scholarly journals Gastric Microbiota beyond H. pylori: An Emerging Critical Character in Gastric Carcinogenesis

Biomedicines ◽  
2021 ◽  
Vol 9 (11) ◽  
pp. 1680
Author(s):  
Jun Wen ◽  
Harry Cheuk-Hay Lau ◽  
Maikel Peppelenbosch ◽  
Jun Yu
Keyword(s):  
Gastric Cancer ◽  
Molecular Mechanisms ◽  
Large Population ◽  
Gastric Carcinogenesis ◽  
Clinical Applications ◽  
Human Stomach ◽  
Cancer Death ◽  
Sequencing Studies ◽  
H Pylori ◽  
Gastric Microbiota

Gastric cancer (GC) is one of the global leading causes of cancer death. The association between Helicobacter pylori, which is a predominant risk factor for GC, with GC development has been well-studied. Recently, accumulating evidence has demonstrated the presence of a large population of microorganisms other than H. pylori in the human stomach. Existing sequencing studies have revealed microbial compositional and functional alterations in patients with GC and highlighted a progressive shift in the gastric microbiota in gastric carcinogenesis with marked enrichments of oral or intestinal commensals. Moreover, using a combination of gastric bacterial signatures, GC patients could be significantly distinguished from patients with gastritis. These findings, therefore, emphasize the importance of a collective microbial community in gastric carcinogenesis. Here, we provide an overview of non-H. pylori gastric microbes in gastric carcinogenesis. The molecular mechanisms of gastric microbes-related carcinogenesis and potential clinical applications of gastric microbiota as biomarkers of GC are also explored.

scholarly journals Induction and prevention of gastric cancer with combined Helicobacter pylori and capsaicin administration and DFMO treatment, respectively

2020 ◽  
Author(s):  
Faisal Aziz ◽  
Mingxia Xin ◽  
Yunfeng Gao ◽  
Josh Monts ◽  
Kjersten Monson ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Helicobacter Pylori ◽  
Mouse Models ◽  
Chronic Gastritis ◽  
Molecular Mechanisms ◽  
Gastric Carcinogenesis ◽  
Lifestyle Changes ◽  
Host Susceptibility ◽  
Anti Inflammatory ◽  
H Pylori

Abstract Background: Gastric cancer risk evolves over time due to environmental, dietary, and lifestyle changes including Helicobacter pylori (H. pylori) infection and consumption of hot peppers (i.e. capsaicin). H. pylori infection promotes gastric mucosal injury in the early phase of capsaicin exposure. In addition, capsaicin consumption is reported to suppress immune function and increase host susceptibility to microbial infection. This relationship suggests a need to investigate the mechanism of how both H. pylori infection and capsaicin contribute to gastric inflammation and lead to gastric cancer. No previous experimental animal models have been developed to study this dual association. Here we developed a series of mouse models that progress from chronic gastritis to gastric cancer. C57-Balb/c mice were infected with the H. pylori (SS1) strain and then fed capsaicin (0.05% or 0.2g/kg/day) or not. Consequently, we investigated the association between H. pylori infection and capsaicin consumption during the initiation of gastric inflammation and the later development of gastric cancer. Tumor size and phenotype were analyzed to determine the molecular mechanism driving the shift from gastritis to stomach cancer. Gastric carcinogenesis was also prevented in these models using the ornithine decarboxylase inhibitor DFMO (2-difluoromethylornithine). Results: This study provides evidence showing that a combination of H. pylori infection and capsaicin consumption leads to gastric carcinogenesis. The transition from chronic gastritis to gastric cancer is mediated through interleukin-6 (IL-6) stimulation with an incidence rate of 50%. However, this progression can be prevented by treating with anti-inflammatory agents. In particular, we used DFMO to prevent gastric tumorigenesis by reducing inflammation and promoting recovery of disease-free stasis. The anti-inflammatory role of DFMO highlights the injurious effect of inflammation in gastric cancer development and the need to reduce gastric inflammation for cancer prevention. Conclusions: Overall, these mouse models provide reliable systems for analyzing the molecular mechanisms and synergistic effects of H. pylori and capsaicin on human cancer etiology. Accordingly, preventive measures like reduced capsaicin consumption, H. pylori clearance, and DFMO treatment can lessen gastric cancer incidence. Lastly, anti-inflammatory agents like DFMO can play important roles in prevention of inflammation-associated gastric cancer.

scholarly journals Gastric tumorigenesis induced either by Helicobacter pylori infection or chronic alcohol consumption through IL-10 inhibition

2020 ◽  
Author(s):  
Faisal Aziz ◽  
Abhijit Chakarobaty ◽  
Kandong Liu ◽  
Hisae Yoshitomi ◽  
Xiang Li ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Alcohol Consumption ◽  
Mitochondrial Dysfunction ◽  
Cell Survival ◽  
Cancer Cell ◽  
Molecular Mechanisms ◽  
Gastric Carcinogenesis ◽  
Cd8 Cells ◽  
Cancer Cell Survival ◽  
H Pylori

Abstract Background Alcohol is class 1 carcinogen and results in 3.3 million deaths every year. H. pylori is also an important factor for gastric carcinogen. Alcohol consumption is emerging as an important contributor to gastric cancer, but there is no direct or experimental evidence of alcohol and H. pylori infection produce gastric cancer in human and animal model alone. Here, we provide insight into the molecular mechanisms driving gastric carcinogenesis. Results Alcohol consumption, together with H. pylori infection, causes gastric cancer; interleukin-10 (IL-10) downregulation and mitochondrial metabolic dysfunction in CD8+ cells are also involved. IL-10 knockout accelerates tumor development in mice with either H. pylori infection or alcohol induced gastric cancer or both. IL-10 downregulation and CD-8+ cell dysfunction stimulates IL-1β secretion. Specifically, we show IL-10 inhibits glucose uptake and glycolysis and promotes oxidative phosphorylation with lactate inhibition. Consequently, In the absence of IL-10 signaling, CD8+ cells accumulate damaged mitochondria in a mouse model of gastric cancer induced with the combination of alcohol plus H. pylori infection, and this results in mitochondrial dysfunction and production of IL-1 β. IL-1β promotes H. pylori infection and reduces NKX6.3 gene expression, resulting in increased cancer cell survival and proliferation. Conclusions Overall, the molecular mechanisms of gastric carcinogenesis include IL-10 inhibition resulting in lowered host immunity via mitochondrial dysfunction of CD8+ lymphocytes; gastric inflammation due to H. pylori infection, alcohol intake, and IL-1β production; and disruption of gastric-specific tumor suppressor NKX6.3 expression, which increases cancer cell survival and proliferation.

scholarly journals The correlation between lncRNAs and Helicobacter pylori in gastric cancer

2019 ◽  
Vol 77 (9) ◽  
Author(s):  
Narges Dastmalchi ◽  
Seyed Mahdi Banan Khojasteh ◽  
Mirsaed Miri Nargesi ◽  
Reza Safaralizadeh
Keyword(s):  
Gastric Cancer ◽  
Helicobacter Pylori ◽  
Molecular Mechanisms ◽  
Gastrointestinal Diseases ◽  
Mechanisms Of Action ◽  
Molecular Pathways ◽  
Gastric Diseases ◽  
Non Coding Rnas ◽  
H Pylori ◽  
The Relationship

ABSTRACT Helicobacter pylori infection performs a key role in gastric tumorigenesis. Long non-coding RNAs (lncRNAs) have demonstrated a great potential to be regarded as effective malignancy biomarkers for various gastrointestinal diseases including gastric cancer (GC). The present review highlights the relationship between lncRNAs and H. pylori in GC. Several studies have examined not only the involvement of lncRNAs in H. pylori-associated GC progression but also their molecular mechanisms of action. Among the pertinent studies, some have addressed the effects of H. pylori infection on modulatory networks of lncRNAs, while others have evaluated the effects of changes in the expression level of lncRNAs in H. pylori-associated gastric diseases, especially GC. The relationship between lncRNAs and H. pylori was found to be modulated by various molecular pathways.

scholarly journals Gastric Cancer Microbiome

Pathobiology ◽  
2021 ◽  
Vol 88 (2) ◽  
pp. 156-169
Author(s):  
Williams Fernandes Barra ◽  
Dionison Pereira Sarquis ◽  
André Salim Khayat ◽  
Bruna Cláudia Meireles Khayat ◽  
Samia Demachki ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Small Sample Size ◽  
Total Sample ◽  
Clinical Situation ◽  
Gastric Carcinogenesis ◽  
Comprehensive Analysis ◽  
Small Sample ◽  
Metagenomic Data ◽  
Clinical Scenarios ◽  
H Pylori

Identifying a microbiome pattern in gastric cancer (GC) is hugely debatable due to the variation resulting from the diversity of the studied populations, clinical scenarios, and metagenomic approach. <i>H. pylori</i> remains the main microorganism impacting gastric carcinogenesis and seems necessary for the initial steps of the process. Nevertheless, an additional non-<i>H. pylori</i> microbiome pattern is also described, mainly at the final steps of the carcinogenesis. Unfortunately, most of the presented results are not reproducible, and there are no consensual candidates to share the <i>H. pylori</i> protagonists. Limitations to reach a consistent interpretation of metagenomic data include contamination along every step of the process, which might cause relevant misinterpretations. In addition, the functional consequences of an altered microbiome might be addressed. Aiming to minimize methodological bias and limitations due to small sample size and the lack of standardization of bioinformatics assessment and interpretation, we carried out a comprehensive analysis of the publicly available metagenomic data from various conditions relevant to gastric carcinogenesis. Mainly, instead of just analyzing the results of each available publication, a new approach was launched, allowing the comprehensive analysis of the total sample amount, aiming to produce a reliable interpretation due to using a significant number of samples, from different origins, in a standard protocol. Among the main results, <i>Helicobacter</i> and <i>Prevotella</i> figured in the “top 6” genera of every group. <i>Helicobacter</i> was the first one in chronic gastritis (CG), gastric cancer (GC), and adjacent (ADJ) groups, while <i>Prevotella</i> was the leader among healthy control (HC) samples. Groups of bacteria are differently abundant in each clinical situation, and bacterial metabolic pathways also diverge along the carcinogenesis cascade. This information may support future microbiome interventions aiming to face the carcinogenesis process and/or reduce GC risk.

scholarly journals The role of the gastric bacterial microbiome in gastric cancer: Helicobacter pylori and beyond

2019 ◽  
Vol 12 ◽  
pp. 175628481989406 ◽  
Author(s):  
Christian Schulz ◽  
Kerstin Schütte ◽  
Julia Mayerle ◽  
Peter Malfertheiner
Keyword(s):  
Gastric Cancer ◽  
Helicobacter Pylori ◽  
Bacterial Pathogen ◽  
Gastric Carcinogenesis ◽  
Nucleotide Sequencing ◽  
Wide Field ◽  
Current State ◽  
Organ Systems ◽  
Bacterial Microbiome ◽  
H Pylori

A link between chronic inflammation and carcinogenesis has been depicted in many organ systems. Helicobacter pylori is the most prevalent bacterial pathogen, induces chronic gastritis and is associated with more than 90% of cases of gastric cancer (GC). However, the introduction of nucleotide sequencing techniques and the development of biocomputional tools have surpassed traditional culturing techniques and opened a wide field for studying the mucosal and luminal composition of the bacterial gastric microbiota beyond H. pylori. In studies applying animal models, a potential role in gastric carcinogenesis for additional bacteria besides H. pylori has been demonstrated. At different steps of gastric carcinogenesis, changes in bacterial communities occur. Whether these microbial changes are a driver of malignant disease or a consequence of the histologic progression along the precancerous cascade, is not clear at present. It is hypothesized that atrophy, as a consequence of chronic gastric inflammation, alters the gastric niche for commensals that might further urge the development of H. pylori-induced GC. Here, we review the current state of knowledge on gastric bacteria other than H. pylori and on their synergism with H. pylori in gastric carcinogenesis.

scholarly journals Cross-sectional study of human coding- and non-coding RNAs in progressive stages of Helicobacter pylori infection

2020 ◽  
Vol 7 (1) ◽  
Author(s):  
Sergio Lario ◽  
María J. Ramírez-Lázaro ◽  
Aintzane González-Lahera ◽  
José L. Lavín ◽  
Maria Vila-Casadesús ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Helicobacter Pylori ◽  
Expression Profiles ◽  
Gastric Carcinogenesis ◽  
Individual Response ◽  
Peptic Ulcers ◽  
Gastric Diseases ◽  
Sequence Of Events ◽  
Non Coding Rnas ◽  
H Pylori

Abstract Helicobacter pylori infects 4.4 billion individuals worldwide and is considered the most important etiologic agent for peptic ulcers and gastric cancer. Individual response to H. pylori infection is complex and depends on complex interactions between host and environmental factors. The pathway towards gastric cancer is a sequence of events known as Correa’s model of gastric carcinogenesis, a stepwise inflammatory process from normal mucosa to chronic-active gastritis, atrophy, metaplasia and gastric adenocarcinoma. This study examines gastric clinical specimens representing different steps of the Correa pathway with the aim of identifying the expression profiles of coding- and non-coding RNAs that may have a role in Correa’s model of gastric carcinogenesis. We screened for differentially expressed genes in gastric biopsies by employing RNAseq, microarrays and qRT-PCR. Here we provide a detailed description of the experiments, methods and results generated. The datasets may help other scientists and clinicians to find new clues to the pathogenesis of H. pylori and the mechanisms of progression of the infection to more severe gastric diseases. Data is available via ArrayExpress.

scholarly journals Modification of the Gastric Mucosal Microbiota by a Strain-Specific Helicobacter pylori Oncoprotein and Carcinogenic Histologic Phenotype

mBio ◽  
2019 ◽  
Vol 10 (3) ◽  
Author(s):  
Jennifer M. Noto ◽  
Joseph P. Zackular ◽  
Matthew G. Varga ◽  
Alberto Delgado ◽  
Judith Romero-Gallo ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Helicobacter Pylori ◽  
Community Structure ◽  
Microbial Community ◽  
Iron Deficiency ◽  
Dependent Manner ◽  
Content Type ◽  
Β Diversity ◽  
H Pylori ◽  
Gastric Microbiota

ABSTRACT Helicobacter pylori is the strongest risk factor for gastric adenocarcinoma; however, most infected individuals never develop this malignancy. Strain-specific microbial factors, such as the oncoprotein CagA, as well as environmental conditions, such as iron deficiency, augment cancer risk. Importantly, dysbiosis of the gastric microbiota is also associated with gastric cancer. To investigate the combinatorial effects of these determinants in an in vivo model of gastric cancer, Mongolian gerbils were infected with the carcinogenic cag+ H. pylori strain 7.13 or a 7.13 cagA isogenic mutant, and microbial DNA extracted from gastric tissue was analyzed by 16S rRNA sequencing. Infection with H. pylori significantly increased gastric inflammation and injury, decreased α-diversity, and altered microbial community structure in a cagA-dependent manner. The effect of iron deficiency on gastric microbial communities was also investigated within the context of infection. H. pylori-induced injury was augmented under conditions of iron deficiency, but despite differences in gastric pathology, there were no significant differences in α- or β-diversity, phyla, or operational taxonomic unit (OTU) abundance among infected gerbils maintained on iron-replete or iron-depleted diets. However, when microbial composition was stratified based solely on the severity of histologic injury, significant differences in α- and β-diversity were present among gerbils harboring premalignant or malignant lesions compared to gerbils with gastritis alone. This study demonstrates that H. pylori decreases gastric microbial diversity and community structure in a cagA-dependent manner and that as carcinogenesis progresses, there are corresponding alterations in community structure that parallel the severity of disease. IMPORTANCE Microbial communities are essential for the maintenance of human health, and when these communities are altered, hosts can become susceptible to inflammation and disease. Dysbiosis contributes to gastrointestinal cancers, and specific bacterial species are associated with this phenotype. This study uses a robust and reproducible animal model to demonstrate that H. pylori infection induces gastric dysbiosis in a cagA-dependent manner and further that dysbiosis and altered microbial community structure parallel the severity of H. pylori-induced gastric injury. Ultimately, such models of H. pylori infection and cancer that can effectively evaluate multiple determinants simultaneously may yield effective strategies for manipulating the gastric microbiota to prevent the development of gastric cancer.

scholarly journals Divergence of Peroxisome Membrane Gene Sequence and Expression Between Yeast Species

2020 ◽  
Vol 10 (6) ◽  
pp. 2079-2085
Author(s):  
Claire A. Dubin ◽  
Jeremy I. Roop ◽  
Rachel B. Brem
Keyword(s):  
Molecular Mechanisms ◽  
Genomic Sequence ◽  
Yeast Species ◽  
Large Population ◽  
Adaptive Divergence ◽  
Comparative Genomic ◽  
Sequencing Studies ◽  
Genes Encoding ◽  
Mechanisms Of Adaptation ◽  
Peroxisome Membrane

Large population-genomic sequencing studies can enable highly-powered analyses of sequence signatures of natural selection. Genome repositories now available for Saccharomyces yeast make it a premier model for studies of the molecular mechanisms of adaptation. We mined the genomes of hundreds of isolates of the sister species S. cerevisiae and S. paradoxus to identify sequence hallmarks of adaptive divergence between the two. From the top hits we focused on a set of genes encoding membrane proteins of the peroxisome, an organelle devoted to lipid breakdown and other specialized metabolic pathways. In-depth population- and comparative-genomic sequence analyses of these genes revealed striking divergence between S. cerevisiae and S. paradoxus. And from transcriptional profiles we detected non-neutral, directional cis-regulatory variation at the peroxisome membrane genes, with overall high expression in S. cerevisiae relative to S. paradoxus. Taken together, these data support a model in which yeast species have differentially tuned the expression of peroxisome components to boost their fitness in distinct niches.

scholarly journals The Role of PPARγinHelicobacter pyloriInfection and Gastric Carcinogenesis

PPAR Research ◽  
2012 ◽  
Vol 2012 ◽  
pp. 1-6 ◽  
Author(s):  
Jong-Min Lee ◽  
Sung Soo Kim ◽  
Young-Seok Cho
Keyword(s):  
Gastric Cancer ◽  
Cell Proliferation ◽  
Current Knowledge ◽  
Mucosal Injury ◽  
Gastric Carcinogenesis ◽  
Etiologic Factor ◽  
Peroxisome Proliferator ◽  
Peroxisome Proliferator Activated Receptor ◽  
H Pylori

Peroxisome proliferator-activated receptorγ(PPARγ) is a nuclear receptor that is important in many physiological and pathological processes, such as lipid metabolism, insulin sensitivity, inflammation, cell proliferation, and carcinogenesis. Several studies have shown that PPARγplays an important role in gastric mucosal injury due toHelicobacter pylori(H. pylori). AsH. pyloriinfection is the main etiologic factor in chronic gastritis and gastric cancer, understanding of the potential roles of PPARγinH. pyloriinfection may lead to the development of a therapeutic target. In this paper, the authors discuss the current knowledge on the role of PPARγinH. pyloriinfection and its related gastric carcinogenesis.

scholarly journals Hydrogen Metabolism inHelicobacter pyloriPlays a Role in Gastric Carcinogenesis through Facilitating CagA Translocation

mBio ◽  
2016 ◽  
Vol 7 (4) ◽  
Author(s):  
Ge Wang ◽  
Judith Romero-Gallo ◽  
Stéphane L. Benoit ◽  
M. Blanca Piazuelo ◽  
Ricardo L. Dominguez ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Cancer Risk ◽  
Respiratory Chain ◽  
Molecular Hydrogen ◽  
Gastric Carcinogenesis ◽  
Hydrogenase Activity ◽  
Hydrogen Metabolism ◽  
Gastric Cancer Risk ◽  
Ags Cells ◽  
H Pylori

ABSTRACTA known virulence factor ofHelicobacter pylorithat augments gastric cancer risk is the CagA cytotoxin. A carcinogenic derivative strain, 7.13, that has a greater ability to translocate CagA exhibits much higher hydrogenase activity than its parent noncarcinogenic strain, B128. A Δhydmutant strain with deletion of hydrogenase genes was ineffective in CagA translocation into human gastric epithelial AGS cells, while no significant attenuation of cell adhesion was observed. The quinone reductase inhibitor 2-n-heptyl-4-hydroxyquinoline-N-oxide (HQNO) was used to specifically inhibit the H2-utilizing respiratory chain of outer membrane-permeabilized bacterial cells; that level of inhibitor also greatly attenuated CagA translocation into AGS cells, indicating the H2-generated transmembrane potential is a contributor to toxin translocation. The Δhydstrain showed a decreased frequency of DNA transformation, suggesting thatH. pylorihydrogenase is also involved in energizing the DNA uptake apparatus. In a gerbil model of infection, the ability of the Δhydstrain to induce inflammation was significantly attenuated (at 12 weeks postinoculation), while all of the gerbils infected with the parent strain (7.13) exhibited a high level of inflammation. Gastric cancer developed in 50% of gerbils infected with the wild-type strain 7.13 but in none of the animals infected with the Δhydstrain. By examining the hydrogenase activities from well-defined clinicalH. pyloriisolates, we observed that strains isolated from cancer patients (n= 6) have a significantly higher hydrogenase (H2/O2) activity than the strains isolated from gastritis patients (n= 6), further supporting an association betweenH. pylorihydrogenase activity and gastric carcinogenesis in humans.IMPORTANCEHydrogen-utilizing hydrogenases are known to be important for some respiratory pathogens to colonize hosts. Here a gastric cancer connection is made via a pathogen’s (H. pylori) use of molecular hydrogen, a host microbiome-produced gas. Delivery of the known carcinogenic factor CagA into host cells is augmented by the H2-utilizing respiratory chain of the bacterium. The role of hydrogenase in carcinogenesis is demonstrated in an animal model, whereby inflammation markers and cancer development were attenuated in the hydrogenase-null strain. Hydrogenase activity comparisons of clinical strains of the pathogen also support a connection between hydrogen metabolism and gastric cancer risk. While molecular hydrogen use is acknowledged to be an alternative high-energy substrate for some pathogens, this work extends the roles of H2oxidation to include transport of a carcinogenic toxin. The work provides a new avenue for exploratory treatment of some cancers via microflora alterations.

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