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Oje A, Galati J, Peek RM. Current Understanding of Optimal Prevention of Helicobacter pylori-Induced Cancer. Gastroenterol Clin North Am 2025; 54:397-413. [PMID: 40348495 DOI: 10.1016/j.gtc.2024.12.005] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 05/14/2025]
Abstract
Gastric cancer is the fifth most common cancer and the fifth most common cause of cancer-related death globally. The key to improving outcomes lies in effective prevention and early detection, which are critical for successful curative interventions. Helicobacter pylori is the strongest known risk factor for gastric cancer, and eradication of this pathogen is critical for reducing cancer risk. By synthesizing current evidence and exploring the advanced therapeutic approaches, this review provides a comprehensive overview of best practices for mitigating gastric cancer through targeted bacterial intervention.
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Affiliation(s)
- Adesola Oje
- Division of Gastroenterology, Hepatology, and Nutrition, Vanderbilt University Medical Center, Nashville, TN, USA.
| | - Jonathan Galati
- Division of Gastroenterology, Hepatology, and Nutrition, Vanderbilt University Medical Center, Nashville, TN, USA
| | - Richard M Peek
- Division of Gastroenterology, Hepatology, and Nutrition, Vanderbilt University Medical Center, Nashville, TN, USA
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2
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Liu Y, Miao R, Xia J, Zhou Y, Yao J, Shao S. Infection of Helicobacter pylori contributes to the progression of gastric cancer through ferroptosis. Cell Death Discov 2024; 10:485. [PMID: 39622791 PMCID: PMC11612470 DOI: 10.1038/s41420-024-02253-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2024] [Revised: 11/21/2024] [Accepted: 11/25/2024] [Indexed: 12/06/2024] Open
Abstract
Helicobacter pylori (H. pylori) is a gram-negative pathogen that colonizes gastric epithelial cells, and its chronic infection is the primary risk factor for the development of gastric cancer (GC). Ferroptosis is an iron-dependent form of cell death characterized by intracellular lipid peroxide accumulation and reactive oxygen species (ROS) imbalance. There is evidence suggesting that pathogens can manipulate ferroptosis to facilitate their replication, transmission, and pathogenesis. However, the interaction between ferroptosis and H. pylori infection requires further elucidation. We reviewed the mechanism of ferroptosis and found that H. pylori virulence factors such as cytotoxin-associated gene A (CagA), vacuolating cytotoxin A (VacA), neutrophil-activating protein A (NapA), superoxide dismutase B (SodB), γ-glutamyl transpeptidase (gGT), lipopolysaccharide (LPS), and outer inflammatory protein A (OipA) affected glutathione (GSH), ROS, and lipid oxidation to regulate ferroptosis. It also affected the progression of GC by regulating ferroptosis-related indicators through abnormal gene expression after H. pylori infected gastric mucosa cells. Finally, we discuss the potential application value of ferroptosis inducers, inhibitors and other drugs in treating H. pylori-infected GC patients while acknowledging that their interactions are still not fully understood.
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Affiliation(s)
- Yun Liu
- Department of Gastroenterology, Institute of Digestive Disease, The Affiliated People's Hospital, Jiangsu University, Zhenjiang, Jiangsu, China
- School of Medicine, Jiangsu University, Zhenjiang, Jiangsu, China
| | - Renjie Miao
- Department of Clinical laboratory, Affiliated Third Hospital of Zhenjiang to Jiangsu University, Zhenjiang, Jiangsu, China
| | - Jinxuan Xia
- Zhenjiang Mental Health Center, Jiangsu, China
| | - Yong Zhou
- Department of Gastroenterology, Institute of Digestive Disease, The Affiliated People's Hospital, Jiangsu University, Zhenjiang, Jiangsu, China.
| | - Jun Yao
- Department of Gastroenterology, Institute of Digestive Disease, The Affiliated People's Hospital, Jiangsu University, Zhenjiang, Jiangsu, China.
| | - Shihe Shao
- School of Medicine, Jiangsu University, Zhenjiang, Jiangsu, China.
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3
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Palmer LD, Traina KA, Juttukonda LJ, Lonergan ZR, Bansah DA, Ren X, Geary JH, Pinelli C, Boyd KL, Yang TS, Skaar EP. Dietary zinc deficiency promotes Acinetobacter baumannii lung infection via IL-13 in mice. Nat Microbiol 2024; 9:3196-3209. [PMID: 39548344 PMCID: PMC11800279 DOI: 10.1038/s41564-024-01849-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2023] [Accepted: 10/07/2024] [Indexed: 11/17/2024]
Abstract
Dietary zinc deficiency is a major risk factor for pneumonia. Acinetobacter baumannii is a leading cause of ventilator-associated pneumonia and a critical public health threat due to increasing rates of multidrug resistance. Patient populations at increased risk for A. baumannii pneumonia are also at increased risk of zinc deficiency. Here we established a mouse model of dietary zinc deficiency and acute A. baumannii pneumonia to test the hypothesis that host zinc deficiency contributes to A. baumannii pathogenesis. We showed that zinc-deficient mice have significantly increased A. baumannii burdens in the lungs, dissemination to the spleen and higher mortality. During infection, zinc-deficient mice produce more pro-inflammatory cytokines, including IL-13. Administration of IL-13 promotes A. baumannii dissemination in zinc-sufficient mice, while antibody neutralization of IL-13 protects zinc-deficient mice from A. baumannii dissemination and mortality during infection. These data highlight the therapeutic potential of anti-IL-13 antibody treatments, which are well tolerated in humans, for the treatment of pneumonia.
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Affiliation(s)
- Lauren D Palmer
- Department of Microbiology and Immunology, University of Illinois Chicago, Chicago, IL, USA.
| | - Kacie A Traina
- Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, TN, USA
- Vanderbilt Institute for Infection, Immunology, and Inflammation, Vanderbilt University Medical Center, Nashville, TN, USA
| | - Lillian J Juttukonda
- Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, TN, USA
- Vanderbilt Institute for Infection, Immunology, and Inflammation, Vanderbilt University Medical Center, Nashville, TN, USA
- Boston Children's Hospital, Boston, MA, USA
| | - Zachery R Lonergan
- Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, TN, USA
- Vanderbilt Institute for Infection, Immunology, and Inflammation, Vanderbilt University Medical Center, Nashville, TN, USA
- Rutgers University, New Brunswick, NJ, USA
| | - Dziedzom A Bansah
- Department of Microbiology and Immunology, University of Illinois Chicago, Chicago, IL, USA
- American University of the Caribbean, Cupecoy, Sint Maarten
| | - Xiaomei Ren
- Department of Microbiology and Immunology, University of Illinois Chicago, Chicago, IL, USA
| | - John H Geary
- Department of Microbiology and Immunology, University of Illinois Chicago, Chicago, IL, USA
| | - Christopher Pinelli
- Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, TN, USA
- Vanderbilt Institute for Infection, Immunology, and Inflammation, Vanderbilt University Medical Center, Nashville, TN, USA
- NAMSA, Minneapolis, MN, USA
| | - Kelli L Boyd
- Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, TN, USA
- Vanderbilt Institute for Infection, Immunology, and Inflammation, Vanderbilt University Medical Center, Nashville, TN, USA
- Gilead Sciences, Inc., Foster City, CA, USA
| | - Tzushan S Yang
- Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, TN, USA
- Vanderbilt Institute for Infection, Immunology, and Inflammation, Vanderbilt University Medical Center, Nashville, TN, USA
| | - Eric P Skaar
- Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, TN, USA.
- Vanderbilt Institute for Infection, Immunology, and Inflammation, Vanderbilt University Medical Center, Nashville, TN, USA.
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Mohammed O, Gizaw ST, Degef M. Potential diagnostic, prognostic, and predictive biomarkers of gastric cancer. Health Sci Rep 2024; 7:e2261. [PMID: 39040881 PMCID: PMC11260885 DOI: 10.1002/hsr2.2261] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2023] [Revised: 06/29/2024] [Accepted: 07/04/2024] [Indexed: 07/24/2024] Open
Abstract
Background Gastric cancer (GC), a malignant epithelial tumor, is the fourth leading cause of cancer-related death worldwide. Therapeutic strategies for GC, despite the biggest challenges, can significantly improve survival rates through early detection and effective screening methods. Aim To provide brief information on the necessity of multiple specific diagnostic, prognostic, and predictive markers for GC. Methods This review was conducted using a variety of search engines, including PubMed Central, Scopus, Web of Science, Google Scholar, and others. Results Some potential biomarkers that provide essential information include circulating tumor cells (CTCs), DNA methylation, claudin 18.2, fibroblast growth factor receptor 2 (FGFR2), long noncoding RNAs (lncRNAs), cell-free DNA (cfDNA), microRNAs, and serum pepsinogens. Conclusion Multiple tumor markers are essential for screening, tumor identification, staging, prognostic assessment, and monitoring recurrence after therapy due to the absence of a single tumor indicator for diagnosing, prognosticating, and predicting GC.
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Affiliation(s)
- Ousman Mohammed
- Department of Medical Laboratory SciencesCollege of Medicine and Health Sciences, Wollo UniversityDessieEthiopia
| | - Solomon Tebeje Gizaw
- Department of Medical BiochemistrySchool of Medicine, College of Health Sciences, AAUAddis AbabaEthiopia
| | - Maria Degef
- Department of Medical BiochemistrySchool of Medicine, College of Health Sciences, AAUAddis AbabaEthiopia
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5
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Weisy OKM, Kedia RA, Mahmoud I, Abu Odeh RO, Mussa BM, Abusnana S, Soliman SSM, Muhammad JS, Hamad M, Ghemrawi R, Khoder G. Assessment of Helicobacter pylori cytotoxin-associated Gene A (Cag A) protein and its association with ferritin and vitamin B12 deficiencies among adult healthy asymptomatic residents in Sharjah, United Arab Emirates. Heliyon 2024; 10:e32141. [PMID: 38882276 PMCID: PMC11180313 DOI: 10.1016/j.heliyon.2024.e32141] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2024] [Revised: 05/28/2024] [Accepted: 05/29/2024] [Indexed: 06/18/2024] Open
Abstract
The United Arab Emirates (UAE) serves as an effective epidemiological site for assessing Helicobacter pylori (H. pylori) infection due to its diverse population. However, comprehensive studies on the prevalence of H. pylori in the UAE are notably scarce. In depth prevalence studies are needed as a preventive measure against gastric cancer and other emerging extra gastric diseases associated with H. pylori infection. Aim: This study aimed to assess H. pylori infection and its virulent oncoprotein, the Cytotoxin-Associated Gene (Cag A) and its association with ferritin and vitamin B12 deficiencies. Methods: The study was conducted on 1094 healthy asymptomatic volunteers residents in the Sharjah Emirate, UAE. Enzyme-linked immunosorbent assay (ELISA) was performed to assess H. pylori infection using H. pylori antibodies (IgG), and detection of CagA protein using Cag A antibody (IgG) in the human serum. Ferritin and vitamin B12 serum levels were assessed and correlated to H. pylori infection. Results: This study focuses mainly on the assessment of H. pylori and its virulent factor CagA, in relation to vitamin B12 and ferritin deficiencies. Remarkably, 49.6 % of the participants were detected positive for H. pylori, with over half of these cases involving CagA positive strains. Notably, among Emirati participants, 76.11 % of those with H. pylori infection were CagA positive. Statistical analysis revealed a significant correlation between H. pylori, CagA level, and ferritin/vitamin B12 deficiencies. Conclusion: These findings emphasize the importance of timely detection and eradication of H. pylori not only as a preventive strategy against gastric cancer but also as an effective strategy to rescue the adverse effects from ferritin and vitamin B12 deficiencies, thereby improving the overall health outcomes of individuals affected by H. pylori infection.
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Affiliation(s)
- Om Kolthoom M Weisy
- Department of Pharmaceutics and Pharmaceuticals Technology, College of Pharmacy, University of Sharjah, Sharjah, United Arab Emirates
| | - Reena A Kedia
- Research Institute for Medical & Health Sciences, University of Sharjah, United Arab Emirates
| | - Ibrahim Mahmoud
- Department of Family and Community Medicine and Behavioral Sciences, College of Medicine, University of Sharjah, Sharjah, United Arab Emirates
| | - Raed O Abu Odeh
- Research Institute for Medical & Health Sciences, University of Sharjah, United Arab Emirates
- Department of Medical Laboratory Sciences, College of Health Sciences, University of Sharjah, Sharjah, United Arab Emirates
| | - Bashair M Mussa
- Department of Basic Medical Sciences, College of Medicine, University of Sharjah, Sharjah, United Arab Emirates
| | - Salah Abusnana
- Diabetes and Endocrinology Department, University Hospital Sharjah, Sharjah, United Arab Emirates
- Clinical Science Department, College of Medicine, University of Sharjah, Sharjah, United Arab Emirates
| | - Sameh S M Soliman
- Department of Medicinal Chemistry, College of Pharmacy, University of Sharjah, Sharjah, United Arab Emirates
| | - Jibran Sualeh Muhammad
- Research Institute for Medical & Health Sciences, University of Sharjah, United Arab Emirates
- Department of Basic Medical Sciences, College of Medicine, University of Sharjah, Sharjah, United Arab Emirates
| | - Mohamad Hamad
- Research Institute for Medical & Health Sciences, University of Sharjah, United Arab Emirates
- Department of Medical Laboratory Sciences, College of Health Sciences, University of Sharjah, Sharjah, United Arab Emirates
| | - Rose Ghemrawi
- College of Pharmacy, Al Ain University, Abu Dhabi, United Arab Emirates
- AAU Health and Biomedical Research Center, Al Ain University, Abu Dhabi, United Arab Emirates
| | - Ghalia Khoder
- Department of Pharmaceutics and Pharmaceuticals Technology, College of Pharmacy, University of Sharjah, Sharjah, United Arab Emirates
- Research Institute for Medical & Health Sciences, University of Sharjah, United Arab Emirates
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6
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Yang M. Interaction between intestinal flora and gastric cancer in tumor microenvironment. Front Oncol 2024; 14:1402483. [PMID: 38835386 PMCID: PMC11148328 DOI: 10.3389/fonc.2024.1402483] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2024] [Accepted: 05/01/2024] [Indexed: 06/06/2024] Open
Abstract
Gastric Cancer (GC) is a prevalent malignancy globally and is the third leading cause of cancer-related deaths. Recent researches focused on the correlation between intestinal flora and GC. Studies indicate that bacteria can influence the development of gastrointestinal tumors by releasing bacterial extracellular vesicles (BEVs). The Tumor microenvironment (TME) plays an important role in tumor survival, with the interaction between intestinal flora, BEVs, and TME directly impacting tumor progression. Moreover, recent studies have demonstrated that intestinal microflora and BEVs can modify TME to enhance the effectiveness of antitumor drugs. This review article provides an overview and comparison of the biological targets through which the intestinal microbiome regulates TME, laying the groundwork for potential applications in tumor diagnosis, treatment, and prognosis.
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Affiliation(s)
- Mingjin Yang
- Department of Gastrointestinal Surgery, The Affiliated People's Hospital of Ningbo University, Ningbo, China
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7
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Yang S, Hao S, Ye H, Zhang X. Cross-talk between Helicobacter pylori and gastric cancer: a scientometric analysis. Front Cell Infect Microbiol 2024; 14:1353094. [PMID: 38357448 PMCID: PMC10864449 DOI: 10.3389/fcimb.2024.1353094] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2023] [Accepted: 01/17/2024] [Indexed: 02/16/2024] Open
Abstract
Background Helicobacter pylori (HP) is considered a leading risk factor for gastric cancer (GC). The aim of this article is to conduct bibliometric and visual analysis to assess scientific output, identify highly cited papers, summarize current knowledge, and explore recent hotspots and trends in HP/GC research. Methods A bibliographic search was conducted on October 24, 2023, to retrieve relevant studies on HP/GC research between 2003 and 2022. The search terms were attached to HP and GC. The main data were from the Web of Science Core Collection (WoSCC). Data visualization was performed using Biblioshiny, VOSviewer, and Microsoft Excel. Results In HP/GC research, 1970 papers were retrieved. The total number of papers (Np) in HP/GC was growing from 2003 to 2022. China and Japan were in the leading position and made the most contributions to HP/GC. Vanderbilt University and the US Department of Veterans Affairs had the highest Np. The most productive authors were Peek Jr Richard M. and Piazuelo M Blanca. Helicobacter received the most Np, while Gastroenterology had the most total citations (TC). High-cited publications and keyword clustering were used to identify the current status and trends in HP/GC research, while historical citation analysis provided insight into the evolution of HP/GC research. The hot topics included the effect of HP on gastric tumorigenesis and progression, the pathogenesis of HP-induced GC (HP factors), and the mechanisms by which HP affects GC (host factors). Research in the coming years could focus on topics such as autophagy, gut microbiota, immunotherapy, exosomes, epithelial-mesenchymal transition (EMT), and gamma-glutamyl transpeptidase (GGT). Conclusion This study evaluated the global scientific output in HP/GC research and its quantitative characteristics, identified the essential works, and collected information on the current status, main focuses and emerging trends in HP/GC research to provide academics with guidance for future paths.
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Affiliation(s)
- Shanshan Yang
- Department of Integrated Traditional Chinese and Western Medicine, Peking University First Hospital, Beijing, China
| | - Shaodong Hao
- Spleen-Stomach Department, Fangshan Hospital, Beijing University of Chinese Medicine, Beijing, China
| | - Hui Ye
- Department of Integrated Traditional Chinese and Western Medicine, Peking University First Hospital, Beijing, China
| | - Xuezhi Zhang
- Department of Integrated Traditional Chinese and Western Medicine, Peking University First Hospital, Beijing, China
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8
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Roszczenko-Jasińska P, Giełdoń A, Mazur D, Spodzieja M, Plichta M, Czaplewski C, Bal W, Jagusztyn-Krynicka EK, Bartosik D. Exploring the inhibitory potential of in silico-designed small peptides on Helicobacter pylori Hp0231 (DsbK), a periplasmic oxidoreductase involved in disulfide bond formation. Front Mol Biosci 2024; 10:1335704. [PMID: 38274095 PMCID: PMC10810133 DOI: 10.3389/fmolb.2023.1335704] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2023] [Accepted: 12/12/2023] [Indexed: 01/27/2024] Open
Abstract
Introduction: Helicobacter pylori is a bacterium that colonizes the gastric epithelium, which affects millions of people worldwide. H. pylori infection can lead to various gastrointestinal diseases, including gastric adenocarcinoma and mucosa-associated lymphoid tissue lymphoma. Conventional antibiotic therapies face challenges due to increasing antibiotic resistance and patient non-compliance, necessitating the exploration of alternative treatment approaches. In this study, we focused on Hp0231 (DsbK), an essential component of the H. pylori Dsb (disulfide bond) oxidative pathway, and investigated peptide-based inhibition as a potential therapeutic strategy. Methods: Three inhibitory peptides designed by computational modeling were evaluated for their effectiveness using a time-resolved fluorescence assay. We also examined the binding affinity between Hp0231 and the peptides using microscale thermophoresis. Results and discussion: Our findings demonstrate that in silico-designed synthetic peptides can effectively inhibit Hp0231-mediated peptide oxidation. Targeting Hp0231 oxidase activity could attenuate H. pylori virulence without compromising bacterial viability. Therefore, peptide-based inhibitors of Hp0231 could be candidates for the development of new targeted strategy, which does not influence the composition of the natural human microbiome, but deprive the bacterium of its pathogenic properties.
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Affiliation(s)
- Paula Roszczenko-Jasińska
- Department of Bacterial Genetics, Institute of Microbiology, Faculty of Biology, University of Warsaw, Warsaw, Poland
| | - Artur Giełdoń
- Faculty of Chemistry, University of Gdańsk, Gdańsk, Poland
| | - Dominika Mazur
- Department of Bacterial Genetics, Institute of Microbiology, Faculty of Biology, University of Warsaw, Warsaw, Poland
| | | | - Maciej Plichta
- Institute of Biochemistry and Biophysics, Polish Academy of Sciences, Warsaw, Poland
| | | | - Wojciech Bal
- Institute of Biochemistry and Biophysics, Polish Academy of Sciences, Warsaw, Poland
| | | | - Dariusz Bartosik
- Department of Bacterial Genetics, Institute of Microbiology, Faculty of Biology, University of Warsaw, Warsaw, Poland
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9
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Tran SC, Bryant KN, Cover TL. The Helicobacter pylori cag pathogenicity island as a determinant of gastric cancer risk. Gut Microbes 2024; 16:2314201. [PMID: 38391242 PMCID: PMC10896142 DOI: 10.1080/19490976.2024.2314201] [Citation(s) in RCA: 22] [Impact Index Per Article: 22.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/18/2023] [Accepted: 01/31/2024] [Indexed: 02/24/2024] Open
Abstract
Helicobacter pylori strains can be broadly classified into two groups based on whether they contain or lack a chromosomal region known as the cag pathogenicity island (cag PAI). Colonization of the human stomach with cag PAI-positive strains is associated with an increased risk of gastric cancer and peptic ulcer disease, compared to colonization with cag PAI-negative strains. The cag PAI encodes a secreted effector protein (CagA) and components of a type IV secretion system (Cag T4SS) that delivers CagA and non-protein substrates into host cells. Animal model experiments indicate that CagA and the Cag T4SS stimulate a gastric mucosal inflammatory response and contribute to the development of gastric cancer. In this review, we discuss recent studies defining structural and functional features of CagA and the Cag T4SS and mechanisms by which H. pylori strains containing the cag PAI promote the development of gastric cancer and peptic ulcer disease.
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Affiliation(s)
- Sirena C. Tran
- Department of Pathology, Microbiology and Immunology, Vanderbilt University Medical Center, Nashville, TN, USA
| | - Kaeli N. Bryant
- Department of Pathology, Microbiology and Immunology, Vanderbilt University Medical Center, Nashville, TN, USA
| | - Timothy L. Cover
- Department of Pathology, Microbiology and Immunology, Vanderbilt University Medical Center, Nashville, TN, USA
- Department of Medicine, Vanderbilt University School of Medicine, Nashville, TN, USA
- Vanderbilt Institute for Infection, Immunology, and Inflammation, Vanderbilt University Medical Center, Nashville, TN, USA
- Veterans Affairs Tennessee Valley Healthcare System, Nashville, TN, USA
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10
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Lei X, Cui ZY, Huang XJ. Exploration of gastric carcinogenesis from the relationship between bile acids and intestinal metaplasia and intragastric microorganisms (H. pylori and non-H. pylori). J Cancer Res Clin Oncol 2023; 149:16947-16956. [PMID: 37707577 DOI: 10.1007/s00432-023-05407-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2023] [Accepted: 09/05/2023] [Indexed: 09/15/2023]
Abstract
Gastric cancer (GC) is a prevalent form of cancer, with Helicobacter pylori (H. pylori) infection being the most common risk factor. Recent studies have highlighted the role of long-term irritation of the gastric mucosa caused by bile reflux in the development of cancer. Bile acids (BAs), which are a significant component in bile reflux, have the potential to promote gastric carcinogenesis through various mechanisms. These mechanisms include the induction of intestinal metaplasia (IM), inhibition of H. pylori activity, modification of H. pylori colonization, and alteration of the abundance and composition of microorganisms in the stomach. Defining the mechanism of bile acid-induced gastric carcinogenesis could potentially be an effective approach to prevent GC. Hence, this paper aims to review the mechanism of bile acid-induced IM, the association between BAs and H. pylori infection as well as microorganisms in the stomach, and the correlation between BAs and gastric carcinogenesis. The ultimate goal is to elucidate the role of BAs in the development of GC.
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Affiliation(s)
- X Lei
- Department of Gastroenterology, The Lanzhou University Second Hospital, No. 82 of Linxia Street, Chengguan District, Lanzhou, 730030, China
| | - Z Y Cui
- Department of Gastroenterology, The Lanzhou University Second Hospital, No. 82 of Linxia Street, Chengguan District, Lanzhou, 730030, China
| | - X J Huang
- Department of Gastroenterology, The Lanzhou University Second Hospital, No. 82 of Linxia Street, Chengguan District, Lanzhou, 730030, China.
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11
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Noto JM, Piazuelo MB, Romero-Gallo J, Delgado AG, Suarez G, Akritidou K, Girod Hoffman M, Roa JC, Taylor CT, Peek RM. Targeting hypoxia-inducible factor-1 alpha suppresses Helicobacter pylori-induced gastric injury via attenuation of both cag-mediated microbial virulence and proinflammatory host responses. Gut Microbes 2023; 15:2263936. [PMID: 37828903 PMCID: PMC10578190 DOI: 10.1080/19490976.2023.2263936] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/02/2023] [Accepted: 09/24/2023] [Indexed: 10/14/2023] Open
Abstract
Helicobacter pylori-induced inflammation is the strongest known risk factor for gastric adenocarcinoma. Hypoxia-inducible factor-1 (HIF-1α) is a key transcriptional regulator of immunity and carcinogenesis. To examine the role of this mediator within the context of H. pylori-induced injury, we first demonstrated that HIF-1α levels were significantly increased in parallel with the severity of gastric lesions in humans. In interventional studies targeting HIF-1α, H. pylori-infected mice were treated ± dimethyloxalylglycine (DMOG), a prolyl hydroxylase inhibitor that stabilizes HIF-1α. H. pylori significantly increased proinflammatory chemokines/cytokines and inflammation in vehicle-treated mice; however, this was significantly attenuated in DMOG-treated mice. DMOG treatment also significantly decreased function of the H. pylori type IV secretion system (T4SS) in vivo and significantly reduced T4SS-mediated NF-κB activation and IL-8 induction in vitro. These results suggest that prolyl hydroxylase inhibition protects against H. pylori-mediated pathologic responses, and is mediated, in part, via attenuation of H. pylori cag-mediated virulence and suppression of host proinflammatory responses.
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Affiliation(s)
- Jennifer M. Noto
- Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA
| | - M. Blanca Piazuelo
- Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA
| | - Judith Romero-Gallo
- Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA
| | - Alberto G. Delgado
- Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA
| | - Giovanni Suarez
- Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA
| | | | | | - Juan Carlos Roa
- Department of Pathology, School of Medicine, Center for Cancer Prevention and Control (CECAN), Pontificia Universidad Catolica de Chile, Santiago, Chile
| | - Cormac T. Taylor
- School of Medicine, Systems Biology Ireland and The Conway Institute, University College Dublin, Dublin, Ireland
| | - Richard M. Peek
- Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA
- Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, TN, USA
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12
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Wang L, Wang H. The putative role of ferroptosis in gastric cancer: a review. Eur J Cancer Prev 2023; 32:575-583. [PMID: 37318883 PMCID: PMC10538621 DOI: 10.1097/cej.0000000000000817] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2023] [Accepted: 04/30/2023] [Indexed: 06/17/2023]
Abstract
Ferroptosis is a unique cell death modality triggered by iron-dependent lipid peroxidation, with cysteine metabolism and glutathione-dependent antioxidant defence responses as the primary triggering mechanisms. Ferroptosis is an independent tumour suppression mechanism and has been implicated in various disorders. In tumourigenesis, ferroptosis plays a dual role in promoting and inhibiting tumours. P53, NFE2L2, BAP1, HIF, and other tumour suppressor genes regulate ferroptosis, releasing damage-associated molecular patterns or lipid metabolites to influence cellular immune responses. Ferroptosis is also involved in tumour suppression and metabolism. The combination of amino acid, lipid, and iron metabolism is involved in the initiation and execution of ferroptosis, and metabolic regulatory mechanisms also play roles in malignancies. Most investigations into ferroptosis in gastric cancer are concentrated on predictive models, not the underlying processes. This review investigates the underlying mechanisms of ferroptosis, tumour suppressor genes, and the tumour microenvironment.
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Affiliation(s)
- Li Wang
- Department of Emergency Medicine, Second Affiliated Hospital of School of Medicine and
| | - Haibin Wang
- Department of Radiology, Hangzhou First People’s Hospital, Zhejiang University, Hangzhou, Zhejiang, China
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13
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Wizenty J, Koop PH, Clusmann J, Tacke F, Trautwein C, Schneider KM, Sigal M, Schneider CV. Association of Helicobacter pylori Positivity With Risk of Disease and Mortality. Clin Transl Gastroenterol 2023; 14:e00610. [PMID: 37367296 PMCID: PMC10522101 DOI: 10.14309/ctg.0000000000000610] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/16/2023] [Accepted: 05/17/2023] [Indexed: 06/28/2023] Open
Abstract
INTRODUCTION Helicobacter pylori colonizes the human stomach. Infection causes chronic gastritis and increases the risk of gastroduodenal ulcer and gastric cancer. Its chronic colonization in the stomach triggers aberrant epithelial and inflammatory signals that are also associated with systemic alterations. METHODS Using a PheWAS analysis in more than 8,000 participants in the community-based UK Biobank, we explored the association of H. pylori positivity with gastric and extragastric disease and mortality in a European country. RESULTS Along with well-established gastric diseases, we dominantly found overrepresented cardiovascular, respiratory, and metabolic disorders. Using multivariate analysis, the overall mortality of H. pylori -positive participants was not altered, while the respiratory and Coronovirus 2019-associated mortality increased. Lipidomic analysis for H. pylori -positive participants revealed a dyslipidemic profile with reduced high-density lipoprotein cholesterol and omega-3 fatty acids, which may represent a causative link between infection, systemic inflammation, and disease. DISCUSSION Our study of H. pylori positivity demonstrates that it plays an organ- and disease entity-specific role in the development of human disease and highlights the importance of further research into the systemic effects of H. pylori infection.
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Affiliation(s)
- Jonas Wizenty
- Department of Hepatology and Gastroenterology, Charité - Universitätsmedizin Berlin, Berlin, Germany
| | - Paul-Henry Koop
- Department for Gastroenterology, Metabolic Diseases and Intensive Care, University Hospital RWTH Aachen, Aachen, Germany
| | - Jan Clusmann
- Department for Gastroenterology, Metabolic Diseases and Intensive Care, University Hospital RWTH Aachen, Aachen, Germany
| | - Frank Tacke
- Department of Hepatology and Gastroenterology, Charité - Universitätsmedizin Berlin, Berlin, Germany
| | - Christian Trautwein
- Department for Gastroenterology, Metabolic Diseases and Intensive Care, University Hospital RWTH Aachen, Aachen, Germany
| | - Kai Markus Schneider
- Department for Gastroenterology, Metabolic Diseases and Intensive Care, University Hospital RWTH Aachen, Aachen, Germany
| | - Michael Sigal
- Department of Hepatology and Gastroenterology, Charité - Universitätsmedizin Berlin, Berlin, Germany
| | - Carolin V. Schneider
- Department for Gastroenterology, Metabolic Diseases and Intensive Care, University Hospital RWTH Aachen, Aachen, Germany
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14
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Livzan MA, Gaus OV, Popello DV. Eating habits and stomach cancer risk. EXPERIMENTAL AND CLINICAL GASTROENTEROLOGY 2023:89-97. [DOI: 10.31146/1682-8658-ecg-211-3-89-97] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 09/17/2024]
Abstract
Stomach cancer (GC) ranks fifth in the structure of cancer incidence and remains the third leading cause of cancer mortality worldwide. The formation of gastric cancer occurs under the influence of genetic and epigenetic factors. Among the latter, eating habits play a significant role. Primary prevention of cancer through lifestyle and dietary changes is an important and high priority strategy in modern health care. This article presents an overview and systematization of the available data on the influence of nutritional factors on the risk of gastric cancer formation.
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Affiliation(s)
| | | | - D. V. Popello
- Central State Medical Academy of the Administration of President of the Russian Federation
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15
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Beccaceci G, Sigal M. Unwelcome guests - the role of gland-associated Helicobacter pylori infection in gastric carcinogenesis. Front Oncol 2023; 13:1171003. [PMID: 37152042 PMCID: PMC10160455 DOI: 10.3389/fonc.2023.1171003] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2023] [Accepted: 04/04/2023] [Indexed: 05/09/2023] Open
Abstract
Helicobacter pylori (H. pylori) are Gram-negative bacteria that cause chronic gastritis and are considered the main risk factor for the development of gastric cancer. H. pylori have evolved to survive the harsh luminal environment of the stomach and are known to cause damage and signaling aberrations in gastric epithelial cells, which can result in premalignant and malignant pathology. As well as colonizing the gastric mucus and surface epithelial cells, a subpopulation of H. pylori can invade deep into the gastric glands and directly interact with progenitor and stem cells. Gland colonization therefore bears the potential to cause direct injury to long-lived cells. Moreover, this bacterial subpopulation triggers a series of host responses that cause an enhanced proliferation of stem cells. Here, we review recent insights into how gastric gland colonization by H. pylori is established, the resulting pro-carcinogenic epithelial signaling alterations, as well as new insights into stem cell responses to infection. Together these point towards a critical role of gland-associated H. pylori in the development of gastric cancer.
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Affiliation(s)
- Giulia Beccaceci
- Medical Department, Division of Gastroenterology and Hepatology, Charité-Universtitätsmedizin Berlin, Berlin, Germany
- The Berlin Institute for Medical Systems Biology (BIMSB), Max Delbrück Center for Molecular Medicine, Berlin, Germany
| | - Michael Sigal
- Medical Department, Division of Gastroenterology and Hepatology, Charité-Universtitätsmedizin Berlin, Berlin, Germany
- The Berlin Institute for Medical Systems Biology (BIMSB), Max Delbrück Center for Molecular Medicine, Berlin, Germany
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16
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Stair MI, Winn CB, Burns MA, Holcombe H, Artim SC, Ge Z, Shen Z, Wang TC, Muthupalani S, Franco-Mahecho O, Ennis K, Georgieff MK, Fox JG. Effects of chronic Helicobacter pylori strain PMSS1 infection on whole brain and gastric iron homeostasis in male INS-GAS mice. Microbes Infect 2023; 25:105045. [PMID: 36162750 DOI: 10.1016/j.micinf.2022.105045] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2022] [Revised: 09/09/2022] [Accepted: 09/18/2022] [Indexed: 02/03/2023]
Abstract
Iron deficiency, the most common micronutrient deficiency in humans, is associated with long-term deficits in cognition and memory if left untreated. Infection with the gastric pathogen Helicobacter pylori has been linked to iron deficiency anemia (IDA). The H. pylori virulence factor cytotoxin-associated gene A (cagA) is proposed to be especially pertinent in iron deficiency. Male INS-GAS/FVB mice were infected with the CagA+ strain pre-murine Sydney strain 1 (PMSS1) for 12-13 or 27-29 weeks to investigate the role of chronic H. pylori infection in iron deficiency and neurological sequelae. Mice at both timepoints demonstrated significantly elevated gastric histopathology scores and inflammatory cytokines compared to sham-dosed controls. However, only mice at 27-29 weeks post infection had changes in hematological parameters, with significantly decreased erythrocyte count, hematocrit, serum hemoglobin, and increased serum total iron binding capacity. Gastric transcription of iron-regulatory genes Hamp and Bmp4 were significantly downregulated at both timepoints. In the brain, iron-dependent myelingergic and synaptic markers were significantly downregulated at 27-29 weeks. These results indicated that long-term infection of the CagA + PMSS1 strain of H. pylori in this study caused anemia, altered gastric iron homeostasis, and neurological changes similar to those reported in other rodent H. pylori CagA- strain infection models.
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Affiliation(s)
- Melissa I Stair
- Division of Comparative Medicine, Massachusetts Institute of Technology, Cambridge, MA, United States; Animal Resource Program, Atrium Health Wake Forest Baptist, Winston Salem, NC, United States
| | - Caroline Bodi Winn
- Division of Comparative Medicine, Massachusetts Institute of Technology, Cambridge, MA, United States; Department of Comparative Medicine, Worldwide Research, Development, and Medical, Pfizer, Cambridge, MA, United States
| | - Monika A Burns
- Division of Comparative Medicine, Massachusetts Institute of Technology, Cambridge, MA, United States; Novartis Institutes for BioMedical Research, Cambridge, MA, United States
| | - Hilda Holcombe
- Division of Comparative Medicine, Massachusetts Institute of Technology, Cambridge, MA, United States
| | - Stephen C Artim
- Division of Comparative Medicine, Massachusetts Institute of Technology, Cambridge, MA, United States; Merck Research Laboratories, Merck, South San Francisco, CA, United States
| | - Zhongming Ge
- Division of Comparative Medicine, Massachusetts Institute of Technology, Cambridge, MA, United States
| | - Zeli Shen
- Division of Comparative Medicine, Massachusetts Institute of Technology, Cambridge, MA, United States
| | - Timothy C Wang
- Department of Medicine, Columbia University, New York, NY, United States
| | - Sureshkumar Muthupalani
- Division of Comparative Medicine, Massachusetts Institute of Technology, Cambridge, MA, United States
| | - Olga Franco-Mahecho
- Division of Comparative Medicine, Massachusetts Institute of Technology, Cambridge, MA, United States
| | - Kathleen Ennis
- Division of Neonatology, Department of Pediatrics, University of Minnesota Medical School, Minneapolis, MN, United States
| | - Michael K Georgieff
- Division of Neonatology, Department of Pediatrics, University of Minnesota Medical School, Minneapolis, MN, United States
| | - James G Fox
- Division of Comparative Medicine, Massachusetts Institute of Technology, Cambridge, MA, United States; Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA, United States.
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17
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Amalia R, Panenggak NSR, Doohan D, Rezkitha YAA, Waskito LA, Syam AF, Lubis M, Yamaoka Y, Miftahussurur M. A comprehensive evaluation of an animal model for Helicobacter pylori-associated stomach cancer: Fact and controversy. Helicobacter 2023; 28:e12943. [PMID: 36627714 DOI: 10.1111/hel.12943] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/15/2022] [Revised: 11/22/2022] [Accepted: 11/22/2022] [Indexed: 01/12/2023]
Abstract
Even though Helicobacter pylori infection was the most causative factor of gastric cancer, numerous in vivo studies failed to induce gastric cancer using H. pylori infection only. The utilization of established animal studies in cancer research is crucial as they aim to investigate the coincidental association between suspected oncogenes and pathogenesis as well as generate models for the development and testing of potential treatments. The methods to establish gastric cancer using infected animal models remain limited, diverse in methods, and showed different results. This study investigates the differences in animal models, which highlight different pathological results in gaster by literature research. Electronic databases searched were performed in PubMed, Science Direct, and Cochrane, without a period filter. A total of 135 articles were used in this study after a full-text assessment was conducted. The most frequent animal models used for gastric cancer were Mice, while Mongolian gerbils and Transgenic mice were the most susceptible model for gastric cancer associated with H. pylori infection. Additionally, transgenic mice showed that the susceptibility to gastric cancer progression was due to genetic and epigenetic factors. These studies showed that in Mongolian gerbil models, H. pylori could function as a single agent to trigger stomach cancer. However, most gastric cancer susceptibilities were not solely relying on H. pylori infection, and numerous factors are involved in cancer progression. Further study using Mongolian gerbils and Transgenic mice is crucial to conduct and establish the best models for gastric cancer associated H. pylori.
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Affiliation(s)
- Rizki Amalia
- Helicobacter pylori and Microbiota Study Group, Institute of Tropical Disease, Universitas Airlangga, Surabaya, Indonesia
| | - Nur Syahadati Retno Panenggak
- Helicobacter pylori and Microbiota Study Group, Institute of Tropical Disease, Universitas Airlangga, Surabaya, Indonesia
| | - Dalla Doohan
- Helicobacter pylori and Microbiota Study Group, Institute of Tropical Disease, Universitas Airlangga, Surabaya, Indonesia.,Department of Anatomy, Histology and Pharmacology, Faculty of Medicine, Universitas Airlangga, Surabaya, Indonesia
| | - Yudith Annisa Ayu Rezkitha
- Helicobacter pylori and Microbiota Study Group, Institute of Tropical Disease, Universitas Airlangga, Surabaya, Indonesia.,Department of Internal Medicine, Faculty of Medicine, Universitas Muhammadiyah Surabaya, Surabaya, Indonesia
| | - Langgeng Agung Waskito
- Helicobacter pylori and Microbiota Study Group, Institute of Tropical Disease, Universitas Airlangga, Surabaya, Indonesia.,Department of Physiology and Medical Biochemistry, Faculty of Medicine, Universitas Airlangga, Surabaya, Indonesia
| | - Ari Fahrial Syam
- Division of Gastroenterology, Department of Internal Medicine, Faculty of Medicine, University of Indonesia, Jakarta, Indonesia
| | - Masrul Lubis
- Department of Internal Medicine, Faculty of Medicine, Universitas Sumatera Utara, Medan, Indonesia
| | - Yoshio Yamaoka
- Department of Environmental and Preventive Medicine, Oita University Faculty of Medicine, Yufu, Japan.,Department of Medicine, Gastroenterology and Hepatology Section, Baylor College of Medicine, Texas, Houston, USA
| | - Muhammad Miftahussurur
- Helicobacter pylori and Microbiota Study Group, Institute of Tropical Disease, Universitas Airlangga, Surabaya, Indonesia.,Division of Gastroentero-Hepatology, Department of Internal Medicine, Faculty of Medicine-Dr. Soetomo Teaching Hospital, Universitas Airlangga, Surabaya, Indonesia
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18
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Wroblewski LE, Peek RM. Clinical Pathogenesis, Molecular Mechanisms of Gastric Cancer Development. Curr Top Microbiol Immunol 2023; 444:25-52. [PMID: 38231214 PMCID: PMC10924282 DOI: 10.1007/978-3-031-47331-9_2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/18/2024]
Abstract
The human pathogen Helicobacter pylori is the strongest known risk factor for gastric disease and cancer, and gastric cancer remains a leading cause of cancer-related death across the globe. Carcinogenic mechanisms associated with H. pylori are multifactorial and are driven by bacterial virulence constituents, host immune responses, environmental factors such as iron and salt, and the microbiota. Infection with strains that harbor the cytotoxin-associated genes (cag) pathogenicity island, which encodes a type IV secretion system (T4SS) confer increased risk for developing more severe gastric diseases. Other important H. pylori virulence factors that augment disease progression include vacuolating cytotoxin A (VacA), specifically type s1m1 vacA alleles, serine protease HtrA, and the outer-membrane adhesins HopQ, BabA, SabA and OipA. Additional risk factors for gastric cancer include dietary factors such as diets that are high in salt or low in iron, H. pylori-induced perturbations of the gastric microbiome, host genetic polymorphisms, and infection with Epstein-Barr virus. This chapter discusses in detail host factors and how H. pylori virulence factors augment the risk of developing gastric cancer in human patients as well as how the Mongolian gerbil model has been used to define mechanisms of H. pylori-induced inflammation and cancer.
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Affiliation(s)
- Lydia E Wroblewski
- Division of Gastroenterology, Hepatology, and Nutrition, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA
| | - Richard M Peek
- Division of Gastroenterology, Hepatology, and Nutrition, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA.
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19
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Song L, Song M, Rabkin CS, Chung Y, Williams S, Torres J, Corvalan AH, Gonzalez R, Bellolio E, Shome M, LaBaer J, Qiu J, Camargo MC. Identification of anti-Helicobacter pylori antibody signatures in gastric intestinal metaplasia. J Gastroenterol 2023; 58:112-124. [PMID: 36301365 PMCID: PMC9610335 DOI: 10.1007/s00535-022-01933-0] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/11/2022] [Accepted: 10/13/2022] [Indexed: 02/04/2023]
Abstract
BACKGROUND Chronic Helicobacter pylori infection may induce gastric intestinal metaplasia (IM). We compared anti-H. pylori antibody profiles between IM cases and non-atrophic gastritis (NAG) controls. METHODS We evaluated humoral responses to 1528 H. pylori proteins among a discovery set of 50 IM and 50 NAG using H. pylori protein arrays. Antibodies with ≥ 20% sensitivity at 90% specificity for either group were selected and further validated in an independent set of 100 IM and 100 NAG using odds ratios (OR). A validated multi-signature was evaluated using the area under the receiver operating characteristics curve (AUC) and net reclassification improvement (NRI). RESULTS Sixty-two immunoglobulin (Ig) G and 11 IgA antibodies were detected in > 10%. Among them, 22 IgG and 6 IgA antibodies were different between IM and NAG in the discovery set. Validated antibodies included 11 IgG (anti-HP1177/Omp27/HopQ [OR = 8.1, p < 0.001], anti-HP0547/CagA [4.6, p < 0.001], anti-HP0596/Tipα [4.0, p = 0.002], anti-HP0103/TlpB [3.8, p = 0.001], anti-HP1125/PalA/Omp18 [3.1, p = 0.001], anti-HP0153/RecA [0.48, p = 0.03], anti-HP0385 [0.41, p = 0.006], anti-HP0243/TlpB [0.39, p = 0.016], anti-HP0371/FabE [0.37, p = 0.017], anti-HP0900/HypB/AccB [0.35, p = 0.048], and anti-HP0709 [0.30, p = 0.003]), and 2 IgA (anti-HP1125/PalA/Omp18 [2.7, p = 0.03] and anti-HP0596/Tipα [2.5, p = 0.027]). A model including all 11 IgG antibodies (AUC = 0.81) had better discriminated IM and NAG compared with an anti-CagA only (AUC = 0.77) model (NRI = 0.44; p = 0.001). CONCLUSIONS Our study represents the most comprehensive assessment of anti-H. pylori antibody profiles in IM. The target antigens for these novel antibodies may act together with CagA in the progression to IM. Along with other biomarkers, specific H. pylori antibodies may identify IM patients, who would benefit from surveillance.
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Affiliation(s)
- Lusheng Song
- Virginia G. Piper Center for Personalized Diagnostics, Biodesign Institute, Arizona State University, 1001 S. McAllister Ave, PO Box 876401, Tempe, AZ, USA
| | - Minkyo Song
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, MD, USA
| | - Charles S Rabkin
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, MD, USA
| | - Yunro Chung
- Virginia G. Piper Center for Personalized Diagnostics, Biodesign Institute, Arizona State University, 1001 S. McAllister Ave, PO Box 876401, Tempe, AZ, USA
- College of Health Solutions, Arizona State University, Phoenix, AZ, USA
| | - Stacy Williams
- Virginia G. Piper Center for Personalized Diagnostics, Biodesign Institute, Arizona State University, 1001 S. McAllister Ave, PO Box 876401, Tempe, AZ, USA
| | - Javier Torres
- Unidad de Investigación en Enfermedades Infecciosas, UMAE Pediatría, Instituto Mexicano del Seguro Social, Ciudad de Mexico, Mexico
| | - Alejandro H Corvalan
- Faculty of Medicine and Advanced Center for Chronic Disease, Pontificia Universidad Católica de Chile, Santiago, Chile
| | - Robinson Gonzalez
- Faculty of Medicine and Advanced Center for Chronic Disease, Pontificia Universidad Católica de Chile, Santiago, Chile
| | - Enrique Bellolio
- Hospital Dr. Hernán Henríquez Aravena, Temuco, Chile
- Departamento de Anatomía Patológica, Universidad de La Frontera, Temuco, Chile
| | - Mahasish Shome
- Virginia G. Piper Center for Personalized Diagnostics, Biodesign Institute, Arizona State University, 1001 S. McAllister Ave, PO Box 876401, Tempe, AZ, USA
| | - Joshua LaBaer
- Virginia G. Piper Center for Personalized Diagnostics, Biodesign Institute, Arizona State University, 1001 S. McAllister Ave, PO Box 876401, Tempe, AZ, USA
| | - Ji Qiu
- Virginia G. Piper Center for Personalized Diagnostics, Biodesign Institute, Arizona State University, 1001 S. McAllister Ave, PO Box 876401, Tempe, AZ, USA.
| | - M Constanza Camargo
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, MD, USA
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20
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Gollapalli P, Tamizh Selvan G, Santoshkumar HS, Ballamoole KK. Functional insights of antibiotic resistance mechanism in Helicobacter pylori: Driven by gene interaction network and centrality-based nodes essentiality analysis. Microb Pathog 2022; 171:105737. [PMID: 36038087 DOI: 10.1016/j.micpath.2022.105737] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2022] [Revised: 08/05/2022] [Accepted: 08/19/2022] [Indexed: 11/29/2022]
Abstract
Increased antibiotic resistance in Helicobacter pylori (H. pylori), a major human pathogen, constitutes a substantial threat to human health. Understanding the pathophysiology and development of antibiotic resistance can aid our battle with the infections caused by H. pylori. The aim of this study is to discover the high-impact key regulatory mechanisms and genes involved in antimicrobial drug resistance (AMR). In this study, we constructed a functional gene interaction network by integrating multiple sources of data related to antibiotic resistant genes (number-77) from H. pylori. The gene interaction network was assortative, with a hierarchical, scale-free topology enriched in a variety of gene ontology (GO) categories and KEGG pathways. Using an iterative clustering methodology, we identified a number of communities in the AMR gene network that comprised nine genes (sodB, groEL, gyrA, recA, polA, tuf, infB, rpsJ, and gyrB) that were present at the deepest level and hence were key regulators of AMR. Further, an antibiotic-resistant gene network-based centrality analysis revealed superoxide dismutase (sodB) as a bottleneck node in the network. Our findings suggested that sodB is critically enriched in the cellular response to oxidative stress, removal of superoxide radicals, cellular oxidant detoxification processes, cellular component biogenesis, response to reactive oxygen species, urea metabolic process, nitrogen cycle metabolic process and reactive oxygen species metabolic process. We demonstrated how the sodB, which are involved in the response to reactive oxygen species, urea metabolic process, nitrogen cycle metabolic process, reactive oxygen species metabolic process, regulated by Fur gene/proteins, claim a major authority over regulation and signal propagation in the AMR.
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Affiliation(s)
- Pavan Gollapalli
- Center for Bioinformatics and Biostatistics, Nitte (Deemed to Be University), Mangalore, 575018, Karnataka, India; Central Research Laboratory, K. S. Hegde Medical Academy, Nitte (Deemed to be University), Mangalore, 575018, Karnataka, India.
| | - G Tamizh Selvan
- Central Research Laboratory, K. S. Hegde Medical Academy, Nitte (Deemed to be University), Mangalore, 575018, Karnataka, India
| | - H S Santoshkumar
- Department of Biotechnology and Bioinformatics, Jnana Sahyadri Campus, Kuvempu University, Shankaraghatta, 577451, Shivamogga, Karnataka, India
| | - Krishna Kumar Ballamoole
- Nitte (Deemed to be University), Division of Infectious Diseases, Nitte University Centre for Science Education and Research (NUCSER), Paneer Campus, Deralakatte, Mangaluru, Karnataka, 575018, India
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21
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Abstract
Like most solid tumours, the microenvironment of epithelial-derived gastric adenocarcinoma (GAC) consists of a variety of stromal cell types, including fibroblasts, and neuronal, endothelial and immune cells. In this article, we review the role of the immune microenvironment in the progression of chronic inflammation to GAC, primarily the immune microenvironment driven by the gram-negative bacterial species Helicobacter pylori. The infection-driven nature of most GACs has renewed awareness of the immune microenvironment and its effect on tumour development and progression. About 75-90% of GACs are associated with prior H. pylori infection and 5-10% with Epstein-Barr virus infection. Although 50% of the world's population is infected with H. pylori, only 1-3% will progress to GAC, with progression the result of a combination of the H. pylori strain, host susceptibility and composition of the chronic inflammatory response. Other environmental risk factors include exposure to a high-salt diet and nitrates. Genetically, chromosome instability occurs in ~50% of GACs and 21% of GACs are microsatellite instability-high tumours. Here, we review the timeline and pathogenesis of the events triggered by H. pylori that can create an immunosuppressive microenvironment by modulating the host's innate and adaptive immune responses, and subsequently favour GAC development.
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22
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Palrasu M, Zaika E, Paulrasu K, Caspa Gokulan R, Suarez G, Que J, El-Rifai W, Peek RM, Garcia-Buitrago M, Zaika AI. Helicobacter pylori pathogen inhibits cellular responses to oncogenic stress and apoptosis. PLoS Pathog 2022; 18:e1010628. [PMID: 35767594 PMCID: PMC9242521 DOI: 10.1371/journal.ppat.1010628] [Citation(s) in RCA: 18] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/07/2022] [Accepted: 05/31/2022] [Indexed: 01/21/2023] Open
Abstract
Helicobacter pylori (H. pylori) is a common gastric pathogen that infects approximately half of the world's population. Infection with H. pylori can lead to diverse pathological conditions, including chronic gastritis, peptic ulcer disease, and cancer. The latter is the most severe consequence of H. pylori infection. According to epidemiological studies, gastric infection with H. pylori is the strongest known risk factor for non-cardia gastric cancer (GC), which remains one of the leading causes of cancer-related deaths worldwide. However, it still remains to be poorly understood how host-microbe interactions result in cancer development in the human stomach. Here we focus on the H. pylori bacterial factors that affect the host ubiquitin proteasome system. We investigated E3 ubiquitin ligases SIVA1 and ULF that regulate p14ARF (p19ARF in mice) tumor suppressor. ARF plays a key role in regulation of the oncogenic stress response and is frequently inhibited during GC progression. Expression of ARF, SIVA1 and ULF proteins were investigated in gastroids, H. pylori-infected mice and human gastric tissues. The role of the H. pylori type IV secretion system was assessed using various H. pylori isogenic mutants. Our studies demonstrated that H. pylori infection results in induction of ULF, decrease in SIVA1 protein levels, and subsequent ubiquitination and degradation of p14ARF tumor suppressor. Bacterial CagA protein was found to sequentially bind to SIVA1 and ULF proteins. This process is regulated by CagA protein phosphorylation at the EPIYA motifs. Downregulation of ARF protein leads to inhibition of cellular apoptosis and oncogenic stress response that may promote gastric carcinogenesis.
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Affiliation(s)
- Manikandan Palrasu
- Department of Surgery, Miller School of Medicine, University of Miami, Miami, Florida, United States of America
| | - Elena Zaika
- Department of Surgery, Miller School of Medicine, University of Miami, Miami, Florida, United States of America
| | - Kodisundaram Paulrasu
- Department of Surgery, Miller School of Medicine, University of Miami, Miami, Florida, United States of America
| | - Ravindran Caspa Gokulan
- Department of Surgery, Miller School of Medicine, University of Miami, Miami, Florida, United States of America
| | - Giovanni Suarez
- Department of Medicine, Vanderbilt University, Nashville, Tennessee, United States of America
| | - Jianwen Que
- Department of Medicine, Columbia University Medical Center, New York, New York, United States of America
| | - Wael El-Rifai
- Department of Surgery, Miller School of Medicine, University of Miami, Miami, Florida, United States of America
- Department of Veterans Affairs, Miami VA Healthcare System, Miami, Florida, United States of America
| | - Richard M. Peek
- Department of Medicine, Vanderbilt University, Nashville, Tennessee, United States of America
| | - Monica Garcia-Buitrago
- Department of Pathology, University of Miami Miller School of Medicine, Miami, Florida, United States of America
| | - Alexander I. Zaika
- Department of Surgery, Miller School of Medicine, University of Miami, Miami, Florida, United States of America
- Department of Veterans Affairs, Miami VA Healthcare System, Miami, Florida, United States of America
- * E-mail:
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23
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Collatuzzo G, Teglia F, Pelucchi C, Negri E, Rabkin CS, Liao LM, Sinha R, López-Carrillo L, Lunet N, Morais S, Aragonés N, Moreno V, Vioque J, Garcia de la Hera M, Ward MH, Malekzadeh R, Pakseresht M, Hernández-Ramírez RU, López-Cervantes M, Bonzi R, Dalmartello M, Tsugane S, Hidaka A, Camargo MC, Curado MP, Zhang ZF, Zubair N, La Vecchia C, Shah S, Boffetta P. Inverse Association between Dietary Iron Intake and Gastric Cancer: A Pooled Analysis of Case-Control Studies of the Stop Consortium. Nutrients 2022; 14:2555. [PMID: 35745285 PMCID: PMC9228527 DOI: 10.3390/nu14122555] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2022] [Revised: 06/15/2022] [Accepted: 06/17/2022] [Indexed: 02/04/2023] Open
Abstract
Background: Inconsistent findings have been reported regarding the relationship between dietary iron intake and the risk of gastric cancer (GC). Methods: We pooled data from 11 case-control studies from the Stomach Cancer Pooling (StoP) Project. Total dietary iron intake was derived from food frequency questionnaires combined with national nutritional tables. We derived the odds ratios (ORs) and 95% confidence intervals (CIs) for quartiles of dietary iron through multivariable unconditional logistic regression models. Secondary analyses stratified by sex, smoking status, caloric intake, anatomical subsite and histological type were performed. Results: Among 4658 cases and 12247 controls, dietary iron intake was inversely associated with GC (per quartile OR 0.88; 95% CI: 0.83-0.93). Results were similar between cardia (OR = 0.85, 95% CI = 0.77-0.94) and non-cardia GC (OR = 0.87, 95% CI = 0.81-0.94), and for diffuse (OR = 0.79, 95% CI = 0.69-0.89) and intestinal type (OR = 0.88, 95% CI = 0.79-0.98). Iron intake exerted an independent effect from that of smoking and salt intake. Additional adjustment by meat and fruit/vegetable intake did not alter the results. Conclusions: Dietary iron is inversely related to GC, with no difference by subsite or histological type. While the results should be interpreted with caution, they provide evidence against a direct effect of iron in gastric carcinogenesis.
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Affiliation(s)
- Giulia Collatuzzo
- Department of Medical and Surgical Sciences, University of Bologna, 40138 Bologna, Italy; (G.C.); (F.T.); (E.N.)
| | - Federica Teglia
- Department of Medical and Surgical Sciences, University of Bologna, 40138 Bologna, Italy; (G.C.); (F.T.); (E.N.)
| | - Claudio Pelucchi
- Branch of Medical Statistics, Biometry, and Epidemiology “G. A. Maccacaro”, Department of Clinical Sciences and Community Health, University of Milan, 20133 Milan, Italy; (C.P.); (R.B.); (M.D.); (C.L.V.)
| | - Eva Negri
- Department of Medical and Surgical Sciences, University of Bologna, 40138 Bologna, Italy; (G.C.); (F.T.); (E.N.)
- Branch of Medical Statistics, Biometry, and Epidemiology “G. A. Maccacaro”, Department of Clinical Sciences and Community Health, University of Milan, 20133 Milan, Italy; (C.P.); (R.B.); (M.D.); (C.L.V.)
| | - Charles S. Rabkin
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, MD 20892, USA; (C.S.R.); (L.M.L.); (R.S.); (M.H.W.); (M.C.C.)
| | - Linda M. Liao
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, MD 20892, USA; (C.S.R.); (L.M.L.); (R.S.); (M.H.W.); (M.C.C.)
| | - Rashmi Sinha
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, MD 20892, USA; (C.S.R.); (L.M.L.); (R.S.); (M.H.W.); (M.C.C.)
| | | | - Nuno Lunet
- EPIUnit—Instituto de Saúde Pública, Universidade do Porto, 4050-600 Porto, Portugal; (N.L.); (S.M.)
- Laboratório para a Investigação Integrativa e Translacional em Saúde Populacional (ITR), 4050-600 Porto, Portugal
- Departamento de Ciências da Saúde Pública e Forenses e Educação Médica, Faculdade de Medicina da Universidade do Porto, 4200-319 Porto, Portugal
| | - Samantha Morais
- EPIUnit—Instituto de Saúde Pública, Universidade do Porto, 4050-600 Porto, Portugal; (N.L.); (S.M.)
- Laboratório para a Investigação Integrativa e Translacional em Saúde Populacional (ITR), 4050-600 Porto, Portugal
- Departamento de Ciências da Saúde Pública e Forenses e Educação Médica, Faculdade de Medicina da Universidade do Porto, 4200-319 Porto, Portugal
| | - Nuria Aragonés
- Consortium for Biomedical Research in Epidemiology and Public Health (CIBERESP), 28029 Madrid, Spain; (N.A.); (J.V.); (M.G.d.l.H.)
- Cancer Epidemiology Section, Public Health Division, Department of Health of Madrid, 28035 Madrid, Spain
| | - Victor Moreno
- Oncology Data Analytics Program, Unit of Biomarkers and Susceptibility, Catalan Institute of Oncology (ICO), Hospital Duran I Reynals, 08907 Barcelona, Spain;
- Colorectal Cancer Group, ONCOBELL Program, Bellvitge Biomedical Research Institute (IDIBELL), 08907 Barcelona, Spain
- Department of Clinical Sciences, Faculty of Medicine, University of Barcelona, 08907 Barcelona, Spain
| | - Jesus Vioque
- Consortium for Biomedical Research in Epidemiology and Public Health (CIBERESP), 28029 Madrid, Spain; (N.A.); (J.V.); (M.G.d.l.H.)
- Instituto de Investigación Sanitaria y Biomédica de Alicante, ISABIAL-UMH, 46020 Alicante, Spain
| | - Manoli Garcia de la Hera
- Consortium for Biomedical Research in Epidemiology and Public Health (CIBERESP), 28029 Madrid, Spain; (N.A.); (J.V.); (M.G.d.l.H.)
| | - Mary H. Ward
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, MD 20892, USA; (C.S.R.); (L.M.L.); (R.S.); (M.H.W.); (M.C.C.)
| | - Reza Malekzadeh
- Digestive Oncology Research Center, Digestive Disease Research Institute, Tehran University of Medical Sciences, Tehran P.O. Box 1411713135, Iran; (R.M.); (M.P.)
| | - Mohammadreza Pakseresht
- Digestive Oncology Research Center, Digestive Disease Research Institute, Tehran University of Medical Sciences, Tehran P.O. Box 1411713135, Iran; (R.M.); (M.P.)
- Department of Agricultural, Food and Nutritional Sciences, University of Alberta, Edmonton, AB T6G 2R3, Canada
- Nutritional Epidemiology Group, Centre for Epidemiology and Biostatistics, University of Leeds, Leeds LS2 9JT, UK
| | | | | | - Rossella Bonzi
- Branch of Medical Statistics, Biometry, and Epidemiology “G. A. Maccacaro”, Department of Clinical Sciences and Community Health, University of Milan, 20133 Milan, Italy; (C.P.); (R.B.); (M.D.); (C.L.V.)
| | - Michela Dalmartello
- Branch of Medical Statistics, Biometry, and Epidemiology “G. A. Maccacaro”, Department of Clinical Sciences and Community Health, University of Milan, 20133 Milan, Italy; (C.P.); (R.B.); (M.D.); (C.L.V.)
| | - Shoichiro Tsugane
- Epidemiology and Prevention Group, Center for Public Health Sciences, National Cancer Center, Tokyo 104-0045, Japan; (S.T.); (A.H.)
- National Institute of Health and Nutrition, National Institutes of Biomedical Innovation, Health and Nutrition, Tokyo 162-8636, Japan
| | - Akihisa Hidaka
- Epidemiology and Prevention Group, Center for Public Health Sciences, National Cancer Center, Tokyo 104-0045, Japan; (S.T.); (A.H.)
| | - M. Constanza Camargo
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, MD 20892, USA; (C.S.R.); (L.M.L.); (R.S.); (M.H.W.); (M.C.C.)
| | - Maria Paula Curado
- Centro Internacional de Pesquisa, A. C. Camargo Cancer Center, São Paulo 01508-010, Brazil;
| | - Zuo-Feng Zhang
- Department of Epidemiology, UCLA Fielding School of Public Health and Jonsson Comprehensive Cancer Center, Los Angeles, CA 90095, USA;
| | - Nadia Zubair
- Icahn School of Medicine at Mount Sinai, New York, NY 10003, USA;
| | - Carlo La Vecchia
- Branch of Medical Statistics, Biometry, and Epidemiology “G. A. Maccacaro”, Department of Clinical Sciences and Community Health, University of Milan, 20133 Milan, Italy; (C.P.); (R.B.); (M.D.); (C.L.V.)
| | - Shailja Shah
- Department of Medicine, University of California San Diego, San Diego, CA 92093, USA;
| | - Paolo Boffetta
- Department of Medical and Surgical Sciences, University of Bologna, 40138 Bologna, Italy; (G.C.); (F.T.); (E.N.)
- Stony Brook Cancer Center, Stony Brook University, Stony Brook, NY 11794, USA
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24
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Idowu S, Bertrand PP, Walduck AK. Gastric organoids: Advancing the study of H. pylori pathogenesis and inflammation. Helicobacter 2022; 27:e12891. [PMID: 35384141 PMCID: PMC9287064 DOI: 10.1111/hel.12891] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/01/2021] [Revised: 03/14/2022] [Accepted: 03/20/2022] [Indexed: 12/13/2022]
Abstract
For decades, traditional in vitro and in vivo models used for the study of Helicobacter pylori infection have relied heavily on the use of gastric cancer cell lines and rodents. Major challenges faced by these methods have been the inability to study cancer initiation in already cancerous cell lines, and the difficulty in translating results obtained in animal models due to genetic differences. These challenges have prevented a thorough understanding of the pathogenesis of disease and slowed the development of cancer therapies and a suitable vaccine against the pathogen. In recent years, the development of gastric organoids has provided great advantages over the traditional in vivo and in vitro models due to their similarities to the human stomach in vivo, their ease of use, and the capacity for long-term culture. This review discusses the advantages and limitations of existing in vivo and in vitro models of H. pylori infection, and how gastric organoids have been applied to study H. pylori pathogenesis, with a focus on how the pathogen interacts with the gastric epithelium, inflammatory processes, epithelial repair, and cancer initiation. The potential applications of organoids to address more complex questions on the role of hormones, vaccine-induced immunity are also discussed.
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25
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Ansari S, Yamaoka Y. Animal Models and Helicobacter pylori Infection. J Clin Med 2022; 11:jcm11113141. [PMID: 35683528 PMCID: PMC9181647 DOI: 10.3390/jcm11113141] [Citation(s) in RCA: 18] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2022] [Revised: 05/25/2022] [Accepted: 05/25/2022] [Indexed: 02/06/2023] Open
Abstract
Helicobacter pylori colonize the gastric mucosa of at least half of the world’s population. Persistent infection is associated with the development of gastritis, peptic ulcer disease, and an increased risk of gastric cancer and gastric-mucosa-associated lymphoid tissue (MALT) lymphoma. In vivo studies using several animal models have provided crucial evidence for understanding the pathophysiology of H. pylori-associated complications. Numerous animal models, such as Mongolian gerbils, transgenic mouse models, guinea pigs, and other animals, including non-human primates, are being widely used due to their persistent association in causing gastric complications. However, finding suitable animal models for in vivo experimentation to understand the pathophysiology of gastric cancer and MALT lymphoma is a complicated task. In this review, we summarized the most appropriate and latest information in the scientific literature to understand the role and importance of H. pylori infection animal models.
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Affiliation(s)
- Shamshul Ansari
- Department of Environmental and Preventive Medicine, Oita University Faculty of Medicine, Yufu 879-5593, Oita, Japan;
| | - Yoshio Yamaoka
- Department of Environmental and Preventive Medicine, Oita University Faculty of Medicine, Yufu 879-5593, Oita, Japan;
- Department of Medicine, Gastroenterology and Hepatology Section, Baylor College of Medicine, Houston, TX 77030, USA
- Institute of Tropical Disease, Universitas Airlangga, Surabaya 60115, Indonesia
- Correspondence: ; Tel.: +81-97-586-5740
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26
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Noto JM, Piazuelo MB, Shah SC, Romero-Gallo J, Hart JL, Di C, Carmichael JD, Delgado AG, Halvorson AE, Greevy RA, Wroblewski LE, Sharma A, Newton AB, Allaman MM, Wilson KT, Washington MK, Calcutt MW, Schey KL, Cummings BP, Flynn CR, Zackular JP, Peek RM. Iron deficiency linked to altered bile acid metabolism promotes Helicobacter pylori-induced inflammation-driven gastric carcinogenesis. J Clin Invest 2022; 132:e147822. [PMID: 35316215 PMCID: PMC9106351 DOI: 10.1172/jci147822] [Citation(s) in RCA: 26] [Impact Index Per Article: 8.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2021] [Accepted: 03/16/2022] [Indexed: 12/24/2022] Open
Abstract
Gastric carcinogenesis is mediated by complex interactions among Helicobacter pylori, host, and environmental factors. Here, we demonstrate that H. pylori augmented gastric injury in INS-GAS mice under iron-deficient conditions. Mechanistically, these phenotypes were not driven by alterations in the gastric microbiota; however, discovery-based and targeted metabolomics revealed that bile acids were significantly altered in H. pylori-infected mice with iron deficiency, with significant upregulation of deoxycholic acid (DCA), a carcinogenic bile acid. The severity of gastric injury was further augmented when H. pylori-infected mice were treated with DCA, and, in vitro, DCA increased translocation of the H. pylori oncoprotein CagA into host cells. Conversely, bile acid sequestration attenuated H. pylori-induced injury under conditions of iron deficiency. To translate these findings to human populations, we evaluated the association between bile acid sequestrant use and gastric cancer risk in a large human cohort. Among 416,885 individuals, a significant dose-dependent reduction in risk was associated with cumulative bile acid sequestrant use. Further, expression of the bile acid receptor transmembrane G protein-coupled bile acid receptor 5 (TGR5) paralleled the severity of carcinogenic lesions in humans. These data demonstrate that increased H. pylori-induced injury within the context of iron deficiency is tightly linked to altered bile acid metabolism, which may promote gastric carcinogenesis.
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Affiliation(s)
- Jennifer M Noto
- Division of Gastroenterology, Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, USA
| | - M Blanca Piazuelo
- Division of Gastroenterology, Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, USA
| | - Shailja C Shah
- Division of Gastroenterology, Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, USA
| | - Judith Romero-Gallo
- Division of Gastroenterology, Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, USA
| | | | - Chao Di
- Division of Protective Immunity, and
- Department of Biomedical and Health Informatics, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA
| | - James D Carmichael
- Department of Biochemistry, Mass Spectrometry Research Center Laboratory, Vanderbilt University, Nashville, Tennessee, USA
| | - Alberto G Delgado
- Division of Gastroenterology, Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, USA
| | - Alese E Halvorson
- Department of Biostatistics, Vanderbilt University Medical Center, Nashville, Tennessee, USA
| | - Robert A Greevy
- Department of Biostatistics, Vanderbilt University Medical Center, Nashville, Tennessee, USA
| | - Lydia E Wroblewski
- Division of Gastroenterology, Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, USA
| | - Ayushi Sharma
- Creighton University School of Medicine, Omaha, Nebraska, USA
| | | | - Margaret M Allaman
- Division of Gastroenterology, Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, USA
| | - Keith T Wilson
- Division of Gastroenterology, Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, USA
- Department of Veterans Affairs, Tennessee Valley Healthcare System, Nashville, Tennessee, USA
- Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, Tennessee, USA
| | - M Kay Washington
- Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, Tennessee, USA
| | - M Wade Calcutt
- Department of Biochemistry, Mass Spectrometry Research Center Laboratory, Vanderbilt University, Nashville, Tennessee, USA
| | - Kevin L Schey
- Department of Biochemistry, Mass Spectrometry Research Center Laboratory, Vanderbilt University, Nashville, Tennessee, USA
| | - Bethany P Cummings
- Department of Surgery, University of California, Davis, Davis, California, USA
| | - Charles R Flynn
- Department of Surgery, Vanderbilt University Medical Center, Nashville, Tennessee, USA
| | - Joseph P Zackular
- Division of Protective Immunity, and
- Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA
| | - Richard M Peek
- Division of Gastroenterology, Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, USA
- Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, Tennessee, USA
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27
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Alizadeh M, Raufman JP. Gastrointestinal neoplasia: carcinogenic interaction between bile acids and Helicobacter pylori in the stomach. J Clin Invest 2022; 132:160194. [PMID: 35575088 PMCID: PMC9106340 DOI: 10.1172/jci160194] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/02/2023] Open
Abstract
Bile acids modulate cell functions in health and disease, however, the mechanisms underlying their actions on neoplastic cells in the gastrointestinal (GI) tract remain largely unknown. In this issue of the JCI, Noto et al. comprehensively analyzed how interactions between Helicobacter pylori infection, iron deficiency, and bile acids modulate gastric inflammation and carcinogenesis. The investigators used sophisticated models, including INS-GAS mice with elevated serum gastrin and gastric acid secretion, in which H. pylori infection mimics human disease progression, to show that selected bile acids potentiated the carcinogenic effects of H. pylori infection and iron depletion. This elegant work has broad translational implications for microbe-associated GI neoplasia. Importantly, bile acid sequestration robustly attenuated the combined effects of H. pylori infection and iron depletion on gastric inflammation and cancer.
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Affiliation(s)
| | - Jean-Pierre Raufman
- Department of Medicine, Division of Gastroenterology and Hepatology, University of Maryland School of Medicine, Baltimore, Maryland, USA.,VA Maryland Healthcare System, Baltimore, Maryland, USA.,Marlene and Stewart Greenebaum Comprehensive Cancer Center and,Department of Biochemistry and Molecular Biology, University of Maryland School of Medicine, Baltimore, Maryland, USA
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28
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Zhang X, Wang C, He Y, Xing J, He Y, Huo X, Fu R, Lu X, Liu X, Lv J, Du X, Chen Z, Li C. Establishment of Noninvasive Methods for the Detection of Helicobacter pylori in Mongolian Gerbils and Application of Main Laboratory Gerbil Populations in China. BIOMED RESEARCH INTERNATIONAL 2022; 2022:6036457. [PMID: 35392259 PMCID: PMC8983185 DOI: 10.1155/2022/6036457] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/30/2021] [Revised: 01/20/2022] [Accepted: 02/15/2022] [Indexed: 11/17/2022]
Abstract
Identifying Helicobacter pylori (H. pylori, Hp) infection in animals before and after artificial infection influences the subsequent experiment. We established effective and noninvasive detection methods, including the gastric fluid nested polymerase chain reaction (PCR) method and the 13C-urea breath test, which can detect Hp before modeling Hp infection in Mongolian gerbils. We designed a gas collection equipment for gerbils. Hp nested PCR was also performed on gastric fluid, gastric mucosa, duodenal contents, and faeces of gerbils challenged with Hp. Conventional Hp detection methods, including rapid urease assay and immunohistochemistry, were compared. Moreover, we assessed the natural infection of Hp in 135 gerbils that had never been exposed to Hp artificially from the major laboratory gerbil groups in China. In 10 Hp infected gerbils, the positive detection results were 100%, 100%, 90%, and 10% in gastric fluid, gastric mucosa, duodenal contents, and faeces with nested PCR, respectively. A rapid urease test performed on gastric mucosa showed that all animals were infected with Hp. Immunohistochemical detection and bacteria culture of gastric mucosa samples that were positive by the nested PCR method also confirmed the presence of Hp. 9% (3/35) and 6% (2/31) natural infection rates were found in conventional gerbil groups from the Capital Medical University and Zhejiang Laboratory Animal Center. In conclusion, we established two noninvasive Hp detection methods that can be performed before modelingHp infection, including the gastric fluid nested PCR method and the 13C-urea breath test.
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Affiliation(s)
- Xiulin Zhang
- Department of Medical Genetics and Developmental Biology, School of Basic Medical Science, Capital Medical University, Beijing Key Laboratory of Cancer Invasion & Metastasis Research, Beijing, China
| | - Cunlong Wang
- Department of Medical Genetics and Developmental Biology, School of Basic Medical Science, Capital Medical University, Beijing Key Laboratory of Cancer Invasion & Metastasis Research, Beijing, China
| | - Yang He
- Department of Medical Genetics and Developmental Biology, School of Basic Medical Science, Capital Medical University, Beijing Key Laboratory of Cancer Invasion & Metastasis Research, Beijing, China
- School of Nursing, Dalian Medical University, Dalian, China
| | - Jin Xing
- Institute for Laboratory Animal Resources, National Institutes for Food and Drug Control, Beijing, China
| | - Yan He
- Department of Epidemiology and Biostatistics, School of Public Health, Capital Medical University, Beijing, China
| | - Xueyun Huo
- Department of Medical Genetics and Developmental Biology, School of Basic Medical Science, Capital Medical University, Beijing Key Laboratory of Cancer Invasion & Metastasis Research, Beijing, China
| | - Rui Fu
- Institute for Laboratory Animal Resources, National Institutes for Food and Drug Control, Beijing, China
| | - Xuancheng Lu
- Laboratory Animal Center, Chinese Center for Disease Control and Prevention, Beijing, China
| | - Xin Liu
- Department of Medical Genetics and Developmental Biology, School of Basic Medical Science, Capital Medical University, Beijing Key Laboratory of Cancer Invasion & Metastasis Research, Beijing, China
| | - Jianyi Lv
- Department of Medical Genetics and Developmental Biology, School of Basic Medical Science, Capital Medical University, Beijing Key Laboratory of Cancer Invasion & Metastasis Research, Beijing, China
| | - Xiaoyan Du
- Department of Medical Genetics and Developmental Biology, School of Basic Medical Science, Capital Medical University, Beijing Key Laboratory of Cancer Invasion & Metastasis Research, Beijing, China
| | - Zhenwen Chen
- Department of Medical Genetics and Developmental Biology, School of Basic Medical Science, Capital Medical University, Beijing Key Laboratory of Cancer Invasion & Metastasis Research, Beijing, China
| | - Changlong Li
- Department of Medical Genetics and Developmental Biology, School of Basic Medical Science, Capital Medical University, Beijing Key Laboratory of Cancer Invasion & Metastasis Research, Beijing, China
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29
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Abstract
Helicobacter pylori colonization of the stomach is a strong risk factor for the development of stomach cancer and peptic ulcer disease. In this study, we tested the hypothesis that H. pylori infection triggers alterations in gastric lipid composition. Mongolian gerbils were experimentally infected with H. pylori for 3 months. Conventional histologic staining revealed mucosal inflammation in stomachs from the H. pylori-infected animals but not in stomachs from uninfected control animals. Atrophic gastritis (a premalignant condition characterized by loss of corpus-specific parietal and chief cells), gastric mucosal hyperplasia, dysplasia, and/or gastric cancer were detected in stomachs from several infected animals. We then used imaging mass spectrometry to analyze the relative abundance and spatial distribution of gastric lipids. We detected ions corresponding to 36 distinct lipids that were differentially abundant when comparing gastric tissues from H. pylori-infected animals with tissues from uninfected animals. Liquid chromatography-tandem mass spectrometry analysis of lipid extracts from homogenized gastric tissues provided additional supportive evidence for the identification of several differentially abundant lipids. Sixteen of the differentially abundant lipids were localized mainly to the gastric corpus in stomachs from uninfected animals and were markedly reduced in abundance in stomachs from H. pylori-infected animals with severe disease (atrophic gastritis and dysplasia or gastric cancer). These findings indicate that H. pylori infection can lead to alterations in gastric lipid composition and constitute a new approach for identifying biomarkers of gastric atrophy and premalignant changes. IMPORTANCE H. pylori colonization of the stomach triggers a cascade of gastric alterations that can potentially culminate in stomach cancer. The molecular alterations that occur in gastric tissue prior to development of stomach cancer are not well understood. We demonstrate here that H. pylori-induced premalignant changes in the stomach are accompanied by extensive alterations in gastric lipid composition. These alterations are predicted to have important functional consequences relevant to H. pylori-host interactions and the pathogenesis of gastric cancer.
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30
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Yang F, Zhang J, Wang S, Sun Z, Zhou J, Li F, Liu Y, Ding L, Liu Y, Chi W, Liu T, He Y, Xiang P, Bao Z, Olszewski MA, Zhao H, Zhang Y. Genomic population structure of Helicobacter pylori Shanghai isolates and identification of genomic features uniquely linked with pathogenicity. Virulence 2021; 12:1258-1270. [PMID: 33904371 PMCID: PMC8081043 DOI: 10.1080/21505594.2021.1920762] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/13/2020] [Revised: 04/01/2021] [Accepted: 04/19/2021] [Indexed: 02/08/2023] Open
Abstract
Severe Helicobacter pylori-linked gastric disorders are especially prevalent in the East Asia region. The ability of H. pylori to cause different clinical outcomes is thought to be associated with unique sets of its genetic features. However, only few genetic features have been definitively linked to specific gastrointestinal pathologies. Genome heterogeneity of clinical H. pylori strains from patients with four different gastric disorders was studied to explore the population structure and molecular genomic features and their association with pathogenicity. Population analysis showed that 92.9% of the Shanghai H. pylori isolates were clustered in the East Asia group. Among 2,866 genes detected in all genomes, 1,146 genes formed the core genome, whereas 209 unique genes were detected in individual disease groups. The unique genes of peptic ulcer and gastric cancer groups represented the inorganic ion transport and metabolism function gene clusters. Sixteen virulence genes were detected with statistically different detection rates among the four disease groups. Furthermore, 127 clustered regularly interspaced short palindromic repeats were found with significantly different rates in the four disease groups. A total of 337 putative genomic islands were identified, and three genomic islands were individually found in more than 10% of strains. The genomic islands included several metabolism-associated genes and many genes with unknown function. In total, 88 sequence types were detected among the 112 Shanghai H. pylori isolates. Our study provides an essential milestone in the mapping of specific genomic features and their functions to identify factors needed to induce specific gastric disorders in H. pylori.
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Affiliation(s)
- Feng Yang
- Department of Laboratory Medicine, Research Center on Aging and Medicine, Fudan University, Shanghai, China
- Department of Laboratory Medicine, Shanghai Key Laboratory of Clinical Geriatric Medicine, Shanghai, China
- Department of Laboratory Medicine, Huadong Hospital, Fudan University, Shanghai, China
| | - Jinghao Zhang
- Department of Laboratory Medicine, Huadong Hospital, Fudan University, Shanghai, China
| | - Su Wang
- Department of Laboratory Medicine, Huadong Hospital, Fudan University, Shanghai, China
| | - Zhaoyang Sun
- Department of Laboratory Medicine, Huadong Hospital, Fudan University, Shanghai, China
| | - Jun Zhou
- Department of Endoscopy, Huadong Hospital, Fudan University, Shanghai, China
| | - Feng Li
- Department of Endoscopy, Huadong Hospital, Fudan University, Shanghai, China
| | - Yue Liu
- Department of Laboratory Medicine, Huadong Hospital, Fudan University, Shanghai, China
| | - Li Ding
- Department of Laboratory Medicine, Huadong Hospital, Fudan University, Shanghai, China
| | - Yixin Liu
- Department of Laboratory Medicine, Huadong Hospital, Fudan University, Shanghai, China
| | - Wenjing Chi
- Department of Laboratory Medicine, Huadong Hospital, Fudan University, Shanghai, China
| | - Tao Liu
- Department of Laboratory Medicine, Huadong Hospital, Fudan University, Shanghai, China
| | - Yongqun He
- Unit for Laboratory Animal Medicine, Department of Microbiology and Immunology, And Center for Computational Medicine and Bioinformatics, University of Michigan Medical School, Ann Arbor, USA
| | - Ping Xiang
- Department of Endoscopy, Huadong Hospital, Fudan University, Shanghai, China
| | - Zhijun Bao
- Department of Laboratory Medicine, Research Center on Aging and Medicine, Fudan University, Shanghai, China
- Department of Laboratory Medicine, Shanghai Key Laboratory of Clinical Geriatric Medicine, Shanghai, China
- Department of Gastroenterology, Gerontology Institute of Shanghai, Huadong Hospital, Fudan University, Shanghai, China
| | - Michal A. Olszewski
- Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, University of Michigan and Research Service, VA Ann Arbor Healthcare System, Ann Arbor, USA
| | - Hu Zhao
- Department of Laboratory Medicine, Research Center on Aging and Medicine, Fudan University, Shanghai, China
- Department of Laboratory Medicine, Shanghai Key Laboratory of Clinical Geriatric Medicine, Shanghai, China
- Department of Laboratory Medicine, Huadong Hospital, Fudan University, Shanghai, China
| | - Yanmei Zhang
- Department of Laboratory Medicine, Research Center on Aging and Medicine, Fudan University, Shanghai, China
- Department of Laboratory Medicine, Shanghai Key Laboratory of Clinical Geriatric Medicine, Shanghai, China
- Department of Laboratory Medicine, Huadong Hospital, Fudan University, Shanghai, China
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Cardos IA, Zaha DC, Sindhu RK, Cavalu S. Revisiting Therapeutic Strategies for H. pylori Treatment in the Context of Antibiotic Resistance: Focus on Alternative and Complementary Therapies. Molecules 2021; 26:molecules26196078. [PMID: 34641620 PMCID: PMC8512130 DOI: 10.3390/molecules26196078] [Citation(s) in RCA: 32] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/11/2021] [Revised: 10/01/2021] [Accepted: 10/02/2021] [Indexed: 12/15/2022] Open
Abstract
The prevalence of Helicobacter pylori infection remains significant worldwide and it depends on many factors: gender, age, socio-economic status, geographic area, diet, and lifestyle. All successful infectious diseases treatments use antibiotic-susceptibility testing, but this strategy is not currently practical for H. pylori and the usual cure rates of H. pylori are lower than other bacterial infections. Actually, there is no treatment that ensures complete eradication of this pathogen. In the context of an alarming increase in resistance to antibiotics (especially to clarithromycin and metronidazole), alternative and complementary options and strategies are taken into consideration. As the success of antibacterial therapy depends not only on the susceptibility to given drugs, but also on the specific doses, formulations, use of adjuvants, treatment duration, and reinfection rates, this review discusses the current therapies for H. pylori treatment along with their advantages and limitations. As an alternative option, this work offers an extensively referenced approach on natural medicines against H. pylori, including the significance of nanotechnology in developing new strategies for treatment of H. pylori infection.
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Affiliation(s)
- Ioana Alexandra Cardos
- Faculty of Medicine and Pharmacy, Doctoral School of Biomedical Sciences, University of Oradea, 1 University Street, 410087 Oradea, Romania;
| | - Dana Carmen Zaha
- Department of Preclinical Sciences, Faculty of Medicine and Pharmacy, University of Oradea, 1 University Street, 410087 Oradea, Romania
- Correspondence: (D.C.Z.); (R.K.S.); (S.C.)
| | - Rakesh K. Sindhu
- Chitkara College of Pharmacy, Chitkara University, Chandigarh 140401, India
- Correspondence: (D.C.Z.); (R.K.S.); (S.C.)
| | - Simona Cavalu
- Department of Preclinical Sciences, Faculty of Medicine and Pharmacy, University of Oradea, 1 University Street, 410087 Oradea, Romania
- Correspondence: (D.C.Z.); (R.K.S.); (S.C.)
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Senchukova MA, Tomchuk O, Shurygina EI. Helicobacter pylori in gastric cancer: Features of infection and their correlations with long-term results of treatment. World J Gastroenterol 2021; 27:6290-6305. [PMID: 34712033 PMCID: PMC8515796 DOI: 10.3748/wjg.v27.i37.6290] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/30/2021] [Revised: 06/21/2021] [Accepted: 08/31/2021] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Helicobacter pylori (H. pylori) is a spiral-shaped bacterium responsible for the development of chronic gastritis, gastric ulcer, gastric cancer (GC), and MALT-lymphoma of the stomach. H. pylori can be present in the gastric mucosa (GM) in both spiral and coccoid forms. However, it is not known whether the severity of GM contamination by various vegetative forms of H. pylori is associated with clinical and morphological characteristics and long-term results of GC treatment. AIM To establish the features of H. pylori infection in patients with GC and their correlations with clinical and morphological characteristics of diseases and long-term results of treatment. METHODS Of 109 patients with GC were included in a prospective cohort study. H. pylori in the GM and tumor was determined by rapid urease test and by immunohistochemically using the antibody to H. pylori. The results obtained were compared with the clinical and morphological characteristics and prognosis of GC. Statistical analysis was performed using the Statistica 10.0 software. RESULTS H. pylori was detected in the adjacent to the tumor GM in 84.5% of cases, of which a high degree of contamination was noted in 50.4% of the samples. Coccoid forms of H. pylori were detected in 93.4% of infected patients, and only coccoid-in 68.9%. It was found that a high degree of GM contamination by the coccoid forms of H. pylori was observed significantly more often in diffuse type of GC (P = 0.024), in poorly differentiated GC (P = 0.011), in stage T3-4 (P = 0.04) and in N1 (P = 0.011). In cases of moderate and marked concentrations of H. pylori in GM, a decrease in 10-year relapse free and overall survival from 55.6% to 26.3% was observed (P = 0.02 and P = 0.07, respectively). The relationship between the severity of the GM contamination by the spiral-shaped forms of H. pylori and the clinical and morphological characteristics and prognosis of GC was not revealed. CONCLUSION The data obtained indicates that H. pylori may be associated not only with induction but also with the progression of GC.
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Affiliation(s)
- Marina A Senchukova
- Department of Oncology, Orenburg State Medical University, Orenburg 460000, Russia
| | - Olesya Tomchuk
- Department of Histology, Cytology, Embryology, Orenburg State Medical University, Orenburg 460000, Russia
| | - Elena I Shurygina
- Department of Pathology, Orenburg State Medical University, Orenburg 460000, Russia
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Öztekin M, Yılmaz B, Ağagündüz D, Capasso R. Overview of Helicobacter pylori Infection: Clinical Features, Treatment, and Nutritional Aspects. Diseases 2021; 9:66. [PMID: 34698140 PMCID: PMC8544542 DOI: 10.3390/diseases9040066] [Citation(s) in RCA: 46] [Impact Index Per Article: 11.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2021] [Revised: 09/11/2021] [Accepted: 09/23/2021] [Indexed: 12/11/2022] Open
Abstract
Helicobacter pylori (H. pylori) is a 0.5-1 µm wide, 2-4 µm long, short helical, S-shaped Gram-negative microorganism. It is mostly found in the pyloric region of the stomach and causes chronic gastric infection. It is estimated that these bacteria infect more than half of the world's population. The mode of transmission and infection of H. pylori is still not known exactly, but the faecal-oral and oral-oral routes via water or food consumption are thought to be a very common cause. In the last three decades, research interest has increased regarding the pathogenicity, microbial activity, genetic predisposition, and clinical treatments to understand the severity of gastric atrophy and gastric cancer caused by H. pylori. Studies have suggested a relationship between H. pylori infection and malabsorption of essential micronutrients, and noted that H. pylori infection may affect the prevalence of malnutrition in some risk groups. On the other hand, dietary factors may play a considerably important role in H. pylori infection, and it has been reported that an adequate and balanced diet, especially high fruit and vegetable consumption and low processed salty food consumption, has a protective effect against the outcomes of H. pylori infection. The present review provides an overview of all aspects of H. pylori infection, such as clinical features, treatment, and nutrition.
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Affiliation(s)
- Merve Öztekin
- Department of Nutrition and Dietetics, Faculty of Health Sciences, Gazi University, Emek, Ankara 06490, Turkey; (M.Ö.); (B.Y.)
| | - Birsen Yılmaz
- Department of Nutrition and Dietetics, Faculty of Health Sciences, Gazi University, Emek, Ankara 06490, Turkey; (M.Ö.); (B.Y.)
- Department of Nutrition and Dietetics, Faculty of Health Sciences, Çukurova University, Sarıçam, Adana 01330, Turkey
| | - Duygu Ağagündüz
- Department of Nutrition and Dietetics, Faculty of Health Sciences, Gazi University, Emek, Ankara 06490, Turkey; (M.Ö.); (B.Y.)
| | - Raffaele Capasso
- Department of Agricultural Sciences, University of Naples Federico II, 80055 Portici, Italy
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Lu J, Haley KP, Francis JD, Guevara MA, Doster RS, Craft KM, Moore RE, Chambers SA, Delgado AG, Piazuelo MB, Damo SM, Townsend SD, Gaddy JA. The Innate Immune Glycoprotein Lactoferrin Represses the Helicobacter pylori cag Type IV Secretion System. Chembiochem 2021; 22:2783-2790. [PMID: 34169626 PMCID: PMC8560179 DOI: 10.1002/cbic.202100249] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2021] [Revised: 06/23/2021] [Indexed: 01/06/2023]
Abstract
Chronic infection with Helicobacter pylori increases risk of gastric diseases including gastric cancer. Despite development of a robust immune response, H. pylori persists in the gastric niche. Progression of gastric inflammation to serious disease outcomes is associated with infection with H. pylori strains which encode the cag Type IV Secretion System (cag T4SS). The cag T4SS is responsible for translocating the oncogenic protein CagA into host cells and inducing pro-inflammatory and carcinogenic signaling cascades. Our previous work demonstrated that nutrient iron modulates the activity of the T4SS and biogenesis of T4SS pili. In response to H. pylori infection, the host produces a variety of antimicrobial molecules, including the iron-binding glycoprotein, lactoferrin. Our work shows that apo-lactoferrin exerts antimicrobial activity against H. pylori under iron-limited conditions, while holo-lactoferrin enhances bacterial growth. Culturing H. pylori in the presence of holo-lactoferrin prior to co-culture with gastric epithelial cells, results in repression of the cag T4SS activity. Concomitantly, a decrease in biogenesis of cag T4SS pili at the host-pathogen interface was observed under these culture conditions by high-resolution electron microscopy analyses. Taken together, these results indicate that acquisition of alternate sources of nutrient iron plays a role in regulating the pro-inflammatory activity of a bacterial secretion system and present novel therapeutic targets for the treatment of H. pylori-related disease.
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Affiliation(s)
- Jacky Lu
- Department of Pathology, Microbiology and Immunology, Vanderbilt University Medical Center, Nashville, Tennessee, 37232, U.S.A
| | - Kathryn P. Haley
- Department of Biology, Grand Valley State University, Allendale, Michigan, 49401, U.S.A
| | - Jamisha D. Francis
- Department of Pathology, Microbiology and Immunology, Vanderbilt University Medical Center, Nashville, Tennessee, 37232, U.S.A
| | - Miriam A. Guevara
- Department of Pathology, Microbiology and Immunology, Vanderbilt University Medical Center, Nashville, Tennessee, 37232, U.S.A
| | - Ryan S. Doster
- Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, 37232, U.S.A
| | - Kelly M. Craft
- Department of Chemistry, Vanderbilt University, Nashville, Tennessee, 37235, U.S.A
| | - Rebecca E. Moore
- Department of Chemistry, Vanderbilt University, Nashville, Tennessee, 37235, U.S.A
| | - Schuyler A. Chambers
- Department of Chemistry, Vanderbilt University, Nashville, Tennessee, 37235, U.S.A
| | - Alberto G. Delgado
- Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, 37232, U.S.A
| | - Maria Blanca Piazuelo
- Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, 37232, U.S.A
| | - Steven M. Damo
- Department of Life and Physical Sciences, Fisk University, Nashville, Tennessee, 37208, U.S.A
- Department of Biochemistry, Vanderbilt University, Nashville, Tennessee, 37232, U.S.A
- Center for Structural Biology, Vanderbilt University, Nashville, Tennessee, 37232, U.S.A
| | - Steven D. Townsend
- Department of Chemistry, Vanderbilt University, Nashville, Tennessee, 37235, U.S.A
| | - Jennifer A. Gaddy
- Department of Pathology, Microbiology and Immunology, Vanderbilt University Medical Center, Nashville, Tennessee, 37232, U.S.A
- Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, 37232, U.S.A
- Tennessee Valley Healthcare Systems, Department of Veterans Affairs, Nashville, Tennessee, 37212, U.S.A
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Effect of Helicobacter pylori and Helminth Coinfection on the Immune Response to Mycobacterium tuberculosis. Curr Microbiol 2021; 78:3351-3371. [PMID: 34251513 DOI: 10.1007/s00284-021-02604-8] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2021] [Accepted: 06/30/2021] [Indexed: 02/07/2023]
Abstract
Tuberculosis remains one of the main causes of morbidity and mortality worldwide despite decades of efforts to eradicate the disease. Although the immune response controls the infection in most infected individuals (90%), the ability of the bacterium to persist throughout the host's life leads to a risk of reactivation. Underlying conditions including human immunodeficiency virus (HIV) infection, organ transplantation, and immunosuppressive therapies are considered risk factors for progression to active disease. However, many individuals infected with Mycobacterium tuberculosis may develop clinical disease in the absence of underlying immunosuppression. It is also possible that unknown conditions may drive the progression to disease. The human microbiota can be an important modulator of the immune system; it can not only trigger inflammatory disorders, but also drive the response to other infectious diseases. In developing countries, chronic mucosal infections with Helicobacter pylori and helminths may be particularly important, as these infections frequently coexist throughout the host's life. However, little is known about the interactions of these pathogens with the immune system and their effects on M. tuberculosis clinical disease, if any. In this review, we discuss the potential effects of H. pylori and helminth co-infections on the immune response to M. tuberculosis. This may contribute to our understanding of host-pathogen interactions and in designing new strategies for the prevention and control of tuberculosis.
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Rueda-Robles A, Rubio-Tomás T, Plaza-Diaz J, Álvarez-Mercado AI. Impact of Dietary Patterns on H. pylori Infection and the Modulation of Microbiota to Counteract Its Effect. A Narrative Review. Pathogens 2021; 10:875. [PMID: 34358024 PMCID: PMC8308520 DOI: 10.3390/pathogens10070875] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2021] [Revised: 07/07/2021] [Accepted: 07/09/2021] [Indexed: 12/12/2022] Open
Abstract
Helicobacter pylori (H. pylori) is a Gram-negative bacterium that colonizes the stomach and can induce gastric disease and intra-gastric lesions, including chronic gastritis, peptic ulcers, gastric adenocarcinoma, and mucosa-associated lymphoid tissue lymphoma. This bacterium is responsible for long-term complications of gastric disease. The conjunction of host genetics, immune response, bacterial virulence expression, diet, micronutrient availability, and microbiome structure influence the disease outcomes related to chronic H. pylori infection. In this regard, the consumption of unhealthy and unbalanced diets can induce microbial dysbiosis, which infection with H. pylori may contribute to. However, to date, clinical trials have reported controversial results and current knowledge in this field is inconclusive. Here, we review preclinical studies concerning the changes produced in the microbiota that may be related to H. pylori infection, as well as the involvement of diet. We summarize and discuss the last approaches based on the modulation of the microbiota to improve the negative impact of H. pylori infection and their potential translation from bench to bedside.
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Affiliation(s)
- Ascensión Rueda-Robles
- Center of Biomedical Research, Institute of Nutrition and Food Technology “José Mataix”, University of Granada, Avda. del Conocimiento s/n., Armilla, 18016 Granada, Spain;
| | - Teresa Rubio-Tomás
- Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), 08036 Barcelona, Spain;
- School of Medicine, University of Crete, 70013 Heraklion, Crete, Greece
| | - Julio Plaza-Diaz
- Children’s Hospital Eastern Ontario Research Institute, Ottawa, ON K1H 8L1, Canada;
- Department of Biochemistry and Molecular Biology II, School of Pharmacy, University of Granada, 18071 Granada, Spain
- Instituto de Investigación Biosanitaria ibs.GRANADA, Complejo Hospitalario Universitario de Granada, 18014 Granada, Spain
| | - Ana I. Álvarez-Mercado
- Center of Biomedical Research, Institute of Nutrition and Food Technology “José Mataix”, University of Granada, Avda. del Conocimiento s/n., Armilla, 18016 Granada, Spain;
- Department of Biochemistry and Molecular Biology II, School of Pharmacy, University of Granada, 18071 Granada, Spain
- Instituto de Investigación Biosanitaria ibs.GRANADA, Complejo Hospitalario Universitario de Granada, 18014 Granada, Spain
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Wu T, Wu L. The Role and Clinical Implications of the Retinoblastoma (RB)-E2F Pathway in Gastric Cancer. Front Oncol 2021; 11:655630. [PMID: 34136392 PMCID: PMC8201093 DOI: 10.3389/fonc.2021.655630] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2021] [Accepted: 05/07/2021] [Indexed: 12/24/2022] Open
Abstract
Gastric cancer is the most common malignant tumor in the digestive tract, with very high morbidity and mortality in developing countries. The pathogenesis of gastric cancer is a complex biological process mediated by abnormal regulation of proto-oncogenes and tumor suppressor genes. Although there have been some in-depth studies on gastric cancer at the molecular level, the specific mechanism has not been fully elucidated. RB family proteins (including RB, p130, and p107) are involved in cell cycle regulation, a process that largely depends on members of the E2F gene family that encode transcriptional activators and repressors. In gastric cancer, inactivation of the RB-E2F pathway serves as a core transcriptional mechanism that drives cell cycle progression, and is regulated by cyclins, cyclin-dependent kinases, cyclin-dependent kinase inhibitors, p53, Helicobacter pylori and some other upstream molecules. The E2F proteins are encoded by eight genes (i.e. E2F1 to E2F8), each of which may play a specific role in gastric cancer. Interestingly, a single E2F such as E2F1 can activate or repress transcription, and enhance or inhibit cell proliferation, depending on the cell environment. Thus, the function of the E2F transcription factor family is very complex and needs further exploration. Importantly, the presence of H. pylori in stomach mucosa may affect the RB and p53 tumor suppressor systems, thereby promoting the occurrence of gastric cancer. This review aims to summarize recent research progress on important roles of the complex RB-E2F signaling network in the development and effective treatment of gastric cancer.
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Affiliation(s)
| | - Lizhao Wu
- Department of Pathophysiology, College of Basic Medical Sciences, China Medical University, Shenyang, China
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Ying JF, Lu ZB, Fu LQ, Tong Y, Wang Z, Li WF, Mou XZ. The role of iron homeostasis and iron-mediated ROS in cancer. Am J Cancer Res 2021; 11:1895-1912. [PMID: 34094660 PMCID: PMC8167679] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2020] [Accepted: 03/01/2021] [Indexed: 06/12/2023] Open
Abstract
As an important trace element, iron plays an essential role in many biology processes like cell proliferation, metabolism, and mitochondrial function. However, the disruption of iron homeostasis tends to cells death and human diseases due to it servers as mediator to promote the production of reactive oxygen species (ROS). In this review, first we introduced the mechanism of complex iron-mediated ROS involved in apoptosis, necroptosis, ferroptosis and pyroptosis. Next, we discussed the controversial role of excess iron and iron deficiency in tumor. Finally, we discussed the anti-cancer effects of iron on both sides, and novel iron-related strategies. This review outlined the mechanisms and regulation of iron homeostasis and iron-mediated ROS in tumors, and discussed the iron-related treatments.
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Affiliation(s)
- Jia-Fu Ying
- Key Laboratory of Tumor Molecular Diagnosis and Individualized Medicine of Zhejiang Province, Zhejiang Provincial People’s Hospital, Affiliated People’s Hospital, Hangzhou Medical CollegeHangzhou 310014, Zhejiang Province, P. R. China
- Clinical Research Institute, Zhejiang Provincial People’s Hospital, Affiliated People’s Hospital, Hangzhou Medical CollegeHangzhou 310014, Zhejiang Province, P. R. China
- Key Laboratory of Molecular Animal Nutrition of The Ministry of Education, Institute of Feed Science, College of Animal Sciences, Zhejiang UniversityHangzhou 310058, Zhejiang Province, P. R. China
| | - Ze-Bei Lu
- Rehabilitation & Sports Medicine Research Institute of Zhejiang Province, Zhejiang Provincial People’s Hospital, Affiliated People’s Hospital, Hangzhou Medical CollegeHangzhou 310014, P. R. China
| | - Luo-Qin Fu
- Clinical Research Institute, Zhejiang Provincial People’s Hospital, Affiliated People’s Hospital, Hangzhou Medical CollegeHangzhou 310014, Zhejiang Province, P. R. China
| | - Yu Tong
- Clinical Research Institute, Zhejiang Provincial People’s Hospital, Affiliated People’s Hospital, Hangzhou Medical CollegeHangzhou 310014, Zhejiang Province, P. R. China
| | - Zhen Wang
- Key Laboratory of Tumor Molecular Diagnosis and Individualized Medicine of Zhejiang Province, Zhejiang Provincial People’s Hospital, Affiliated People’s Hospital, Hangzhou Medical CollegeHangzhou 310014, Zhejiang Province, P. R. China
| | - Wei-Fen Li
- Key Laboratory of Molecular Animal Nutrition of The Ministry of Education, Institute of Feed Science, College of Animal Sciences, Zhejiang UniversityHangzhou 310058, Zhejiang Province, P. R. China
| | - Xiao-Zhou Mou
- Key Laboratory of Tumor Molecular Diagnosis and Individualized Medicine of Zhejiang Province, Zhejiang Provincial People’s Hospital, Affiliated People’s Hospital, Hangzhou Medical CollegeHangzhou 310014, Zhejiang Province, P. R. China
- Clinical Research Institute, Zhejiang Provincial People’s Hospital, Affiliated People’s Hospital, Hangzhou Medical CollegeHangzhou 310014, Zhejiang Province, P. R. China
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Xu X, Chen J, Huang X, Feng S, Zhang X, She F, Wen Y. The Role of a Dipeptide Transporter in the Virulence of Human Pathogen, Helicobacter pylori. Front Microbiol 2021; 12:633166. [PMID: 33732225 PMCID: PMC7959749 DOI: 10.3389/fmicb.2021.633166] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/24/2020] [Accepted: 02/05/2021] [Indexed: 12/16/2022] Open
Abstract
Helicobacter pylori harbors a dipeptide (Dpp) transporter consisting of a substrate-binding protein (DppA), two permeases (DppB and C), and two ATPases (DppD and F). The Dpp transporter is responsible for the transportation of dipeptides and short peptides. We found that its expression is important for the growth of H. pylori. To understand the role of the Dpp transporter in the pathogenesis of H. pylori, the expression of virulence factors and H. pylori-induced IL-8 production were investigated in H. pylori wild-type and isogenic H. pylori Dpp transporter mutants. We found that expression of CagA was downregulated, while expression of type 4 secretion system (T4SS) components was upregulated in Dpp transporter mutants. The DppA mutant strain expressed higher levels of outer membrane proteins (OMPs), including BabA, HopZ, OipA, and SabA, and showed a higher adhesion level to gastric epithelial AGS cells compared with the H. pylori 26695 wild-type strain. After infection of AGS cells, H. pylori ΔdppA induced a higher level of NF-κB activation and IL-8 production compared with wild-type. These results suggested that in addition to supporting the growth of H. pylori, the Dpp transporter causes bacteria to alter the expression of virulence factors and reduces H. pylori-induced NF-κB activation and IL-8 production in gastric epithelial cells.
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Affiliation(s)
- Xiaohong Xu
- Key Laboratory of Gastrointestinal Cancer (Fujian Medical University), Ministry of Education, Fuzhou, China.,Fujian Key Laboratory of Tumor Microbiology, Department of Medical Microbiology, Fujian Medical University, Fuzhou, China.,Fujian Medical University Union Hospital, Fuzhou, China
| | - Junwei Chen
- Key Laboratory of Gastrointestinal Cancer (Fujian Medical University), Ministry of Education, Fuzhou, China.,Fujian Key Laboratory of Tumor Microbiology, Department of Medical Microbiology, Fujian Medical University, Fuzhou, China
| | - Xiaoxing Huang
- Key Laboratory of Gastrointestinal Cancer (Fujian Medical University), Ministry of Education, Fuzhou, China.,Fujian Key Laboratory of Tumor Microbiology, Department of Medical Microbiology, Fujian Medical University, Fuzhou, China
| | - Shunhang Feng
- Key Laboratory of Gastrointestinal Cancer (Fujian Medical University), Ministry of Education, Fuzhou, China.,Fujian Key Laboratory of Tumor Microbiology, Department of Medical Microbiology, Fujian Medical University, Fuzhou, China
| | - Xiaoyan Zhang
- Key Laboratory of Gastrointestinal Cancer (Fujian Medical University), Ministry of Education, Fuzhou, China.,Fujian Key Laboratory of Tumor Microbiology, Department of Medical Microbiology, Fujian Medical University, Fuzhou, China
| | - Feifei She
- Key Laboratory of Gastrointestinal Cancer (Fujian Medical University), Ministry of Education, Fuzhou, China.,Fujian Key Laboratory of Tumor Microbiology, Department of Medical Microbiology, Fujian Medical University, Fuzhou, China
| | - Yancheng Wen
- Key Laboratory of Gastrointestinal Cancer (Fujian Medical University), Ministry of Education, Fuzhou, China.,Fujian Key Laboratory of Tumor Microbiology, Department of Medical Microbiology, Fujian Medical University, Fuzhou, China
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Abstract
The Helicobacter pylori type IV secretion system (T4SS) encoded on the cag pathogenicity island (cagPAI) secretes the CagA oncoprotein and other effectors into the gastric epithelium. During murine infection, T4SS function is lost in an immune-dependent manner, typically as a result of in-frame recombination in the middle repeat region of cagY, though single nucleotide polymorphisms (SNPs) in cagY or in other essential genes may also occur. Loss of T4SS function also occurs in gerbils, nonhuman primates, and humans, suggesting that it is biologically relevant and not simply an artifact of the murine model. Here, we sought to identify physiologically relevant conditions under which T4SS function is maintained in the murine model. We found that loss of H. pylori T4SS function in mice was blunted by systemic Salmonella coinfection and completely eliminated by dietary iron restriction. Both have epidemiologic parallels in humans, since H. pylori strains from individuals in developing countries, where iron deficiency and systemic infections are common, are also more often cagPAI+ than strains from developed countries. These results have implications for our fundamental understanding of the cagPAI and also provide experimental tools that permit the study of T4SS function in the murine model.IMPORTANCE The type IV secretion system (T4SS) is the major Helicobacter pylori virulence factor, though its function is lost during murine infection. Loss of function also occurs in gerbils and in humans, suggesting that it is biologically relevant, but the conditions under which T4SS regulation occurs are unknown. Here, we found that systemic coinfection with Salmonella and iron deprivation each promote retention of T4SS function. These results improve our understanding of the cag pathogenicity island (cagPAI) and provide experimental tools that permit the study of T4SS function in the murine model.
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Gravina AG, Priadko K, Ciamarra P, Granata L, Facchiano A, Miranda A, Dallio M, Federico A, Romano M. Extra-Gastric Manifestations of Helicobacter pylori Infection. J Clin Med 2020; 9:3887. [PMID: 33265933 PMCID: PMC7761397 DOI: 10.3390/jcm9123887] [Citation(s) in RCA: 54] [Impact Index Per Article: 10.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2020] [Revised: 11/21/2020] [Accepted: 11/26/2020] [Indexed: 12/13/2022] Open
Abstract
Helicobacter Pylori (H. pylori) is a Gram-negative flagellated microorganism that has been extensively studied since its first isolation due to its widespread diffusion and association with numerous diseases. While the bacterium is proved to be a causative factor for a number of gastric diseases such as gastritis, gastric adenocarcinoma, and MALT-lymphoma, its role at other gastrointestinal levels and in other systems is being thoroughly studied. In this article, we reviewed the latest published clinical and laboratory studies that investigated associations of H. pylori with hematologic diseases such as Vitamin B12- and iron-deficiency anemia, primary immune thrombocytopenia, and with a number of dermatologic and ophthalmic diseases. In addition, the putative role of the bacterium in inflammatory bowel diseases, esophageal disorders, metabolic, diseases, neurologic diseases and allergy were outlined.
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Affiliation(s)
- Antonietta G. Gravina
- Hepatogastroenterology Division, Department of Precision Medicine, University of Campania Luigi Vanvitelli, via Pansini 5, 80131 Naples, Italy; (K.P.); (P.C.); (L.G.); (A.F.); (A.M.); (M.D.); (A.F.)
| | | | | | | | | | | | | | | | - Marco Romano
- Hepatogastroenterology Division, Department of Precision Medicine, University of Campania Luigi Vanvitelli, via Pansini 5, 80131 Naples, Italy; (K.P.); (P.C.); (L.G.); (A.F.); (A.M.); (M.D.); (A.F.)
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Pirzadeh M, Khalili N, Rezaei N. The interplay between aryl hydrocarbon receptor, H. pylori, tryptophan, and arginine in the pathogenesis of gastric cancer. Int Rev Immunol 2020; 41:299-312. [DOI: 10.1080/08830185.2020.1851371] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Affiliation(s)
- Marzieh Pirzadeh
- Student Research Committee, Babol University of Medical Sciences, Babol, Iran
| | - Nastaran Khalili
- Cancer Immunology Project (CIP), Universal Scientific Education and Research Network (USERN), Tehran, Iran
| | - Nima Rezaei
- Research Center for Immunodeficiencies, Children's Medical Center, Tehran University of Medical Sciences, Tehran, Iran
- Department of Immunology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
- Cancer Immunology Project (CIP), Universal Scientific Education and Research Network (USERN), Sheffield, UK
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Roszczenko-Jasińska P, Wojtyś MI, Jagusztyn-Krynicka EK. Helicobacter pylori treatment in the post-antibiotics era-searching for new drug targets. Appl Microbiol Biotechnol 2020; 104:9891-9905. [PMID: 33052519 PMCID: PMC7666284 DOI: 10.1007/s00253-020-10945-w] [Citation(s) in RCA: 71] [Impact Index Per Article: 14.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2020] [Revised: 09/28/2020] [Accepted: 10/04/2020] [Indexed: 12/14/2022]
Abstract
Abstract Helicobacter pylori, a member of Epsilonproteobacteria, is a Gram-negative microaerophilic bacterium that colonizes gastric mucosa of about 50% of the human population. Although most infections caused by H. pylori are asymptomatic, the microorganism is strongly associated with serious diseases of the upper gastrointestinal tract such as chronic gastritis, peptic ulcer, duodenal ulcer, and gastric cancer, and it is classified as a group I carcinogen. The prevalence of H. pylori infections varies worldwide. The H. pylori genotype, host gene polymorphisms, and environmental factors determine the type of induced disease. Currently, the most common therapy to treat H. pylori is the first line clarithromycin–based triple therapy or a quadruple therapy replacing clarithromycin with new antibiotics. Despite the enormous recent effort to introduce new therapeutic regimens to combat this pathogen, treatment for H. pylori still fails in more than 20% of patients, mainly due to the increased prevalence of antibiotic resistant strains. In this review we present recent progress aimed at designing new anti-H. pylori strategies to combat this pathogen. Some novel therapeutic regimens will potentially be used as an extra constituent of antibiotic therapy, and others may replace current antibiotic treatments. Key points • Attempts to improve eradication rate of H. pylori infection. • Searching for new drug targets in anti-Helicobacter therapies.
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Affiliation(s)
- Paula Roszczenko-Jasińska
- Department of Bacterial Genetics, Institute of Microbiology, Faculty of Biology, Univeristy of Warsaw, Miecznikowa 1, 02-096, Warszawa, Poland
| | - Marta Ilona Wojtyś
- Department of Bacterial Genetics, Institute of Microbiology, Faculty of Biology, Univeristy of Warsaw, Miecznikowa 1, 02-096, Warszawa, Poland.,Division of Biophysics, Institute of Experimental Physics, Faculty of Physics, Univeristy of Warsaw, Pasteura 5, 02-093, Warszawa, Poland
| | - Elżbieta K Jagusztyn-Krynicka
- Department of Bacterial Genetics, Institute of Microbiology, Faculty of Biology, Univeristy of Warsaw, Miecznikowa 1, 02-096, Warszawa, Poland.
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Huang RJ, Koh H, Hwang JH. A Summary of the 2020 Gastric Cancer Summit at Stanford University. Gastroenterology 2020; 159:1221-1226. [PMID: 32707045 PMCID: PMC7577947 DOI: 10.1053/j.gastro.2020.05.100] [Citation(s) in RCA: 20] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/04/2020] [Accepted: 05/04/2020] [Indexed: 02/06/2023]
Abstract
There exists no coherent national strategy for the early detection or prevention of gastric cancer in the United States (US), even among identified high-risk groups such as Asian Americans, African Americans, Hispanic Americans, and Alaska Native/American Indian peoples. As a result, patients with gastric cancer in the US are diagnosed at later stages and demonstrate worse overall survival compared to nations of East Asia with established screening programs (Table 1). The under-recognition of gastric cancer risk within minority communities is a significant unaddressed healthcare disparity.
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Affiliation(s)
- Robert J Huang
- Division of Gastroenterology and Hepatology, Department of Medicine, Stanford University, Stanford, California
| | - Howard Koh
- The Harvard T.H. Chan School of Public Health, Harvard University, Boston, Massachusetts
| | - Joo Ha Hwang
- Division of Gastroenterology and Hepatology, Department of Medicine, Stanford University, Stanford, California.
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45
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Eisenbart SK, Alzheimer M, Pernitzsch SR, Dietrich S, Stahl S, Sharma CM. A Repeat-Associated Small RNA Controls the Major Virulence Factors of Helicobacter pylori. Mol Cell 2020; 80:210-226.e7. [PMID: 33002424 DOI: 10.1016/j.molcel.2020.09.009] [Citation(s) in RCA: 23] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2020] [Revised: 07/29/2020] [Accepted: 09/04/2020] [Indexed: 12/12/2022]
Abstract
Many bacterial pathogens regulate their virulence genes via phase variation, whereby length-variable simple sequence repeats control the transcription or coding potential of those genes. Here, we have exploited this relationship between DNA structure and physiological function to discover a globally acting small RNA (sRNA) regulator of virulence in the gastric pathogen Helicobacter pylori. Our study reports the first sRNA whose expression is affected by a variable thymine (T) stretch in its promoter. We show the sRNA post-transcriptionally represses multiple major pathogenicity factors of H. pylori, including CagA and VacA, by base pairing to their mRNAs. We further demonstrate transcription of the sRNA is regulated by the nickel-responsive transcriptional regulator NikR (thus named NikS for nickel-regulated sRNA), thereby linking virulence factor regulation to nickel concentrations. Using in-vitro infection experiments, we demonstrate NikS affects host cell internalization and epithelial barrier disruption. Together, our results show NikS is a phase-variable, post-transcriptional global regulator of virulence properties in H. pylori.
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Affiliation(s)
- Sara K Eisenbart
- Chair of Molecular Infection Biology II, Institute of Molecular Infection Biology (IMIB), University of Würzburg, 97080 Würzburg, Germany
| | - Mona Alzheimer
- Chair of Molecular Infection Biology II, Institute of Molecular Infection Biology (IMIB), University of Würzburg, 97080 Würzburg, Germany
| | - Sandy R Pernitzsch
- Chair of Molecular Infection Biology II, Institute of Molecular Infection Biology (IMIB), University of Würzburg, 97080 Würzburg, Germany
| | - Sascha Dietrich
- Core Unit Systems Medicine, Interdisciplinary Center for Clinical Research (IZKF) of the University Hospital Würzburg, 97080 Würzburg, Germany
| | - Stephanie Stahl
- Chair of Molecular Infection Biology II, Institute of Molecular Infection Biology (IMIB), University of Würzburg, 97080 Würzburg, Germany
| | - Cynthia M Sharma
- Chair of Molecular Infection Biology II, Institute of Molecular Infection Biology (IMIB), University of Würzburg, 97080 Würzburg, Germany.
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Temporal Control of the Helicobacter pylori Cag Type IV Secretion System in a Mongolian Gerbil Model of Gastric Carcinogenesis. mBio 2020; 11:mBio.01296-20. [PMID: 32605987 PMCID: PMC7327173 DOI: 10.1128/mbio.01296-20] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023] Open
Abstract
The Helicobacter pylori Cag type IV secretion system (T4SS) translocates the effector protein CagA and nonprotein bacterial constituents into host cells. In this study, we infected Mongolian gerbils with an H. pylori strain in which expression of the cagUT operon (required for Cag T4SS activity) is controlled by a TetR/tetO system. Transcript levels of cagU were significantly higher in gastric tissue from H. pylori-infected animals receiving doxycycline-containing chow (to derepress Cag T4SS activity) than in tissue from infected control animals receiving drug-free chow. At 3 months postinfection, infected animals receiving doxycycline had significantly increased gastric inflammation compared to infected control animals. Dysplasia (a premalignant histologic lesion) and/or invasive gastric adenocarcinoma were detected only in infected gerbils receiving doxycycline, not in infected control animals. We then conducted experiments in which Cag T4SS activity was derepressed during defined stages of infection. Continuous Cag T4SS activity throughout a 3-month time period resulted in higher rates of dysplasia and/or gastric cancer than observed when Cag T4SS activity was limited to early or late stages of infection. Cag T4SS activity for the initial 6 weeks of infection was sufficient for the development of gastric inflammation at the 3-month time point, with gastric cancer detected in a small proportion of animals. These experimental results, together with previous studies of cag mutant strains, provide strong evidence that Cag T4SS activity contributes to gastric carcinogenesis and help to define the stages of H. pylori infection during which Cag T4SS activity causes gastric alterations relevant for cancer pathogenesis.IMPORTANCE The "hit-and-run model" of carcinogenesis proposes that an infectious agent triggers carcinogenesis during initial stages of infection and that the ongoing presence of the infectious agent is not required for development of cancer. H. pylori infection and actions of CagA (an effector protein designated a bacterial oncoprotein, secreted by the Cag T4SS) are proposed to constitute a paradigm for hit-and-run carcinogenesis. In this study, we report the development of methods for controlling H. pylori Cag T4SS activity in vivo and demonstrate that Cag T4SS activity contributes to gastric carcinogenesis. We also show that Cag T4SS activity during an early stage of infection is sufficient to initiate a cascade of cellular alterations leading to gastric inflammation and gastric cancer at later time points.
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The Helicobacter pylori Cag Type IV Secretion System. Trends Microbiol 2020; 28:682-695. [PMID: 32451226 DOI: 10.1016/j.tim.2020.02.004] [Citation(s) in RCA: 85] [Impact Index Per Article: 17.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2019] [Revised: 01/30/2020] [Accepted: 02/25/2020] [Indexed: 12/24/2022]
Abstract
Colonization of the human stomach with Helicobacter pylori strains containing the cag pathogenicity island is a risk factor for development of gastric cancer. The cag pathogenicity island contains genes encoding a secreted effector protein (CagA) and components of a type IV secretion system (Cag T4SS). The molecular architecture of the H. pylori Cag T4SS is substantially more complex than that of prototype T4SSs in other bacterial species. In this review, we discuss recent discoveries pertaining to the structure and function of the Cag T4SS and its role in gastric cancer pathogenesis.
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Seeger AY, Ringling MD, Zohair H, Blanke SR. Risk factors associated with gastric malignancy during chronic Helicobacter pylori Infection. MEDICAL RESEARCH ARCHIVES 2020; 8:2068. [PMID: 37655156 PMCID: PMC10470974 DOI: 10.18103/mra.v8i3.2068] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 09/02/2023]
Abstract
Chronic Helicobacter pylori (Hp) infection is considered to be the single most important risk factor for the development of gastric adenocarcinoma in humans, which is a leading cause of cancer-related death worldwide. Nonetheless, Hp infection does not always progress to malignancy, and, gastric adenocarcinoma can occur in the absence of detectable Hp carriage, highlighting the complex and multifactorial nature of gastric cancer. Here we review known contributors to gastric malignancy, including Hp virulence factors, host genetic variation, and multiple environmental variables. In addition, we assess emerging evidence that resident gastric microflora in humans might impact disease progression in Hp-infected individuals. Molecular approaches for microbe identification have revealed differences in the gastric microbiota composition between cancer and non-cancerous patients, as well as infected and uninfected individuals. Although the reasons underlying differences in microbial community structures are not entirely understood, gastric atrophy and hypochlorhydria that accompany chronic Hp infection may be a critical driver of gastric dysbiosis that promote colonization of microbes that contribute to increased risk of malignancy. Defining the importance and role of the gastric microbiota as a potential risk factor for Hp-associated gastric cancer is a vital and exciting area of current research.
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Affiliation(s)
- Ami Y. Seeger
- Department of Microbiology, School of Molecular and Cellular Biology, College of Liberal Arts and Sciences, University of Illinois Urbana-Champaign, Urbana, Illinois, 61801
| | - Megan D. Ringling
- Department of Microbiology, School of Molecular and Cellular Biology, College of Liberal Arts and Sciences, University of Illinois Urbana-Champaign, Urbana, Illinois, 61801
| | - Huzaifa Zohair
- Department of Microbiology, School of Molecular and Cellular Biology, College of Liberal Arts and Sciences, University of Illinois Urbana-Champaign, Urbana, Illinois, 61801
| | - Steven R. Blanke
- Department of Microbiology, School of Molecular and Cellular Biology, College of Liberal Arts and Sciences, University of Illinois Urbana-Champaign, Urbana, Illinois, 61801
- Department of Pathobiology, College of Veterinary Medicine, University of Illinois Urbana-Champaign, Urbana, Illinois, 61801
- Biomedical and Translational Sciences Department, Carle Illinois College of Medicine, University of Illinois Urbana-Champaign, Urbana, Illinois, 61801
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Helicobacter pylori and Epstein-Barr Virus Infection in Gastric Diseases: Correlation with IL-10 and IL1RN Polymorphism. JOURNAL OF ONCOLOGY 2019; 2019:1785132. [PMID: 31885568 PMCID: PMC6918935 DOI: 10.1155/2019/1785132] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 03/12/2019] [Revised: 07/10/2019] [Accepted: 08/18/2019] [Indexed: 02/06/2023]
Abstract
Introduction Helicobacter pylori and Epstein–Barr virus (EBV) infection have recently been shown to be associated with gastric diseases. Polymorphisms in genes encoding cytokines such as interleukin 10 (IL-10) and interleukin 1 Receptor (IL-1RN) influence cytokine secretion levels and appear to contribute to the risk of developing gastroduodenal diseases. To our knowledge, this is the first preliminary study to address the association of coinfection with H. pylori and EBV and their correlation with genetic predisposition in the development of gastric diseases. Methods Gastric biopsy samples of 96 patients with different gastric diseases were used. Results Our results showed that the rate of coinfection was higher in patients with gastric cancer than in patients with normal gastric mucosa, active chronic gastritis, and MALT lymphoma. As regards the characterization of H. pilory strains, the polymorphism s1m1i1 of vacA gene was more frequent in patients with MALT Lymphoma in comparison to others, while the polymorphism s2m2i2 was most frequent in patients with normal gastric mucosa. In addition, patients who tested positive for the cagA gene were more frequently those affected with gastric cancer than those with inactive chronic gastritis. Similarly, the patients with oipA gene ON were more frequently those with gastric cancer than those with inactive chronic gastritis. Conclusion According to our analysis, there was no correlation between coinfection and polymorphisms in genes encoding IL-10 and IL-1RN. We conclude that various factors can be involved in the development of gastric diseases.
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Suzuki R, Satou K, Shiroma A, Shimoji M, Teruya K, Matsumoto T, Akada J, Hirano T, Yamaoka Y. Genome-wide mutation analysis of Helicobacter pylori after inoculation to Mongolian gerbils. Gut Pathog 2019; 11:45. [PMID: 31558915 PMCID: PMC6754630 DOI: 10.1186/s13099-019-0326-5] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/08/2019] [Accepted: 09/12/2019] [Indexed: 12/23/2022] Open
Abstract
Background Helicobacter pylori is a pathogenic bacterium that causes various gastrointestinal diseases in the human stomach. H. pylori is well adapted to the human stomach but does not easily infect other animals. As a model animal, Mongolian gerbils are often used, however, the genome of the inoculated H. pylori may accumulate mutations to adapt to the new host. To investigate mutations occurring in H. pylori after infection in Mongolian gerbils, we compared the whole genome sequence of TN2 wild type strain (TN2wt) and next generation sequencing data of retrieved strains from the animals after different lengths of infection. Results We identified mutations in 21 loci of 17 genes of the post-inoculation strains. Of the 17 genes, five were outer membrane proteins that potentially influence on the colonization and inflammation. Missense and nonsense mutations were observed in 15 and 6 loci, respectively. Multiple mutations were observed in three genes. Mutated genes included babA, tlpB, and gltS, which are known to be associated with adaptation to murine. Other mutations were involved with chemoreceptor, pH regulator, and outer membrane proteins, which also have potential to influence on the adaptation to the new host. Conclusions We confirmed mutations in genes previously reported to be associated with adaptation to Mongolian gerbils. We also listed up genes that mutated during the infection to the gerbils, though it needs experiments to prove the influence on adaptation.
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Affiliation(s)
- Rumiko Suzuki
- 1Department of Environmental and Preventive Medicine, Oita University Faculty of Medicine, 1-1 Idaigaoka, Hasama-machi, Yufu, Oita 879-5593 Japan
| | - Kazuhito Satou
- Okinawa Institute of Advanced Sciences, 5-1 Suzaki, Uruma, Okinawa 904-2234 Japan
| | - Akino Shiroma
- Okinawa Institute of Advanced Sciences, 5-1 Suzaki, Uruma, Okinawa 904-2234 Japan
| | - Makiko Shimoji
- Okinawa Institute of Advanced Sciences, 5-1 Suzaki, Uruma, Okinawa 904-2234 Japan
| | - Kuniko Teruya
- Okinawa Institute of Advanced Sciences, 5-1 Suzaki, Uruma, Okinawa 904-2234 Japan
| | - Takashi Matsumoto
- 1Department of Environmental and Preventive Medicine, Oita University Faculty of Medicine, 1-1 Idaigaoka, Hasama-machi, Yufu, Oita 879-5593 Japan
| | - Junko Akada
- 1Department of Environmental and Preventive Medicine, Oita University Faculty of Medicine, 1-1 Idaigaoka, Hasama-machi, Yufu, Oita 879-5593 Japan
| | - Takashi Hirano
- Okinawa Institute of Advanced Sciences, 5-1 Suzaki, Uruma, Okinawa 904-2234 Japan
| | - Yoshio Yamaoka
- 1Department of Environmental and Preventive Medicine, Oita University Faculty of Medicine, 1-1 Idaigaoka, Hasama-machi, Yufu, Oita 879-5593 Japan.,3Department of Medicine-Gastroenterology, Baylor College of Medicine, 2002 Holcombe Blvd., Houston, TX 77030 USA.,Global Oita Medical Advanced Research Center for Health, 1-1 Idaigaoka, Hasama-machi, Yufu, Oita 879-5593 Japan
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