Helicobacter pylori-Induced Inflammation: Possible Factors Modulating the Risk of Gastric Cancer

Chronic inflammation and long-term tissue injury are related to many malignancies, including gastric cancer (GC). Helicobacter pylori (H. pylori), classified as a class I carcinogen, induces chronic superficial gastritis followed by gastric carcinogenesis. Despite a high prevalence of H. pylori infection, only about 1–3% of people infected with this bacterium develop GC worldwide. Furthermore, the development of chronic gastritis in some, but not all, H. pylori-infected subjects remains unexplained. These conflicting findings indicate that clinical outcomes of aggressive inflammation (atrophic gastritis) to gastric carcinogenesis are influenced by several other factors (in addition to H. pylori infection), such as gut microbiota, co-existence of intestinal helminths, dietary habits, and host genetic factors. This review has five goals: (1) to assess our current understanding of the process of H. pylori-triggered inflammation and gastric precursor lesions; (2) to present a hypothesis on risk modulation by the gut microbiota and infestation with intestinal helminths; (3) to identify the dietary behavior of the people at risk of GC; (4) to check the inflammation-related genetic polymorphisms and role of exosomes together with other factors as initiators of precancerous lesions and gastric carcinoma; and (5) finally, to conclude and suggest a new direction for future research.

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Eradication of Helicobacter pylori and Gastric Cancer: A Controversial Relationship

Frontiers in Microbiology ◽

10.3389/fmicb.2021.630852 ◽

2021 ◽

Vol 12 ◽

Author(s):

Mariagrazia Piscione ◽

Mariangela Mazzone ◽

Maria Carmela Di Marcantonio ◽

Raffaella Muraro ◽

Gabriella Mincione

Keyword(s):

Gastric Cancer ◽

Helicobacter Pylori ◽

Atrophic Gastritis ◽

Precancerous Lesions ◽

Eradication Therapy ◽

Developed Countries ◽

Gastric Carcinogenesis ◽

Gastric Disease ◽

Type I ◽

H Pylori

Worldwide, gastric cancer (GC) represents the fifth cancer for incidence, and the third as cause of death in developed countries. Indeed, it resulted in more than 780,000 deaths in 2018. Helicobacter pylori appears to be responsible for the majority of these cancers. On the basis of recent studies, and either alone or combined with additional etiological factors, H. pylori is considered a “type I carcinogen.” Over recent decades, new insights have been obtained into the strategies that have been adopted by H. pylori to survive the acidic conditions of the gastric environment, and to result in persistent infection, and dysregulation of host functions. The multistep processes involved in the development of GC are initiated by transition of the mucosa into chronic non-atrophic gastritis, which is primarily triggered by infection with H. pylori. This gastritis then progresses into atrophic gastritis and intestinal metaplasia, and then to dysplasia, and following Correa’s cascade, to adenocarcinoma. The use of antibiotics for eradication of H. pylori can reduce the incidence of precancerous lesions only in the early stages of gastric carcinogenesis. Here, we first survey the etiology and risk factors of GC, and then we analyze the mechanisms underlying tumorigenesis induced by H. pylori, focusing attention on virulence factor CagA, inflammation, oxidative stress, and ErbB2 receptor tyrosine kinase. Moreover, we investigate the relationships between H. pylori eradication therapy and other diseases, considering not only cardia (upper stomach) cancers and Barrett’s esophagus, but also asthma and allergies, through discussion of the “hygiene hypothesis. ” This hypothesis suggests that improved hygiene and antibiotic use in early life reduces microbial exposure, such that the immune response does not become primed, and individuals are not protected against atopic disorders, asthma, and autoimmune diseases. Finally, we overview recent advances to uncover the complex interplay between H. pylori and the gut microbiota during gastric carcinogenesis, as characterized by reduced bacterial diversity and increased microbial dysbiosis. Indeed, it is of particular importance to identify the bacterial taxa of the stomach that might predict the outcome of gastric disease through the stages of Correa’s cascade, to improve prevention and therapy of gastric carcinoma.

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

10.21203/rs.2.21633/v1 ◽

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.

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

Therapeutic Advances in Gastroenterology ◽

10.1177/1756284819894062 ◽

2019 ◽

Vol 12 ◽

pp. 175628481989406 ◽

Cited By ~ 8

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.

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

Scientific Data ◽

10.1038/s41597-020-00636-6 ◽

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.

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Will Treatment of Helicobacter Pylori Infection in Childhood Alter the Risk of Developing Gastric Cancer?

Canadian Journal of Gastroenterology ◽

10.1155/2005/732369 ◽

2005 ◽

Vol 19 (7) ◽

pp. 409-411 ◽

Cited By ~ 41

Author(s):

Billy Bourke

Keyword(s):

Gastric Cancer ◽

Helicobacter Pylori ◽

Precancerous Lesions ◽

Positive Family History ◽

Population Based ◽

Screening Programs ◽

History Of ◽

Different Populations ◽

H Pylori ◽

Developed Nations

Helicobacter pylori has been classified as a group 1 carcinogen for gastric cancer. It is estimated that there is between a two- and sixfold increase in the risk of developing gastric cancer among infected patients. Among different populations, the risk of H pylori-infected individuals developing gastric cancer varies greatly. However, on a worldwide scale, gastric cancer is the second most common cause of cancer-related death. Therefore, H pylori eradication could help prevent up to three to four million gastric cancer deaths per year. H pylori is usually acquired in childhood. Because infected children have not harboured the organism for long enough to have developed precancerous lesions, childhood is theoretically an attractive time for H pylori eradication and, thus, could help prevent gastric cancer later in life. However, as H pylori prevalence and the incidence of gastric cancer are falling rapidly in developed nations, widespread population screening programs aimed at the eradication of H pylori in these countries would be enormously expensive. Therefore, except in groups with a high risk for development of gastric cancer (eg, Japanese or those with a strong positive family history of gastric cancer), a population-based test-and-treat policy is not justified.

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Interplay and cooperation of Helicobacter pylori and gut microbiota in gastric carcinogenesis

BMC Microbiology ◽

10.1186/s12866-021-02315-x ◽

2021 ◽

Vol 21 (1) ◽

Author(s):

Seyedeh Zahra Bakhti ◽

Saeid Latifi-Navid

Keyword(s):

Helicobacter Pylori ◽

Gut Microbiota ◽

Intestinal Microbiota ◽

Bacterial Species ◽

Short Chain Fatty Acids ◽

Gastric Carcinogenesis ◽

Oncogenic Signaling ◽

Comprehensive Overview ◽

H Pylori ◽

Oncogenic Signaling Pathways

AbstractChronic Helicobacter pylori infection is a critical risk factor for gastric cancer (GC). However, only 1–3 % of people with H. pylori develop GC. In gastric carcinogenesis, non-H. pylori bacteria in the stomach might interact with H. pylori. Bacterial dysbiosis in the stomach can strengthen gastric neoplasia development via generating tumor-promoting metabolites, DNA damaging, suppressing antitumor immunity, and activating oncogenic signaling pathways. Other bacterial species may generate short-chain fatty acids like butyrate that may inhibit carcinogenesis and inflammation in the human stomach. The present article aimed at providing a comprehensive overview of the effects of gut microbiota and H. pylori on the development of GC. Next, the potential mechanisms of intestinal microbiota were discussed in gastric carcinogenesis. We also disserted the complicated interactions between H. pylori, intestinal microbiota, and host in gastric carcinogenesis, thus helping us to design new strategies for preventing, diagnosing, and treating GC.

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Effect of Helicobacter pylori Eradication on Epigenetic Changes in Gastric Cancer-related Genes

The Korean Journal of Helicobacter and Upper Gastrointestinal Research ◽

10.7704/kjhugr.2021.0042 ◽

2021 ◽

Vol 21 (4) ◽

pp. 256-266

Author(s):

Ji Min Choi ◽

Sang Gyun Kim

Keyword(s):

Gastric Cancer ◽

Helicobacter Pylori ◽

Gastric Mucosa ◽

Gastric Carcinogenesis ◽

Point Of View ◽

Epigenetic Changes ◽

Epigenetic Alterations ◽

Helicobacter Pylori Eradication ◽

Gastric Cancer Prevention ◽

H Pylori

It is known that gastric carcinogenesis results from the progressive changes from chronic gastritis to gastric atrophy, intestinal metaplasia, dysplasia, and invasive carcinoma. Several genetic and epigenetic alterations are involved in this process, and Helicobacter pylori (H. pylori) infection is believed to induce the initiation and progression of these steps. From an epigenetic point of view, H. pylori induces hypermethylation of genes involved in the development of gastric cancer and regulates the expression of various microRNAs (miRNAs). These H. pylori-related epigenetic changes are accumulated not only at the site of neoplasm but also in the adjacent non-cancerous gastric mucosa. Thereby, a state vulnerable to gastric cancer known as an epigenetic field defect is formed. H. pylori eradication can have an effective chemopreventive effect in gastric carcinogenesis. However, the molecular biological changes that occur in the stomach environment during H. pylori eradication have not yet been established. Several studies have reported that H. pylori eradication can restore infection-related changes, especially epigenetic alterations in gastric cancer-related genes, but some studies have shown otherwise. Simply put, it appears that the recovery of methylated gastric cancer-related genes and miRNAs during H. pylori eradication may vary among genes and may also differ depending on the histological subtype of the gastric mucosa. In this review, we will discuss the potential mechanism of gastric cancer prevention by H. pylori eradication, mainly from an epigenetic perspective.

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Association of Helicobacter pylori infection and stomach cancer: our experience

International Surgery Journal ◽

10.18203/2349-2902.isj20183193 ◽

2018 ◽

Vol 5 (8) ◽

pp. 2794

Author(s):

N. G. Javan ◽

Wormi Sharon

Keyword(s):

Gastric Cancer ◽

Helicobacter Pylori ◽

Gastric Carcinoma ◽

Stomach Cancer ◽

Histopathological Examination ◽

Chronic Atrophic Gastritis ◽

Helicobacter Pylori Infection ◽

Future Research ◽

Gastric Cancer Prevention ◽

H Pylori

Background: Infection with Helicobacter pylori (H. pylori) has been linked with chronic atrophic gastritis, an inflammatory precursor of gastric adenocarcinoma. There are data on the epidemiology, pathophysiology, and histology of this disease that show that Helicobacter pylori gastritis has an important role in gastric carcinogenesis. However, it has to be considered that only very few of those infected with Helicobacter pylori will develop gastric cancer. Hence, it will be a major target of future research to identify individuals who carry a greater risk for developing gastric cancer, and therefore may benefit from eradication of Helicobacter pylori in terms of gastric cancer prevention. Various studies revealed that approximately more than 50% of the world’s human population is infected by Helicobacter pylori. In underdeveloped countries, this association is shown to be much higher according to different studies.Methods: This study was conducted over a period of 36 months from 1st January 2014 till December 31st, 2016. All patients who underwent Gastrectomy during this period were taken. All specimens were investigated to see presence of helicobacter pylori by histological examination. A total of 50 Gastrectomy was performed by one surgical team over 36-month period.Results: Out of 50 patients, Helicobacter pylori positivity was seen in 33 (66%) cases by histopathological examination (HPE). Gastric cancer is more prevalent among males 31 (62%) as compared to 19 (38%) in females. It is more common among the older age group.Conclusions: Helicobacter pylori infection is higher in prevalence in cases of stomach cancer. Present study also showed that there is significant association of Helicobacter pylori infection with gastric carcinoma. Helicobacter pylori infection could be one of the etiological factors for gastric carcinoma.

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Differential Helicobacter pylori Plasticity in the Gastric Niche of Subjects at Increased Gastric Cancer Risk

Pathogens ◽

10.3390/pathogens8020065 ◽

2019 ◽

Vol 8 (2) ◽

pp. 65

Author(s):

Mariateresa Casarotto ◽

Chiara Pratesi ◽

Ettore Bidoli ◽

Stefania Maiero ◽

Raffaella Magris ◽

...

Keyword(s):

Gastric Cancer ◽

Helicobacter Pylori ◽

Precancerous Lesions ◽

Neutrophil Infiltration ◽

Host Bacterium ◽

Gastric Cancer Risk ◽

Increased Risk ◽

Cytotoxin Associated Gene A ◽

Sydney System ◽

H Pylori

Helicobacter pylori (H. pylori) represents an independent risk factor for Gastric Cancer (GC). First Degree Relatives (FDR) of GC subjects and Autoimmune Gastritis (AG) patients are both at increased risk for GC. H. pylori genetic heterogeneity within the gastric niche of FDR and AG individuals has been little explored. To understand whether they exploit an increased H. pylori stability and virulence, 14 AG, 25 FDR, 39 GC and 13 dyspeptic patients (D) were investigated by a cultural PCR-based approach characterizing single colonies-forming-units. We chose three loci within the Cytotoxin-associated gene-A Pathogenicity Island (CagPAI) (cagA,cagE,virB11), vacA, homA and homB as markers of virulence with reported association to GC. Inflammatory/precancerous lesions were staged according to Sydney System. When compared to D, FDR, similarly to GC patients, were associated to higher atrophy (OR = 6.29; 95% CI:1.23–31.96 in FDR; OR = 7.50; 95% CI:1.67–33.72 in GC) and a lower frequency of mixed infections (OR = 0.16; 95% CI:0.03–0.81 in FDR; OR = 0.10; 95% CI:0.02–0.48 in GC). FDR presented also an increased neutrophil infiltration (OR = 7.19; 95% CI:1.16–44.65). Both FDR and GC carried a higher proportion of CagPAI+vacAs1i1mx+homB+ profiles (OR = 2.71; 95% CI: 1.66–4.41 and OR = 3.43; 95% CI: 2.16–5.44, respectively). Conversely, AG patients presented a lower frequency of subtypes carrying a stable CagPAI and vacAs1i1mx. These results underline different H. pylori plasticity in FDR and AG individuals, and thus, a different host-bacterium interaction capacity that should be considered in the context of eradication therapies.

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Lifestyles, genetics, and future perspectives on gastric cancer in east Asian populations

Journal of Human Genetics ◽

10.1038/s10038-021-00960-8 ◽

2021 ◽

Author(s):

Hiroto Katoh ◽

Shumpei Ishikawa

Keyword(s):

Gastric Cancer ◽

Helicobacter Pylori ◽

Cancer Genomics ◽

State Of The Art ◽

East Asian ◽

Gastric Carcinogenesis ◽

Review Article ◽

Future Perspectives ◽

Asian Populations ◽

H Pylori

AbstractThe prevalence of gastric cancer (GC) differs among regions worldwide, with the highest occurrence in east Asia. Thus, its etiology, with respect to ethnic background, environmental factors, and lifestyles, is also thought to differ essentially. In addition, etiology of GC is speculated to be changing due to the recent decrease in the Helicobacter pylori (H. pylori) infection in Japan. State-of-the-art somatic/germline cancer genomics has clarified the etiologies of gastric carcinogenesis. In this review article, we summarize past and present milestones in our understanding of GC achieved through genomic approaches, including a recent report that revealed higher-than-expected frequencies of GCs attributed to east Asian-specific germline variants in ALDH2 or CDH1 in combination with lifestyles. Based on this updated knowledge, we also discuss the possible impact of and high-risk approaches for GCs in the upcoming “H. pylori-negative era.”

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