofHelicobacter pyloriin bacterial overgrowth is mainly as a cause of hypochlorhydria resulting from atrophic gastritis, leading to a reduction in the parietal cell mass.Acid-suppressing drugs can result in bacterial overgrowth and increased nitrites and NOCs, although there is no current evidence for an increased risk of gastric cancer in patients taking them. One explanation is that the stomach appears to be colonized by different organisms than those in patients with hypochlorhydria for other reasons. There is some evidence that bacterial overgrowth per se can cause gastric inflammation in mice; however, although in humans the degree of gastric inflammation is greater when overgrowth is more prominant this may simply reflect the greater degree of hypochlorhydria in patients with a more severe H pylori-induced inflammation.

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Long-term use of proton-pump inhibitors and risk of gastric cancer: a review of the current evidence

Therapeutic Advances in Gastroenterology ◽

10.1177/1756284819834511 ◽

2019 ◽

Vol 12 ◽

pp. 175628481983451 ◽

Cited By ~ 26

Author(s):

Ka Shing Cheung ◽

Wai K. Leung

Keyword(s):

Gastric Cancer ◽

Proton Pump Inhibitors ◽

Proton Pump ◽

Randomized Clinical Trials ◽

Bacterial Overgrowth ◽

Current Evidence ◽

Neoplastic Progression ◽

Increased Risk ◽

H Pylori

Gastric cancer remains one of the leading cancers in the world with a high mortality, particularly in East Asia. Helicobacter pylori infection accounts for the majority of the noncardia gastric cancers by triggering gastric inflammation and subsequent neoplastic progression. Eradication of H. pylori can reduce, but not totally eliminate, subsequent risk of developing gastric cancer. Proton-pump inhibitors (PPIs) are one of the most widely prescribed medications worldwide. With their profound gastric-acid suppression, there are concerns about a possible carcinogenic role in gastric cancer, due to induced hypergastrinemia, gastric atrophy and bacterial overgrowth in the stomach. While randomized clinical trials to establish causality between long-term PPI use and gastric cancer are lacking, current evidence based on observational studies suggests PPIs are associated with an increased gastric cancer risk. However, opinions on causality remain divergent due to unmeasured and possible residual confounding in various studies. Our recent study has showed that even after H. pylori eradication, long-term PPI use is still associated with an increased risk of gastric cancer by more than twofold. Hence, long-term PPIs should be used judiciously after considering individual’s risk–benefit profile, particularly among those with history of H. pylori infection. Further well-designed prospective studies are warranted to confirm the potential role of PPIs in gastric cancer according to baseline gastric histology and its interaction with other chemopreventive agents like aspirin, statins and metformin.

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Molecular characterization of the stomach microbiota in patients with gastric cancer and in controls

Journal of Medical Microbiology ◽

10.1099/jmm.0.007302-0 ◽

2009 ◽

Vol 58 (4) ◽

pp. 509-516 ◽

Cited By ~ 156

Author(s):

Johan Dicksved ◽

Mathilda Lindberg ◽

Magnus Rosenquist ◽

Helena Enroth ◽

Janet K. Jansson ◽

...

Keyword(s):

Gastric Cancer ◽

Gastric Acid ◽

Rflp Analysis ◽

Rrna Gene ◽

Bacterial Phyla ◽

Increased Risk ◽

H Pylori ◽

Development Of Gastric Cancer

Persistent infection of the gastric mucosa by Helicobacter pylori can initiate an inflammatory cascade that progresses into atrophic gastritis, a condition associated with reduced capacity for secretion of gastric acid and an increased risk of developing gastric cancer. The role of H. pylori as an initiator of inflammation is evident but the mechanism for development into gastric cancer has not yet been proven. A reduced capacity for gastric acid secretion allows survival and proliferation of other microbes that normally are killed by the acidic environment. It has been postulated that some of these species may be involved in the development of gastric cancer; however, their identities are poorly defined. In this study, the gastric microbiota from ten patients with gastric cancer was characterized and compared with that from five dyspeptic controls using the molecular profiling approach terminal restriction fragment length polymorphism (T-RFLP), in combination with 16S rRNA gene cloning and sequencing. T-RFLP analysis revealed a complex bacterial community in the cancer patients that was not significantly different from that in the controls. Sequencing of 140 clones revealed 102 phylotypes, with representatives from five bacterial phyla (Firmicutes, Bacteroidetes, Proteobacteria, Actinobacteria and Fusobacteria). The data revealed a relatively low abundance of H. pylori and showed that the gastric cancer microbiota was instead dominated by different species of the genera Streptococcus, Lactobacillus, Veillonella and Prevotella. The respective role of these species in development of gastric cancer remains to be determined.

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Chronic gastritis and carcinogenesis issues

Herald of Pancreatic Club ◽

10.33149/vkp.2019.04.09 ◽

2019 ◽

Vol 45 (4) ◽

pp. 65-70

Author(s):

M. M. Karimov ◽

G. N. Sobirova ◽

U. K. Abdullayeva

Keyword(s):

Gastric Cancer ◽

Intestinal Metaplasia ◽

Chronic Atrophic Gastritis ◽

Precancerous Conditions ◽

Increased Risk ◽

Operated Stomach ◽

Increasing Risk ◽

H Pylori ◽

Definition Of

Risk factors contributing to the transformation of chronic atrophic gastritis into gastric cancer are analyzed. Detection and monitoring of patients with precancerous conditions/lesions (precancerous changes), proper screening of H. pylori make early diagnosis of gastric cancer real. Features of precancerous conditions are given in order of increasing risk of developing gastric cancer. Adenomatous polyps of the stomach take the first place. Subsequent precancerous conditions include: cancer of the operated stomach, Menetria disease (hypertrophic gastropathy), B12-deficient anemia, and gastric ulcer. A definition of intestinal metaplasia subtypes is proposed as a risk factor for gastric cancer, dividing into complete and incomplete one, taking into account reduction in the expression of gastric mucins MUC1, MUC5AC and MUC6. Currently, the development of gastric cancer (mainly of the “intestinal type”) is considered as a multistage process involving the sequence of mucosal change, such as chronic inflammation, atrophy, intestinal metaplasia, dysplasia and adenocarcinoma. Role of the organism’s genetic susceptibility to H. pylori infection, factors of pathogenicity contributing to epithelial metaplasia, are analyzed. Role of Toll-like type 4 receptors (TLR4) involved in the recognition of H. pylori is clarified. It is with this type of receptors that the development of an excessive immune response of the host is associated, resulting in damage to the mucous membrane in H. pylori-infected individuals. In particular, carriers of TLR4+896A> G polymorphism have a more severe atrophy of the stomach and degree of inflammation, as well as an increased risk of non-cardiac gastric cancer.

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The Evolving Epidemiology ofHelicobacter pyloriInfection and Gastric Cancer

Canadian Journal of Gastroenterology ◽

10.1155/2003/692808 ◽

2003 ◽

Vol 17 (suppl b) ◽

pp. 18B-20B ◽

Cited By ~ 20

Author(s):

Jia-Qing Huang ◽

Richard H Hunt

Keyword(s):

Gastric Cancer ◽

Helicobacter Pylori ◽

Meta Analysis ◽

Epidemiological Studies ◽

Increased Risk ◽

H Pylori ◽

The Relationship

The relationship betweenHelicobacter pyloriinfection and the risk of gastric cancer has been well established in the last decade. Four metaanalyses have found that the infection increases the risk of noncardia gastric cancer by 2- to 6-fold compared with noninfected control populations. However, the role ofcagAstrains ofH pyloriin relation to gastric cancer has not been evaluated systematically. We undertook a meta-analysis of epidemiological studies examining the relationship between infection withcagA-positive strains ofH pyloriand the risk of gastric cancer, and found that patients who are seropositive forcagAstrains ofH pyloriare at an increased risk for developing noncardia gastric cancer compared with those withH pyloriinfection alone. Therefore, searching forcagA-positive strains ofH pylorimay help identify populations at a greater risk for developing gastric cancer.

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Role of vitamin C in gastric cancer

10.33118/oap.radiol/01.001 ◽

2018 ◽

Vol 01 (1) ◽

Author(s):

Takalkar U Vidyadhar

Keyword(s):

Gastric Cancer ◽

Vitamin C ◽

Gastric Juice ◽

Oxidative Dna Damage ◽

Preventive Measure ◽

Dietary Factors ◽

Preventive Strategy ◽

H Pylori

Gastric cancer is a multifactorial disease with complex interplay of environmental and genetic factors. Helicobacter pylori (H. pylori) infestation has been identified as the most important etiological agent in the pathogenesis of gastric cancer. Also, the role of dietary factors that is low consumption of fruits and vegetables have been found to be associated with gastric cancer. Among the dietary factors, antioxidants especially vitamin C has been found to confer the strongest protection against gastric cancer. Its anti-proliferative and pro-apoptotic action has been suggested in vitro. Because of its antioxidant activity, it protects cells against oxidative DNA damage caused by toxic effects of reactive oxygen species. It also inhibits production of carcinogenic N-nitroso compound in the stomach. The person with H. pylori infection has low levels of vitamin C in their gastric juice and levels of vitamin C normalizes on eradication of H. pylori. Vitamin C levels are high in gastric mucosa and gastric juice, sometimes more than that of in plasma. But gastric pathological conditions cause lowered secretion of vitamin C into gastric juice. Effect of H. pylori on vitamin C in gastric juice is reversible and on eradication of H. pylori, it returns to normal level. Hence, eradication of H. pylori and chemoprevention with antioxidant supplementation will be an effective preventive strategy to reduce the incidence of gastric cancer and related mortality. Vitamin C and gastric cancer is an area of potential interest for researchers as a preventive measure. Keywords: Vitamin C, H. pylori, gastric cancer.

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TLR1 and PRKAA1 Gene Polymorphisms in the Development of Atrophic Gastritis and Gastric Cancer

Journal of Gastrointestinal and Liver Diseases ◽

10.15403/jgld.2014.1121.274.tlr ◽

2018 ◽

Vol 27 (4) ◽

pp. 363-369 ◽

Cited By ~ 4

Author(s):

Gintare Dargiene ◽

Greta Streleckiene ◽

Jurgita Skieceviciene ◽

Marcis Leja ◽

Alexander Link ◽

...

Keyword(s):

Gastric Cancer ◽

Atrophic Gastritis ◽

Genetic Polymorphisms ◽

Association Studies ◽

Control Group ◽

Similar Distribution ◽

Genome Wide Association Studies ◽

Increased Risk ◽

Infection Susceptibility ◽

H Pylori

Background & Aims: Previous genome-wide association studies showed that genetic polymorphisms in toll-like receptor 1 (TLR1) and protein kinase AMP-activated alpha 1 catalytic subunit (PRKAA1) genes were associated with gastric cancer (GC) or increased Helicobacter pylori (H. pylori) infection susceptibility. The aim of this study was to evaluate the association between TLR1 and PRKAA1 genes polymorphisms and H.pylori infection, atrophic gastritis (AG) or GC in the European population.Methods: Single-nucleotide polymorphisms (SNPs) were analysed in 511 controls, 340 AG patients and 327 GC patients. TLR1 C>T (rs4833095) and PRKAA1 C>T (rs13361707) were genotyped by the real-time polymerase chain reaction. H. pylori status was determined by testing for anti-H. pylori IgG antibodies in the serum.Results: The study included 697 (59.2%) H. pylori positive and 481 (40.8%) H. pylori negative cases. We observed similar distribution of TLR1 and PRKAA1 alleles and genotypes in H. pylori positive and negative cases. TLR1 and PRKAA1 SNPs were not linked with the risk of AG. TC genotype of TLR1 gene was more prevalent in GC patients compared to the control group (29.7% and 22.3% respectively, p=0.002). Carriers of TC genotype had a higher risk of GC (aOR=1.89, 95% CI: 1.26–2.83, p=0.002). A similar association was observed in a dominant inheritance model for TLR1 gene SNP, where comparison of CC+TC vs. TT genotypes showed an increased risk of GC (aOR=1.86, 95% CI: 1.26–2.75, p=0.002). No association between genetic polymorphism in PRKAA1 gene and GC was observed.Conclusions: TLR1 rs4833095 SNP was associated with an increased risk of GC in a European population, while PRKAA1 rs13361707 genetic variant was not linked with GC. Both genetic polymorphisms were not associated with H. pylori infection susceptibility or the risk of AG.

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Systems Modeling of the Role of Interleukin-21 in the Maintenance of Effector CD4+ T Cell Responses during Chronic Helicobacter pylori Infection

mBio ◽

10.1128/mbio.01243-14 ◽

2014 ◽

Vol 5 (4) ◽

Cited By ~ 36

Author(s):

Adria Carbo ◽

Danyvid Olivares-Villagómez ◽

Raquel Hontecillas ◽

Josep Bassaganya-Riera ◽

Rupesh Chaturvedi ◽

...

Keyword(s):

Gastric Cancer ◽

Helicobacter Pylori ◽

T Cell ◽

Wild Type ◽

Content Type ◽

Interleukin 21 ◽

H Pylori ◽

Deficient Mice

ABSTRACTThe development of gastritis duringHelicobacter pyloriinfection is dependent on an activated adaptive immune response orchestrated by T helper (Th) cells. However, the relative contributions of the Th1 and Th17 subsets to gastritis and control of infection are still under investigation. To investigate the role of interleukin-21 (IL-21) in the gastric mucosa duringH. pyloriinfection, we combined mathematical modeling of CD4+T cell differentiation within vivomechanistic studies. We infected IL-21-deficient and wild-type mice withH. pyloristrain SS1 and assessed colonization, gastric inflammation, cellular infiltration, and cytokine profiles. ChronicallyH. pylori-infected IL-21-deficient mice had higherH. pyloricolonization, significantly less gastritis, and reduced expression of proinflammatory cytokines and chemokines compared to these parameters in infected wild-type littermates. Thesein vivodata were used to calibrate anH. pyloriinfection-dependent, CD4+T cell-specific computational model, which then described the mechanism by which IL-21 activates the production of interferon gamma (IFN-γ) and IL-17 during chronicH. pyloriinfection. The model predicted activated expression of T-bet and RORγt and the phosphorylation of STAT3 and STAT1 and suggested a potential role of IL-21 in the modulation of IL-10. Driven by our modeling-derived predictions, we found reduced levels of CD4+splenocyte-specifictbx21androrcexpression, reduced phosphorylation of STAT1 and STAT3, and an increase in CD4+T cell-specific IL-10 expression inH. pylori-infected IL-21-deficient mice. Our results indicate that IL-21 regulates Th1 and Th17 effector responses during chronicH. pyloriinfection in a STAT1- and STAT3-dependent manner, therefore playing a major role controllingH. pyloriinfection and gastritis.IMPORTANCEHelicobacter pyloriis the dominant member of the gastric microbiota in more than 50% of the world’s population.H. pyloricolonization has been implicated in gastritis and gastric cancer, as infection withH. pyloriis the single most common risk factor for gastric cancer. Current data suggest that, in addition to bacterial virulence factors, the magnitude and types of immune responses influence the outcome of colonization and chronic infection. This study uses a combined computational and experimental approach to investigate how IL-21, a proinflammatory T cell-derived cytokine, maintains the chronic proinflammatory T cell immune response driving chronic gastritis duringH. pyloriinfection. This research will also provide insight into a myriad of other infectious and immune disorders in which IL-21 is increasingly recognized to play a central role. The use of IL-21-related therapies may provide treatment options for individuals chronically colonized withH. pylorias an alternative to aggressive antibiotics.

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Genetic Polymorphisms of CXCL8 (−251) Are Associated with the Susceptibility of Helicobacter pylori Infection Increased the Risk of Inflammation and Gastric Cancer in Thai Gastroduodenal Patients

Iranian Journal of Allergy Asthma and Immunology ◽

10.18502/ijaai.v18i4.1417 ◽

2019 ◽

Cited By ~ 1

Author(s):

Wongwarut Boonyanugomol ◽

Kamolchanok Rukseree ◽

Worrarat Kongkasame ◽

Prasit Palittapongarnpim ◽

Seung-Chul Baik ◽

...

Keyword(s):

Gene Expression ◽

Gastric Cancer ◽

Helicobacter Pylori ◽

Cancer Progression ◽

Chemokine Receptor ◽

Gene Polymorphisms ◽

Inflammatory Responses ◽

Increased Risk ◽

Cxc Chemokine ◽

H Pylori

CXC Chemokine Ligand 8 (CXCL8) plays an important role in gastric inflammation and in the progression of gastric cancer induced by Helicobacter pylori (H. pylori) infection. The association of CXCL8, CXC Chemokine Receptor 1 (CXCR1), and CXC Chemokine Receptor 2 (CXCR2) polymorphisms with H. pylori infection and gastric cancer progression needs to be investigated in a population within an enigma area consisting of multiple ethnicities, such as Thailand. To analyze the relative risk of H. pylori infection and gastric cancer among Thai gastroduodenal patients, gene polymorphisms in CXCL8 (promoter region -251) and in CXCR1 and CXCR2 (receptors for CXCL8) were detected by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) and allele specific-PCR (AS-PCR). We also determined the presence of cytotoxin-associated gene A (cagA) in Thai patients with H. pylori infection. Correlation between the CXCL8 (-251) polymorphism and CXCL8 gene expression was evaluated by quantitative reverse transcriptase-PCR (qRT-PCR). We found a significant association between the T/A and A/A genotypes of CXCL8 (-251) with H. pylori infection. However, no significant correlation was found between the CXCR1 (+2607) and CXCR2 (+1208) gene polymorphisms with H. pylori infection among Thai gastroduodenal subjects. Within the H. pylori-infected group of Thai gastroduodenal patients, no significant differences in cagA were observed. In addition, the A/A genotype of CXCL8 (-251) significantly correlated with the risk of gastric cancer and correlated with higher CXCL8 gene expression levels in Thai gastroduodenal patients. These results suggest that CXCL8 (-251) polymorphisms are associated with H. pylori infection, an increased risk of stronger inflammatory responses, and gastric cancer in Thai gastroduodenal patients.

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Two Distinct Etiologies of Gastric Cancer: Infection and Autoimmunity

Frontiers in Cell and Developmental Biology ◽

10.3389/fcell.2021.752346 ◽

2021 ◽

Vol 9 ◽

Author(s):

Stella G. Hoft ◽

Christine N. Noto ◽

Richard J. DiPaolo

Keyword(s):

Gastric Cancer ◽

T Cells ◽

Gastric Adenocarcinoma ◽

Inflammatory Diseases ◽

The United States ◽

Autoimmune Gastritis ◽

Gastric Disease ◽

Increased Risk ◽

H Pylori ◽

Gastrointestinal Ulceration

Gastric cancer is a leading cause of mortality worldwide. The risk of developing gastric adenocarcinoma, which comprises >90% of gastric cancers, is multifactorial, but most associated with Helicobacter pylori infection. Autoimmune gastritis is a chronic autoinflammatory syndrome where self-reactive immune cells are activated by gastric epithelial cell autoantigens. This cause of gastritis is more so associated with the development of neuroendocrine tumors. However, in both autoimmune and infection-induced gastritis, high risk metaplastic lesions develop within the gastric mucosa. This warrants concern for carcinogenesis in both inflammatory settings. There are many similarities and differences in disease progression between these two etiologies of chronic gastritis. Both diseases have an increased risk of gastric adenocarcinoma development, but each have their own unique comorbidities. Autoimmune gastritis is a primary cause of pernicious anemia, whereas chronic infection typically causes gastrointestinal ulceration. Both immune responses are driven by T cells, primarily CD4+ T cells of the IFN-γ producing, Th1 phenotype. Neutrophilic infiltrates help clear H. pylori infection, but neutrophils are not necessarily recruited in the autoimmune setting. There have also been hypotheses that infection with H. pylori initiates autoimmune gastritis, but the literature is far from definitive with evidence of infection-independent autoimmune gastric disease. Gastric cancer incidence is increasing among young women in the United States, a population at higher risk of developing autoimmune disease, and H. pylori infection rates are falling. Therefore, a better understanding of these two chronic inflammatory diseases is needed to identify their roles in initiating gastric cancer.

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