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Clyne M, Ó Cróinín T. Pathogenicity and virulence of Helicobacter pylori: A paradigm of chronic infection. Virulence 2025; 16:2438735. [PMID: 39725863 DOI: 10.1080/21505594.2024.2438735] [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: 05/13/2024] [Revised: 11/18/2024] [Accepted: 12/02/2024] [Indexed: 12/28/2024] Open
Abstract
Infection with Helicobacter pylori is one of the most common infections of mankind. Infection typically occurs in childhood and persists for the lifetime of the host unless eradicated with antimicrobials. The organism colonizes the stomach and causes gastritis. Most infected individuals are asymptomatic, but infection also causes gastric and duodenal ulceration, and gastric cancer. H. pylori possesses an arsenal of virulence factors, including a potent urease enzyme for protection from acid, flagella that mediate motility, an abundance of outer membrane proteins that can mediate attachment, several immunomodulatory proteins, and an ability to adapt to specific conditions in individual human stomachs. The presence of a type 4 secretion system that injects effector molecules into gastric cells and subverts host cell signalling is associated with virulence. In this review we discuss the interplay of H. pylori colonization and virulence factors with host and environmental factors to determine disease outcome in infected individuals.
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Affiliation(s)
- Marguerite Clyne
- School of Medicine, University College Dublin, Dublin, Ireland
- The Conway Institute of Biomolecular and Biomedical Science, University College Dublin, Dublin, Ireland
| | - Tadhg Ó Cróinín
- The Conway Institute of Biomolecular and Biomedical Science, University College Dublin, Dublin, Ireland
- School of Biomolecular and Biomedical Science, University College Dublin, Dublin, Ireland
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Chen Y, Mu Q, Ouyang G. Causal Relationship between Helicobacter Pylori Antibodies and Immune Thrombocytopenia: A Mendelian Randomization Study. Mediterr J Hematol Infect Dis 2025; 17:e2025003. [PMID: 39830794 PMCID: PMC11740916 DOI: 10.4084/mjhid.2025.003] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2024] [Accepted: 12/14/2024] [Indexed: 01/22/2025] Open
Abstract
Background Previous observational studies have suggested a potential causal relationship between Helicobacter pylori (H. pylori) infection and immune thrombocytopenia (ITP). However, the evidence for causal inference remains contentious, and the underlying mechanisms require further investigation. To delve deeper into the relationship between H. pylori and ITP, we conducted a Mendelian randomization (MR) analysis. Method In this study, we used two-sample Mendelian Randomization (MR) to assess the causality of seven different specific protein antibodies targeting H. pylori on ITP. 76 single nucleotide polymorphisms (SNPs) related to H. pylori antibody levels were obtained from the European Bioinformatics Institute (EBI). Summary data on ITP was obtained from the FinnGen database, and inverse variance weighted (IVW) analysis was identified as our main method. The reliability of the findings was ensured by performing many sensitivity analyses. Result Genetically predicted serum levels of H. pylori GroEL antibodies were positively associated with an increased risk of ITP (odds ratio [OR] = 1.802, 95% CI 1.106-2.936, P = 0.01799). No causal relationship was found between other H. pylori antibodies and ITP. Conclusion The outcomes derived from our two-sample Mendelian randomization analysis demonstrate a discernible link between the levels of H. pylori GroEL antibodies and an augmented susceptibility to ITP. However, it is imperative to expand the sample size further in order to corroborate the correlation between H. pylori infection and ITP.
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Affiliation(s)
- Yuzhan Chen
- Department of Hematology, The First Affiliated Hospital of Ningbo University, Ningbo, Zhejiang, China
- Health Science Center, Ningbo University, Ningbo, Zhejiang, China
| | - Qitian Mu
- Laboratory of Stem Cell Transplantation, The First Affiliated Hospital of Ningbo University, Ningbo, Zhejiang, China
| | - Guifang Ouyang
- Department of Hematology, The First Affiliated Hospital of Ningbo University, Ningbo, Zhejiang, China
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Ghadersoltani P, Shoraka S, Sadjadi A, Saniee P. Long-term assessment of Helicobacter pylori cagA EPIYA motif changes and pathology outcomes in gastric biopsies of dyspeptic patients: 10-year follow-up. BMC Gastroenterol 2024; 24:466. [PMID: 39702056 DOI: 10.1186/s12876-024-03516-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/19/2024] [Accepted: 11/12/2024] [Indexed: 12/21/2024] Open
Abstract
INTRODUCTION Helicobacter pylori exhibit considerable genetic diversity, especially in the cagA gene, which is prone to rearrangement, affecting gastric pathology. This study aims to identify changes in the cagA EPIYA motif patterns and gastric pathology during long-term colonization and to explore how factors such as smoking, alcohol consumption, gender, and age influence these changes. METHODS Paired formalin-fixed paraffin-embedded (FFPE) gastric biopsies from 100 H. pylori-positive patients with digestive disorders obtained 10 years apart. After DNA extraction, the presence of H. pylori was detected by PCR amplification of the 16 S rRNA gene, and the cagA gene and its EPIYA motif patterns were identified by PCR using specific primers. RESULTS Our results showed that 90% and 91% of primary and secondary samples were cagA positive respectively. The most frequent patterns were AB and ABC, and in 52% of patients, notable changes occurred in the motif pattern of cagA. The most frequent gastric pathology was chronic inflammation in both sets of samplings and in 45% of patients, changes in pathology outcomes were reported. A significant association was found between changes in pathology outcomes and gender (P = 0.01), with alterations observed in 24 male patients and 21 female patients, and between changes in pathology outcomes and smoking (P = 0.00). Among those with changes in pathology outcomes, only 18 patients had smoking habits, indicating a potential inverse correlation between smoking and the observed changes. A logistic regression analysis was performed to examine the association between smoking, gender, changes in cagA and alterations in gastric pathology. The finding revealed no significant relationship with smoking (P = 0.978 OR = 1.012) and gender (P = 0.901, OR = 0.950), but identified a significant association with changes in the cagA gene (p = 0.001, OR = 0.296), CONCLUSION: he study highlights substantial heterogeneity in the cagA EPIYA motif patterns in long-term H. pylori colonization and notes an inverse relationship between pathology outcomes and smoking, warranting further investigation.
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Affiliation(s)
- Paria Ghadersoltani
- Department of Microbiology and Microbial Biotechnology, Faculty of Life Science and Biotechnology, Shahid Beheshti University, Tehran, Iran
| | - Shahrzad Shoraka
- Department of Microbiology and Microbial Biotechnology, Faculty of Life Science and Biotechnology, Shahid Beheshti University, Tehran, Iran
| | - Alireza Sadjadi
- Digestive Oncology Research Center, Digestive Diseases Research Institute, Shariati Hospital, Tehran University of Medical Sciences, Tehran, Iran
| | - Parastoo Saniee
- Department of Microbiology and Microbial Biotechnology, Faculty of Life Science and Biotechnology, Shahid Beheshti University, Tehran, Iran.
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Ji X, Sun Z, Wu H, Zhang J, Liu S, Cao X, Wang B, Wang F, Zhang Y, Li B, Feng J, Zhao H. More powerful dysregulation of Helicobacter pylori East Asian-type CagA on intracellular signalings. BMC Microbiol 2024; 24:467. [PMID: 39528935 PMCID: PMC11552142 DOI: 10.1186/s12866-024-03619-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2024] [Accepted: 11/04/2024] [Indexed: 11/16/2024] Open
Abstract
BACKGROUND Chronic infection by Helicobacter pylori strains expressing cytotoxin-associated gene A (CagA) are the strongest risk factor for gastric cancer. CagA can be classified into East Asian-type and Western-type (CagAE and CagAW), with CagAE being more closely associated with gastric cancer. This study aimed to investigate the impact of CagAE on intracellular signaling pathways to explain its high oncogenicity. RESULTS Mutant H. pylori strains expressing either CagAE or CagAW were generated by transforming CagAE/W-expression plasmid into CagA-deleted G27 strain (G27ΔCagA). In human gastric epithelial cells (GES-1) infection, CagAE induced more severe cytopathic changes, including higher interleukin-8 (IL-8) secretion, reduced cell viability, more pronounced "hummingbird phenotype" alterations, and increased cell migration and invasion compared to CagAW. Transcriptome analysis revealed that CagAE had a stronger effect on the up-regulation of key intracellular processes, including tumor necrosis factor-ɑ (TNF-ɑ) signal pathway via nuclear factor kappa-B (NF-κB), inflammatory response, interferon-γ (IFN-γ) response, hypoxia, ultraviolet (UV) response, and Kirsten Rat Sarcoma Viral Oncogene Homolog (KRAS) signaling. A significant upregulation of hypoxia-related genes was a notable feature of CagAE. GES-1 cells infected with CagAE exhibited more severe intracellular hypoxia and higher levels of reactive oxygen species (ROS) than those infected with CagAW. Inhibition of hypoxia-inducible factor-1α (HIF-1α), which blocks hypoxia signaling, mitigated CagAE-induced cell migration, emphasizing the role of hypoxia in mediating CagAE effects. CONCLUSIONS The study provides transcriptome evidence of CagA-associated intracellular regulation during H. pylori infection, demonstrating that CagAE exerts stronger effects on intracellular signaling than CagAW. These findings offer insights into the heightened carcinogenic potential of CagAE in H. pylori-induced gastric cancer.
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Affiliation(s)
- Xiaofei Ji
- Binzhou Medical University, Yantai, China
| | - Zekun Sun
- Binzhou Medical University, Yantai, China
| | - Hao Wu
- Binzhou Medical University, Yantai, China
- Department of Blood Transfusion, Jining First People's Hospital, Jining, China
| | | | | | | | - Bin Wang
- Binzhou Medical University, Yantai, China
| | | | - Ying Zhang
- Binzhou Medical University, Yantai, China
| | - Boqing Li
- Binzhou Medical University, Yantai, China
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Alvarez-Aldana A, Ikhimiukor OO, Guaca-González YM, Montoya-Giraldo M, Souza SSR, Buiatte ABG, Andam CP. Genomic insights into the antimicrobial resistance and virulence of Helicobacter pylori isolates from gastritis patients in Pereira, Colombia. BMC Genomics 2024; 25:843. [PMID: 39251950 PMCID: PMC11382513 DOI: 10.1186/s12864-024-10749-6] [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: 03/31/2024] [Accepted: 08/30/2024] [Indexed: 09/11/2024] Open
Abstract
BACKGROUND Helicobacter pylori infects the stomach and/or small intestines in more than half of the human population. Infection with H. pylori is the most common cause of chronic gastritis, which can lead to more severe gastroduodenal pathologies such as peptic ulcer, mucosa-associated lymphoid tissue lymphoma, and gastric cancer. H. pylori infection is particularly concerning in Colombia in South America, where > 80% of the population is estimated to be infected with H. pylori and the rate of stomach cancer is one of the highest in the continent. RESULTS We compared the antimicrobial susceptibility profiles and short-read genome sequences of five H. pylori isolates obtained from patients diagnosed with gastritis of varying severity (chronic gastritis, antral erosive gastritis, superficial gastritis) in Pereira, Colombia sampled in 2015. Antimicrobial susceptibility tests revealed the isolates to be resistant to at least one of the five antimicrobials tested: four isolates were resistant to metronidazole, two to clarithromycin, two to levofloxacin, and one to rifampin. All isolates were susceptible to tetracycline and amoxicillin. Comparative genome analyses revealed the presence of genes associated with efflux pump, restriction modification systems, phages and insertion sequences, and virulence genes including the cytotoxin genes cagA and vacA. The five genomes represent three novel sequence types. In the context of the Colombian and global populations, the five H. pylori isolates from Pereira were phylogenetically distant to each other but were closely related to other lineages circulating in the country. CONCLUSIONS H. pylori from gastritis of different severity varied in their antimicrobial susceptibility profiles and genome content. This knowledge will be useful in implementing appropriate eradication treatment regimens for specific types of gastritis. Understanding the genetic and phenotypic heterogeneity in H. pylori across the geographical landscape is critical in informing health policies for effective disease prevention and management that is most effective at local and country-wide scales. This is especially important in Colombia and other South American countries that are poorly represented in global genomic surveillance studies of bacterial pathogens.
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Affiliation(s)
- Adalucy Alvarez-Aldana
- Grupo de Investigación en Microbiología y Biotecnología (MICROBIOTEC), Universidad Libre Seccional Pereira, Programa de Microbiología, Pereira, Colombia
- Grupo de Investigación en Enfermedades Infecciosas (GRIENI), Universidad Tecnológica de Pereira, Programa de Medicina, Pereira, Colombia
| | - Odion O Ikhimiukor
- Department of Biological Sciences, University at Albany, State University of New York, Albany, NY, USA
| | - Yina Marcela Guaca-González
- Grupo de Investigación en Microbiología y Biotecnología (MICROBIOTEC), Universidad Libre Seccional Pereira, Programa de Microbiología, Pereira, Colombia
- Grupo de Investigación en Enfermedades Infecciosas (GRIENI), Universidad Tecnológica de Pereira, Programa de Medicina, Pereira, Colombia
| | - Manuela Montoya-Giraldo
- Department of Biological Sciences, University at Albany, State University of New York, Albany, NY, USA
| | - Stephanie S R Souza
- Department of Biological Sciences, University at Albany, State University of New York, Albany, NY, USA
| | - Ana Beatriz Garcez Buiatte
- Department of Biological Sciences, University at Albany, State University of New York, Albany, NY, USA
- Molecular Epidemiology Laboratory, Federal University of Uberlândia, Minas Gerais, Brazil
| | - Cheryl P Andam
- Department of Biological Sciences, University at Albany, State University of New York, Albany, NY, USA.
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de Back TR, van Hooff SR, Sommeijer DW, Vermeulen L. Transcriptomic subtyping of gastrointestinal malignancies. Trends Cancer 2024; 10:842-856. [PMID: 39019673 DOI: 10.1016/j.trecan.2024.06.007] [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: 04/25/2024] [Revised: 06/17/2024] [Accepted: 06/20/2024] [Indexed: 07/19/2024]
Abstract
Gastrointestinal (GI) cancers are highly heterogeneous at multiple levels. Tumor heterogeneity can be captured by molecular profiling, such as genetic, epigenetic, proteomic, and transcriptomic classification. Transcriptomic subtyping has the advantage of combining genetic and epigenetic information, cancer cell-intrinsic properties, and the tumor microenvironment (TME). Unsupervised transcriptomic subtyping systems of different GI malignancies have gained interest because they reveal shared biological features across cancers and bear prognostic and predictive value. Importantly, transcriptomic subtypes accurately reflect complex phenotypic states varying not only per tumor region, but also throughout disease progression, with consequences for clinical management. Here, we discuss methodologies of transcriptomic subtyping, proposed taxonomies for GI malignancies, and the challenges posed to clinical implementation, highlighting opportunities for future transcriptomic profiling efforts to optimize clinical impact.
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Affiliation(s)
- Tim R de Back
- Cancer Center Amsterdam, Laboratory for Experimental Oncology and Radiobiology, Center for Experimental and Molecular Medicine, Meibergdreef 9, 1105 AZ, Amsterdam, The Netherlands; Amsterdam Gastroenterology Endocrinology Metabolism, Laboratory for Experimental Oncology and Radiobiology, Center for Experimental and Molecular Medicine, Meibergdreef 9, 1105 AZ, Amsterdam, The Netherlands; Oncode Institute, Meibergdreef 9, 1105 AZ, Amsterdam, The Netherlands
| | - Sander R van Hooff
- Cancer Center Amsterdam, Laboratory for Experimental Oncology and Radiobiology, Center for Experimental and Molecular Medicine, Meibergdreef 9, 1105 AZ, Amsterdam, The Netherlands; Amsterdam Gastroenterology Endocrinology Metabolism, Laboratory for Experimental Oncology and Radiobiology, Center for Experimental and Molecular Medicine, Meibergdreef 9, 1105 AZ, Amsterdam, The Netherlands; Oncode Institute, Meibergdreef 9, 1105 AZ, Amsterdam, The Netherlands
| | - Dirkje W Sommeijer
- Flevohospital, Department of Internal Medicine, Hospitaalweg 1, 1315 RA, Almere, The Netherlands
| | - Louis Vermeulen
- Cancer Center Amsterdam, Laboratory for Experimental Oncology and Radiobiology, Center for Experimental and Molecular Medicine, Meibergdreef 9, 1105 AZ, Amsterdam, The Netherlands; Amsterdam Gastroenterology Endocrinology Metabolism, Laboratory for Experimental Oncology and Radiobiology, Center for Experimental and Molecular Medicine, Meibergdreef 9, 1105 AZ, Amsterdam, The Netherlands; Oncode Institute, Meibergdreef 9, 1105 AZ, Amsterdam, The Netherlands.
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Lai J, Angulmaduwa S, Kim MA, Kim A, Tissera K, Cho YJ, Cha JH. Influence of oipA Phase Variation on Virulence Phenotypes Related to Type IV Secretion System in Helicobacter pylori. Helicobacter 2024; 29:e13140. [PMID: 39440915 DOI: 10.1111/hel.13140] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/05/2024] [Revised: 08/23/2024] [Accepted: 09/11/2024] [Indexed: 10/25/2024]
Abstract
BACKGROUND oipA, an outer membrane protein of Helicobacter pylori, is linked to IL-8 induction and gastric inflammation, but its role is debated due to inconsistent findings. This study aims to explore the role of oipA phase variation in modulating the virulence traits of H. pylori, a bacterium strongly associated with the development of gastric cancer. MATERIAL AND METHODS American clinical isolate AH868 strain for naturally occurring phase variations of the oipA gene, and G27 strain for in vitro-induced phase variations were used to elucidate oipA's impact on key virulence phenotypes, including cell elongation, CagA phosphorylation, and IL-8 induction. RESULTS Using AH868 strain, natural oipA phase variation does not affect cell elongation and IL-8 induction. Interestingly, however, in vitro-induced oipA phase variations in G27 strain uncovered that 9.4% of oipA "Off" transformants exhibit reduced cell elongation while all maintaining consistent IL-8 induction levels. Additionally, complementation of oipA "Off to On" status restores the cell elongation phenotype in 12.5% of transformants, highlighting the importance of oipA in maintaining normal cell morphology. Crucially, these variations in cell elongation are not linked to changes in bacterial adherence capabilities. Furthermore, the study shows a correlation among oipA phase variation, cell elongation, and CagA phosphorylation, suggesting that oipA influences the functionality of the Type IV secretion system. Whole-genome sequencing of selected transformants reveals genetic variations in bab paralogue, cagY gene, and other genomic regions, underscoring the complex genetic interactions that shape H. pylori's virulence. CONCLUSIONS Our research provides new insights into the subtle yet significant role of oipA phase variation in H. pylori pathogenicity, emphasizing the need for further studies to explore the intricate molecular mechanisms involved. This understanding could pave the way for targeted therapeutic strategies to mitigate the impact of H. pylori on human health.
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Affiliation(s)
- Jing Lai
- Department of Periodontics, Changsha Stomatological Hospital, Changsha, Hunan, China
- Department of Oral Biology, Oral Science Research Center, Yonsei University College of Dentistry, Seoul, Republic of Korea
- Department of Applied Life Science, The Graduate School, BK21 FOUR Project, Yonsei University College of Dentistry, Seoul, Republic of Korea
| | - Sacheera Angulmaduwa
- Department of Oral Biology, Oral Science Research Center, Yonsei University College of Dentistry, Seoul, Republic of Korea
- Department of Applied Life Science, The Graduate School, BK21 FOUR Project, Yonsei University College of Dentistry, Seoul, Republic of Korea
| | - Myeong-A Kim
- Department of Oral Biology, Oral Science Research Center, Yonsei University College of Dentistry, Seoul, Republic of Korea
- Department of Applied Life Science, The Graduate School, BK21 FOUR Project, Yonsei University College of Dentistry, Seoul, Republic of Korea
| | - Aeryun Kim
- Department of Oral Biology, Oral Science Research Center, Yonsei University College of Dentistry, Seoul, Republic of Korea
- Department of Applied Life Science, The Graduate School, BK21 FOUR Project, Yonsei University College of Dentistry, Seoul, Republic of Korea
- Oral Health Research Institute, Apple Tree Dental Hospital, Bucheon, Republic of Korea
| | - Kavinda Tissera
- Department of Medical Laboratory Science, Faculty of Allied Health Sciences, University of Peradeniya, Peradeniya, Sri Lanka
| | - Yong-Joon Cho
- Department of Molecular Bioscience and Multidimensional Genomics Research Center, Kangwon National University, Chuncheon, Republic of Korea
| | - Jeong-Heon Cha
- Department of Oral Biology, Oral Science Research Center, Yonsei University College of Dentistry, Seoul, Republic of Korea
- Department of Applied Life Science, The Graduate School, BK21 FOUR Project, Yonsei University College of Dentistry, Seoul, Republic of Korea
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Zhu X, Ma C, Sa R, Wang Y, Zhu C, Zhao Y, Luo J, Liu X. CagA 3' region polymorphism of Helicobacter pylori and its association with chronic gastritis in the Chinese population. J Med Microbiol 2024; 73. [PMID: 39171760 DOI: 10.1099/jmm.0.001880] [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: 08/23/2024] Open
Abstract
Introduction. Cytotoxin-associated gene A (CagA) from Helicobacter pylori is highly related to chronic gastritis. Tyrosine phosphorylation of Glu-Pro-Ile-Tyr-Ala (EPIYA) motifs from CagA determines the pathogenicity of H. pylori.Gap statement. The precise amino acid variations surrounding the EPIYA motifs and their correlation with clinical outcomes have been poorly explored.Aim. The purpose of this study was to examine the CagA 3' region polymorphism of H. pylori and its association with chronic gastritis in the Chinese population.Method. A total of 86 cagA-positive H. pylori strains were isolated from patients with chronic gastritis in two different hospitals in Beijing, PR China. Genomic DNA was extracted commercial kits, and the cagA 3' variable region of H. pylori was amplified by polymerase chain reaction (PCR). The PCR products were sequenced and analysed using the CLC Sequence Viewer, BioEdit, and WebLogo 3.Results. Two hundred and fifty-nine EPIYA motifs were identified from cagA-positive H. pylori strains. Notably, EPIYA-B exhibited a higher frequency of variation in comparison to EPIYA-A, EPIYA-C, and EPIYA-D. The prevalent sequences for East-Asian-type CagA were QVNK and TIDF, while KVNK and TIDD were most commonly observed for Western-type CagA. The CRPIA motifs of East-Asian-type CagA and Western-type CagA varied at positions 4, 6, 7, 8, and 10. CagA-ABD (73.2%) was the most prevalent type, followed by CagA-ABC (18.6%) and CagA-AB (3.4%). The ratio of CagA-ABD was observed to be higher in cases of chronic non-atrophic gastritis with erosive (NAGE) or chronic atrophic gastritis (AG) compared to chronic non-atrophic gastritis (NAG), and the difference was found to be statistically significant (χ2=59.000/64.000, P<0.001).Conclusions. The EPIYA segments of Western-type CagA and East-Asian-type CagA differ significantly and the presence of CagA-ABD may be associated with severe chronic gastritis from this study.
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Affiliation(s)
- Xiaoyan Zhu
- Department of Clinical Laboratory, The First Affiliated Hospital of Kunming Medical University, Kunming, PR China
- Yunnan Province Clinical Research Center for Laboratory Medicine, Kunming, PR China
- Yunnan Key Laboratory of Laboratory Medicine, Kunming, PR China
| | - Chao Ma
- Beijing Institute of Occupational Disease Prevention and Treatment, Beijing, PR China
- Department of Clinical Laboratory, The Beijing Prevention and Treatment Hospital of Occupational Disease for Chemical Industry, Beijing, PR China
| | - Rina Sa
- General internal medicine, Jingdong Medical Area, General Hospital of Chinese PLA, Beijing, PR China
| | - Yaxuan Wang
- National Center for Clinical Laboratories, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Beijing Hospital/National Center of Gerontology, Beijing, PR China
| | - Chaohui Zhu
- Department of Gastroenterology, The Eighth Medical Center of PLA General Hospital, Beijing, PR China
| | - Yajiao Zhao
- Department of Gastroenterology, Emergency General Hospital, Beijing, PR China
| | - Juan Luo
- Department of Gastroenterology, The First Affiliated Hospital of Kunming Medical University, Kunming, PR China
- Yunnan Institute of Digestive Diseases, Kunming, PR China
| | - Xiaochuan Liu
- Department of Gastroenterology, Emergency General Hospital, Beijing, PR China
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Zhang L, Yu F, Zhang Y, Li P. Implications of lncRNAs in Helicobacter pylori-associated gastrointestinal cancers: underlying mechanisms and future perspectives. Front Cell Infect Microbiol 2024; 14:1392129. [PMID: 39035354 PMCID: PMC11257847 DOI: 10.3389/fcimb.2024.1392129] [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: 02/27/2024] [Accepted: 06/19/2024] [Indexed: 07/23/2024] Open
Abstract
Helicobacter pylori (H. pylori) is a harmful bacterium that is difficult to conveniently diagnose and effectively eradicate. Chronic H. pylori infection increases the risk of gastrointestinal diseases, even cancers. Despite the known findings, more underlying mechanisms are to be deeply explored to facilitate the development of novel prevention and treatment strategies of H. pylori infection. Long noncoding RNAs (lncRNAs) are RNAs with more than 200 nucleotides. They may be implicated in cell proliferation, inflammation and many other signaling pathways of gastrointestinal cancer progression. The dynamic expression of lncRNAs indicates their potential to be diagnostic or prognostic biomarkers. In this paper, we comprehensively summarize the processes of H. pylori infection and the treatment methods, review the known findings of lncRNA classification and functional mechanisms, elucidate the roles of lncRNAs in H. pylori-related gastrointestinal cancer, and discuss the clinical perspectives of lncRNAs.
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Affiliation(s)
- Lei Zhang
- Institute for Translational Medicine, The Affiliated Hospital of Qingdao University, Qingdao University, Qingdao, China
| | | | | | - Peifeng Li
- Institute for Translational Medicine, The Affiliated Hospital of Qingdao University, Qingdao University, Qingdao, China
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Sukthaworn S, Moungthard H, Sirisai C, Anuponganan W, Peerathippayamongkol C, Mus-U-Dee M, Taengchaiyaphum S. Helicobacter pylori Cytotoxin-Associated Gene A (cagA) and Vacuolating Cytotoxin Gene A (vacA) Genotypes in Gastrointestinal Patients From Central Thailand. Cureus 2024; 16:e64164. [PMID: 39119398 PMCID: PMC11309081 DOI: 10.7759/cureus.64164] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 07/09/2024] [Indexed: 08/10/2024] Open
Abstract
Introduction The development of diseases associated with Helicobacter pylori (H. pylori) infection is closely linked to its virulence genes, which vary by geographic region. This study aimed to determine the prevalence of H. pylori cytotoxin-associated gene A (cagA) and vacuolating cytotoxin gene A (vacA) genes and their genotypes in patients with gastrointestinal diseases. Methods Patients diagnosed with gastrointestinal disease based on endoscopic findings were recruited for the study. Gastric biopsies were collected to screen for H. pylori infection using polymerase chain reaction (PCR). Subsequently, infected samples were tested for cagA and vacA genes, and their genotypes were analyzed by sequencing. Results Among 250 cases, 56% (140/250) exhibited gastrointestinal diseases. Of these cases, 32.1% (45/140) were infected with H. pylori. Regarding gene detection, 40 (88.9%) samples were positive for cagA, while all samples were positive for vacA. For cagA, the Western type with the ABC pattern was the most prominent. There was a statistically significant association between cagA genotypes and clinical outcomes, with the Western type being more prevalent in gastritis patients. For vacA, there was a high prevalence of the s1 and i1, while the m1 and m2 showed similar prevalence. In our combined analysis, the dominant vacA genotype combinations were s1m1i1 (46.7%). There were no statistical differences between the vacA genotypes and clinical outcomes (P > 0.05). Conclusion This study revealed a high prevalence of H. pylori cagA and vacA genes, but there were variations in their genotypes. A correlation was observed between the Western-type cagA and gastritis; however, no association was found between vacA genotypes and clinical outcomes.
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Affiliation(s)
| | | | | | | | | | - Maneerut Mus-U-Dee
- Department of Anatomical Pathology, National Cancer Institute, Bangkok, THA
| | - Suparat Taengchaiyaphum
- National Center for Genetic Engineering and Biotechnology, National Science and Technology Development Agency (NSTDA), Bangkok, THA
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Drnovsek J, Homan M, Zidar N, Smid LM. Pathogenesis and potential reversibility of intestinal metaplasia - a milestone in gastric carcinogenesis. Radiol Oncol 2024; 58:186-195. [PMID: 38643513 PMCID: PMC11165985 DOI: 10.2478/raon-2024-0028] [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: 11/03/2023] [Accepted: 03/19/2024] [Indexed: 04/23/2024] Open
Abstract
BACKGROUND Non-cardia gastric cancer remains a major cause of cancer-related mortality worldwide, despite declining incidence rates in many industrialized countries. The development of intestinal-type gastric cancer occurs through a multistep process in which normal mucosa is sequentially transformed into hyperproliferative epithelium, followed by metaplastic processes leading to carcinogenesis. Chronic infection with Helicobacter pylori is the primary etiological agent that causes chronic inflammation of the gastric mucosa, induces atrophic gastritis, and can lead to intestinal metaplasia and dysplasia. Both intestinal metaplasia and dysplasia are precancerous lesions, in which gastric cancer is more likely to occur. Atrophic gastritis often improves after eradication of Helicobacter pylori; however, the occurrence of intestinal metaplasia has been traditionally regarded as "the point of no return" in the carcinogenesis sequence. Helicobacter pylori eradication heals non-atrophic chronic gastritis, may lead to regression of atrophic gastritis, and reduces the risk of gastric cancer in patients with these conditions. In this article, we discuss the pathogenesis, epigenomics, and reversibility of intestinal metaplasia and briefly touch upon potential treatment strategy. CONCLUSIONS Gastric intestinal metaplasia no longer appears to be an irreversible precancerous lesion. However, there are still many controversies regarding the improvement of intestinal metaplasia after Helicobacter pylori eradication.
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Affiliation(s)
- Jan Drnovsek
- Department of Gastroenterology, University Medical Centre Ljubljana, Ljubljana, Slovenia
- Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia
| | - Matjaz Homan
- Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia
- Department of Gastroenterology, Hepatology and Nutrition, University Children’s Hospital, Ljubljana, Slovenia
| | - Nina Zidar
- Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia
- Institute of Pathology, Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia
| | - Lojze M Smid
- Department of Gastroenterology, University Medical Centre Ljubljana, Ljubljana, Slovenia
- Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia
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12
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Guzmán J, Castillo D, González-Siccha AD, Bussalleu A, Trespalacios-Rangel AA, Lescano AG, Sauvain M. Helicobacter pylori cagA, vacA, iceA and babA Genotypes from Peruvian Patients with Gastric Intestinal Metaplasia. Cancers (Basel) 2024; 16:1476. [PMID: 38672558 PMCID: PMC11047899 DOI: 10.3390/cancers16081476] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2024] [Revised: 03/10/2024] [Accepted: 03/13/2024] [Indexed: 04/28/2024] Open
Abstract
We explored the clinical-stage association of gastric intestinal metaplasia (IM) compared to cases of chronic non-atrophic gastritis (CNAG) and its relationship with virulence genotypes of Helicobacter pylori (H. pylori) clinical isolates from patients with dyspepsia in Peru. This study was cross-sectional and included 158 H. pylori clinical isolates; each isolate corresponded to a different Peruvian patient, genotyped by polymerase chain reaction to detect cagA gene and EPIYA motifs, the vacA gene (alleles s1, s2, i1, i2, d1, d2, m1, m2 and subtypes s1a, s1b and s1c), the iceA gene (alleles 1 and 2), and the babA gene (allele 2). We observed that 38.6% presented with IM and that all clinical isolates were CagA positive. The EPIYA-ABC motif was predominant (68.4%), and we observed a high frequency for the vacA gene alleles s1 (94.9%), m1 (81.7%), i1 (63.9%), and d1 (70.9%). Strains with both iceA alleles were also detected (69.6%) and 52.2% were babA2 positive. In addition, it was observed that the cagA+/vacAs1m1 (PR: 2.42, 1.14 to 5.13, p < 0.05) and cagA+/vacAs1am1 (PR: 1.67, 1.13 to 2.45, p < 0.01) genotypes were associated with IM. Our findings revealed the cagA and vacA risk genotypes predominance, and we provided clinically relevant associations between Peruvian patients with H. pylori infection and IM clinical stage.
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Affiliation(s)
- Jesús Guzmán
- Laboratorio Centinela de Helicobacter pylori, Instituto de Medicina Tropical Alexander von Humboldt, Universidad Peruana Cayetano Heredia, Lima 15024, Peru; (D.C.); (A.B.); (M.S.)
- Facultad de Salud Pública y Administración, Universidad Peruana Cayetano Heredia, Lima 15102, Peru;
| | - Denis Castillo
- Laboratorio Centinela de Helicobacter pylori, Instituto de Medicina Tropical Alexander von Humboldt, Universidad Peruana Cayetano Heredia, Lima 15024, Peru; (D.C.); (A.B.); (M.S.)
| | - Anabel D. González-Siccha
- Departamento de Bioquímica, Facultad de Farmacia y Bioquímica, Universidad Nacional de Trujillo, Trujillo 13011, Peru;
| | - Alejandro Bussalleu
- Laboratorio Centinela de Helicobacter pylori, Instituto de Medicina Tropical Alexander von Humboldt, Universidad Peruana Cayetano Heredia, Lima 15024, Peru; (D.C.); (A.B.); (M.S.)
| | - Alba A. Trespalacios-Rangel
- Grupo de Investigación en Enfermedades Infecciosas, Departamento de Microbiología, Facultad de Ciencias, Pontificia Universidad Javeriana, Bogotá 110231, Colombia;
| | - Andres G. Lescano
- Facultad de Salud Pública y Administración, Universidad Peruana Cayetano Heredia, Lima 15102, Peru;
| | - Michel Sauvain
- Laboratorio Centinela de Helicobacter pylori, Instituto de Medicina Tropical Alexander von Humboldt, Universidad Peruana Cayetano Heredia, Lima 15024, Peru; (D.C.); (A.B.); (M.S.)
- UMR 152 Pharmacochimie et Biologie pour le Développement (PHARMA-DEV), Institut de Recherche pour le Développement (IRD), Université de Toulouse, CEDEX 9, 31062 Toulouse, France
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13
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Oudouhou F, Morin C, Bouin M, Gaudreau C, Baron C. Inhibition of the type IV secretion system from antibiotic-resistant Helicobacter pylori clinical isolates supports the potential of Cagα as an anti-virulence target. Can J Microbiol 2024; 70:119-127. [PMID: 38176008 DOI: 10.1139/cjm-2023-0168] [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: 01/06/2024]
Abstract
Helicobacter pylori resistance to antibiotics is a growing problem and it increasingly leads to treatment failure. While the bacterium is present worldwide, the severity of clinical outcomes is highly dependent on the geographical origin and genetic characteristics of the strains. One of the major virulence factors identified in H. pylori is the cag pathogenicity island (cagPAI), which encodes a type IV secretion system (T4SS) used to translocate effectors into human cells. Here, we investigated the genetic variability of the cagPAI among 13 antibiotic-resistant H. pylori strains that were isolated from patient biopsies in Québec. Seven of the clinical strains carried the cagPAI, but only four could be readily cultivated under laboratory conditions. We observed variability of the sequences of CagA and CagL proteins that are encoded by the cagPAI. All clinical isolates induce interleukin-8 secretion and morphological changes upon co-incubation with gastric cancer cells and two of them produce extracellular T4SS pili. Finally, we demonstrate that molecule 1G2, a small molecule inhibitor of the Cagα protein from the model strain H. pylori 26695, reduces interleukin-8 secretion in one of the clinical isolates. Co-incubation with 1G2 also inhibits the assembly of T4SS pili, suggesting a mechanism for its action on T4SS function.
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Affiliation(s)
- Flore Oudouhou
- Department of Biochemistry and Molecular Medicine, Faculty of Medicine, Université de Montréal, Montréal, QC, Canada
| | - Claire Morin
- Department of Biochemistry and Molecular Medicine, Faculty of Medicine, Université de Montréal, Montréal, QC, Canada
| | - Mickael Bouin
- Department of Medicine, Faculty of Medicine, Université de Montréal and Centre Hospitalier de l'Université de Montréal (CHUM), Montréal, QC, Canada
| | - Christiane Gaudreau
- Department of Microbiology, Infectiology and Immunology, Faculty of Medicine, Université de Montréal and Centre Hospitalier de l'Université de Montréal (CHUM), Montréal, QC, Canada
| | - Christian Baron
- Department of Biochemistry and Molecular Medicine, Faculty of Medicine, Université de Montréal, Montréal, QC, Canada
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14
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Chen S, Zhao H, Tian Y, Wu Q, Zhang J, Liu S, Zhang Y, Wu Y, Li B, Chen S, Wang Z, Xiao R, Ji X. Antagonizing roles of SHP1 in the pathogenesis of Helicobacter pylori infection. Helicobacter 2024; 29:e13066. [PMID: 38468575 DOI: 10.1111/hel.13066] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/27/2023] [Revised: 02/16/2024] [Accepted: 02/29/2024] [Indexed: 03/13/2024]
Abstract
BACKGROUND SHP1 has been documented as a tumor suppressor and it was thought to play an antagonistic role in the pathogenesis of Helicobacter pylori infection. In this study, the exact mechanism of this antagonistic action was studied. MATERIALS AND METHODS AGS, MGC803, and GES-1 cells were infected with H. pylori, intracellular distribution changes of SHP1 were first detected by immunofluorescence. SHP1 overexpression and knockdown were then constructed in these cells to investigate its antagonistic roles in H. pylori infection. Migration and invasion of infected cells were detected by transwell assay, secretion of IL-8 was examined via ELISA, the cells with hummingbird-like alteration were determined by microexamination, and activation of JAK2/STAT3, PI3K/Akt, and ERK pathways were detected by immunoblotting. Mice infection model was established and gastric pathological changes were evaluated. Finally, the SHP1 activator sorafenib was used to analyze the attenuating effect of SHP1 activation on H. pylori pathogenesis in vitro and in vivo. RESULTS The sub-localization of SHP1 changed after H. pylori infection, specifically that the majority of the cytoplasmic SHP1 was transferred to the cell membrane. SHP1 inhibited H. pylori-induced activation of JAK2/STAT3 pathway, PI3K/Akt pathway, nuclear translocation of NF-κB, and then reduced EMT, migration, invasion, and IL-8 secretion. In addition, SHP1 inhibited the formation of CagA-SHP2 complex by dephosphorylating phosphorylated CagA, reduced ERK phosphorylation and the formation of CagA-dependent hummingbird-like cells. In the mice infection model, gastric pathological changes were observed and increased IL-8 secretion, indicators of cell proliferation and EMT progression were also detected. By activating SHP1 with sorafenib, a significant curative effect against H. pylori infection was obtained in vitro and in vivo. CONCLUSIONS SHP1 plays an antagonistic role in H. pylori pathogenesis by inhibiting JAK2/STAT3 and PI3K/Akt pathways, NF-κB nuclear translocation, and CagA phosphorylation, thereby reducing cell EMT, migration, invasion, IL-8 secretion, and hummingbird-like changes.
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Affiliation(s)
- Si Chen
- Binzhou Medical University, Yantai, China
| | | | - Yue Tian
- Binzhou Medical University, Yantai, China
- Binzhou People's Hospital, Binzhou, China
| | - Qianwen Wu
- Binzhou Medical University, Yantai, China
| | | | | | - Ying Zhang
- Binzhou Medical University, Yantai, China
| | - Yulong Wu
- Binzhou Medical University, Yantai, China
| | - Boqing Li
- Binzhou Medical University, Yantai, China
| | - Shu Chen
- Binzhou Medical University, Yantai, China
| | | | - Ruoyu Xiao
- Binzhou Medical University, Yantai, China
| | - Xiaofei Ji
- Binzhou Medical University, Yantai, China
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15
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González-Stegmaier R, Aguila-Torres P, Villarroel-Espíndola F. Historical and Molecular Perspectives on the Presence of Helicobacter pylori in Latin America: A Niche to Improve Gastric Cancer Risk Assessment. Int J Mol Sci 2024; 25:1761. [PMID: 38339039 PMCID: PMC10855479 DOI: 10.3390/ijms25031761] [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: 01/16/2024] [Revised: 01/26/2024] [Accepted: 01/30/2024] [Indexed: 02/12/2024] Open
Abstract
Helicobacter pylori (H. pylori) is responsible for causing chronic gastritis, which can cause peptic ulcer and premalignant lesions such as atrophic gastritis, intestinal metaplasia, and dysplasia, with the risk of developing gastric cancer. Recent data describe that H. pylori colonizes the gastric mucosa of more than 50% of the world's population; however, this bacterium has been described as infecting the human population since its prehistory. This review focuses on the populations and subpopulations of H. pylori, differentiated by the polymorphisms present in their constitutive and virulence genes. These genes have spread and associated with different human populations, showing variability depending on their geographical distribution, and have evolved together with the human being. The predominant genotypes worldwide, Latin America and Chile, are described to understand the genetic diversity and pathogenicity of H. pylori in different populations and geographic regions. The high similarity in the sequence of virulence genes between H. pylori strains present in Peruvian and Spanish natives in Latin America suggests a European influence. The presence of cagA-positive strains and vacA s1 m1 allelic variants is observed with greater prevalence in Chilean patients with more severe gastrointestinal diseases and is associated with its geographical distribution. These findings highlight the importance of understanding the genetic diversity of H. pylori in different regions of the world for a more accurate assessment of the risk of associated diseases and their potential impact on health.
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Affiliation(s)
- Roxana González-Stegmaier
- Traslational Medicine Laboratory, Instituto Oncológico Fundación Arturo López Pérez, Santiago 7500000, Chile;
| | - Patricia Aguila-Torres
- Laboratorio de Microbiología Molecular, Escuela de Tecnología Médica, Universidad Austral de Chile, Puerto Montt 5480000, Chile;
| | - Franz Villarroel-Espíndola
- Traslational Medicine Laboratory, Instituto Oncológico Fundación Arturo López Pérez, Santiago 7500000, Chile;
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16
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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: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [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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17
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Liu T, Guo Y, Liao Y, Liu J. Mechanism-guided fine-tuned microbiome potentiates anti-tumor immunity in HCC. Front Immunol 2023; 14:1333864. [PMID: 38169837 PMCID: PMC10758498 DOI: 10.3389/fimmu.2023.1333864] [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: 11/06/2023] [Accepted: 12/05/2023] [Indexed: 01/05/2024] Open
Abstract
Microbiome, including bacteria, fungi, and viruses, plays a crucial role in shaping distal and proximal anti-tumor immunity. Mounting evidence showed that commensal microbiome critically modulates immunophenotyping of hepatocellular carcinoma (HCC), a leading cause of cancer-related death. However, their role in anti-tumor surveillance of HCC is still poorly understood. Herein, we spotlighted growing interests in how the microbiome influences the progression and immunotherapeutic responses of HCC via changing local tumor microenvironment (TME) upon translocating to the sites of HCC through different "cell-type niches". Moreover, we summarized not only the associations but also the deep insight into the mechanisms of how the extrinsic microbiomes interplay with hosts to shape immune surveillance and regulate TME and immunotherapeutic responses. Collectively, we provided a rationale for a mechanism-guided fine-tuned microbiome to be neoadjuvant immunotherapy in the near future.
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Affiliation(s)
- Tao Liu
- State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou, China
| | - Ya Guo
- State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou, China
| | - Yanxia Liao
- State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou, China
| | - Jinping Liu
- State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou, China
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18
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Buyuk F, Karakaya E, Akar M, Kayman T, Tarhane S, Ozcan HE, Celebi O, Saticioglu IB, Anuk T, Abay S, Otlu S, Aydin F. A comprehensive study of Helicobacter pylori infection: molecular analysis, antibacterial susceptibility, and histopathological examination. Antonie Van Leeuwenhoek 2023; 116:1261-1273. [PMID: 37603113 DOI: 10.1007/s10482-023-01868-3] [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: 02/14/2023] [Accepted: 08/07/2023] [Indexed: 08/22/2023]
Abstract
Helicobacter pylori is a pathogen associated with gastroduodenal diseases. This study aimed; (i) to investigate H. pylori presence by invasive tests in adult dyspeptic patients, (ii) to determine antibiotic susceptibility and genotypic characteristics of the H. pylori isolates, and (iii) to investigate the relationship between the H. pylori genotypes and the histopathological findings. In this cross-sectional study, gastric biopsy samples from 208 adult dyspeptic patients were used for culture, tissue Polymerase Chain Reaction (PCR), and histopathological analysis. Antibiotic susceptibility of the H. pylori isolates was analyzed by gradient method. Analysis of the virulence genes was performed by monoplex PCR. Genetic profiles (from A to H) were created based on the virulence genes presence. Enterobacterial Repetitive Intergenic Consensus-PCR (ERIC-PCR) was used for the genotyping of the H. pylori isolates. The mean age of the patients was 46 (± 15) years and 128 (61.5%) of them were female. H. pylori positivity was detected by culture, tissue PCR and histopathological examination in 59 (28.4%), 114 (54.8%) and 81 (38.9%) patients, respectively. The overall prevalence of H. pylori was found to be 63% (131/208). All H. pylori isolates were susceptible to tetracycline and amoxicillin. The resistance rates for metronidazole, clarithromycin, levofloxacin, and rifampicin were 67.2%, 27.9%, 34.4% and 13.11%, respectively. Multi drug resistance (MDR) was detected at the rate of 45.9% (28/61). While the most common virulence gene was cagA (93.44%), the least common was vacAm1 (23%). The predominant genetic profile was profile A (47.5%). ERIC-PCR results revealed a total of 26 different patterns. A high prevalence of H. pylori was detected in adult dyspeptic patients as in developing countries. It was observed significant genotypic heterogeneity and virulence gene diversity within the isolates. A considerable resistance rate detected against antibiotics such as clarithromycin, metronidazole, and levofloxacin, which are frequently used in the eradication of H. pylori, should be taken into consideration when creating regional empirical treatment regimens.
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Affiliation(s)
- Fatih Buyuk
- Department of Microbiology, Faculty of Veterinary Medicine, Kafkas University, Kars, Türkiye.
| | - Emre Karakaya
- Department of Microbiology, Faculty of Veterinary Medicine, Erciyes University, Kayseri, Türkiye
| | - Mustafa Akar
- Department of Gastroenterology, University of Health Sciences, Bursa Yüksek İhtisas Training and Research Hospital, Bursa, Türkiye
| | - Tuba Kayman
- Department of Medical Microbiology, Faculty of Medicine, Kırıkkale University, Kırıkkale, Türkiye
| | - Serdal Tarhane
- Veterinary Department, Eldivan Vocational School of Health Services, Çankırı Karatekin University, Çankırı, Türkiye
| | - Hacer Ece Ozcan
- Department of Medical Pathology, Mersin City Hospital, Mersin, Türkiye
| | - Ozgur Celebi
- Department of Microbiology, Faculty of Veterinary Medicine, Kafkas University, Kars, Türkiye
| | - Izzet Burcin Saticioglu
- Department of Aquatic Animal Diseases, Faculty of Veterinary Medicine, Uludağ University, Bursa, Türkiye
| | - Turgut Anuk
- Department of General Surgery, Erzurum Faculty of Medicine, University of Health Sciences, Erzurum, Türkiye
| | - Secil Abay
- Department of Microbiology, Faculty of Veterinary Medicine, Erciyes University, Kayseri, Türkiye
| | - Salih Otlu
- Department of Microbiology, Faculty of Veterinary Medicine, Kafkas University, Kars, Türkiye
| | - Fuat Aydin
- Department of Microbiology, Faculty of Veterinary Medicine, Erciyes University, Kayseri, Türkiye
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19
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Luo S, Ru J, Mirzaei MK, Xue J, Peng X, Ralser A, Mejías-Luque R, Gerhard M, Deng L. Gut virome profiling identifies an association between temperate phages and colorectal cancer promoted by Helicobacter pylori infection. Gut Microbes 2023; 15:2257291. [PMID: 37747149 PMCID: PMC10578192 DOI: 10.1080/19490976.2023.2257291] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/09/2023] [Accepted: 09/06/2023] [Indexed: 09/26/2023] Open
Abstract
Colorectal cancer (CRC) is one of the most commonly diagnosed cancers worldwide. While a close correlation between chronic Helicobacter pylori infection and CRC has been reported, the role of the virome has been overlooked. Here, we infected Apc-mutant mouse models and C57BL/6 mice with H. pylori and conducted a comprehensive metagenomics analysis of H. pylori-induced changes in lower gastrointestinal tract bacterial and viral communities. We observed an expansion of temperate phages in H. pylori infected Apc+/1638N mice at the early stage of carcinogenesis. Some of the temperate phages were predicted to infect bacteria associated with CRC, including Enterococcus faecalis. We also observed a high prevalence of virulent genes, such as flgJ, cwlJ, and sleB, encoded by temperate phages. In addition, we identified phages associated with pre-onset and onset of H. pylori-promoted carcinogenesis. Through co-occurrence network analysis, we found strong associations between the viral and bacterial communities in infected mice before the onset of carcinogenesis. These findings suggest that the expansion of temperate phages, possibly caused by prophage induction triggered by H. pylori infection, may have contributed to the development of CRC in mice by interacting with the bacterial community.
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Affiliation(s)
- Shiqi Luo
- Institute of Virology, Helmholtz Centre Munich — German Research Centre for Environmental Health, Neuherberg, Germany
- Chair for Preventions of Microbial Diseases, School of Life Sciences, Technical University of Munich, Freising, Germany
| | - Jinlong Ru
- Institute of Virology, Helmholtz Centre Munich — German Research Centre for Environmental Health, Neuherberg, Germany
- Chair for Preventions of Microbial Diseases, School of Life Sciences, Technical University of Munich, Freising, Germany
| | - Mohammadali Khan Mirzaei
- Institute of Virology, Helmholtz Centre Munich — German Research Centre for Environmental Health, Neuherberg, Germany
- Chair for Preventions of Microbial Diseases, School of Life Sciences, Technical University of Munich, Freising, Germany
| | - Jinling Xue
- Institute of Virology, Helmholtz Centre Munich — German Research Centre for Environmental Health, Neuherberg, Germany
- Chair for Preventions of Microbial Diseases, School of Life Sciences, Technical University of Munich, Freising, Germany
| | - Xue Peng
- Institute of Virology, Helmholtz Centre Munich — German Research Centre for Environmental Health, Neuherberg, Germany
- Faculty of Biology, Biocenter, Ludwig Maximilian University of Munich, Munich, Germany
| | - Anna Ralser
- Institute for Medical Microbiology, Immunology and Hygiene, Technical University of Munich, Munich, Germany
| | - Raquel Mejías-Luque
- Institute for Medical Microbiology, Immunology and Hygiene, Technical University of Munich, Munich, Germany
- German Center for Infection Research (DZIF), Munich Partner Site, Munich, Germany
| | - Markus Gerhard
- Institute for Medical Microbiology, Immunology and Hygiene, Technical University of Munich, Munich, Germany
- German Center for Infection Research (DZIF), Munich Partner Site, Munich, Germany
| | - Li Deng
- Institute of Virology, Helmholtz Centre Munich — German Research Centre for Environmental Health, Neuherberg, Germany
- Chair for Preventions of Microbial Diseases, School of Life Sciences, Technical University of Munich, Freising, Germany
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20
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Ailloud F, Gottschall W, Suerbaum S. Methylome evolution suggests lineage-dependent selection in the gastric pathogen Helicobacter pylori. Commun Biol 2023; 6:839. [PMID: 37573385 PMCID: PMC10423294 DOI: 10.1038/s42003-023-05218-x] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2023] [Accepted: 08/04/2023] [Indexed: 08/14/2023] Open
Abstract
The bacterial pathogen Helicobacter pylori, the leading cause of gastric cancer, is genetically highly diverse and harbours a large and variable portfolio of restriction-modification systems. Our understanding of the evolution and function of DNA methylation in bacteria is limited. Here, we performed a comprehensive analysis of the methylome diversity in H. pylori, using a dataset of 541 genomes that included all known phylogeographic populations. The frequency of 96 methyltransferases and the abundance of their cognate recognition sequences were strongly influenced by phylogeographic structure and were inter-correlated, positively or negatively, for 20% of type II methyltransferases. Low density motifs were more likely to be affected by natural selection, as reflected by higher genomic instability and compositional bias. Importantly, direct correlation implied that methylation patterns can be actively enriched by positive selection and suggests that specific sites have important functions in methylation-dependent phenotypes. Finally, we identified lineage-specific selective pressures modulating the contraction and expansion of the motif ACGT, revealing that the genetic load of methylation could be dependent on local ecological factors. Taken together, natural selection may shape both the abundance and distribution of methyltransferases and their specific recognition sequences, likely permitting a fine-tuning of genome-encoded functions not achievable by genetic variation alone.
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Affiliation(s)
- Florent Ailloud
- Medical Microbiology and Hospital Epidemiology, Max von Pettenkofer Institute, Faculty of Medicine, LMU Munich, Munich, Germany.
- German Center for Infection Research (DZIF), Partner Site Munich, Munich, Germany.
| | - Wilhelm Gottschall
- Medical Microbiology and Hospital Epidemiology, Max von Pettenkofer Institute, Faculty of Medicine, LMU Munich, Munich, Germany
| | - Sebastian Suerbaum
- Medical Microbiology and Hospital Epidemiology, Max von Pettenkofer Institute, Faculty of Medicine, LMU Munich, Munich, Germany.
- German Center for Infection Research (DZIF), Partner Site Munich, Munich, Germany.
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Jamal Eddin TM, Nasr SM, Gupta I, Zayed H, Al Moustafa AE. Helicobacter pylori and epithelial mesenchymal transition in human gastric cancers: An update of the literature. Heliyon 2023; 9:e18945. [PMID: 37609398 PMCID: PMC10440535 DOI: 10.1016/j.heliyon.2023.e18945] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2023] [Revised: 07/25/2023] [Accepted: 08/03/2023] [Indexed: 08/24/2023] Open
Abstract
Gastric cancer, a multifactorial disease, is considered one of the most common malignancies worldwide. In addition to genetic and environmental risk factors, infectious agents, such as Epstein-Barr virus (EBV) and Helicobacter pylori (H.pylori) contribute to the onset and development of gastric cancer. H. pylori is a type I carcinogen that colonizes the gastric epithelium of approximately 50% of the world's population, thus increasing the risk of gastric cancer development. On the other hand, epithelial mesenchymal transition (EMT) is a fundamental process crucial to embryogenic growth, wound healing, organ fibrosis and cancer progression. Several studies associate gastric pathogen infection of the epithelium with EMT initiation, provoking cancer metastasis in the gastric mucosa through various molecular signaling pathways. Additionally, EMT is implicated in the progression and development of H. pylori-associated gastric cancer. In this review, we recapitulate recent findings elucidating the association between H. pylori infection in EMT promotion leading to gastric cancer progression and metastasis.
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Affiliation(s)
- Tala M. Jamal Eddin
- College of Health Sciences, QU Health, Qatar University, PO Box 2713, Doha, Qatar
| | - Shahd M.O. Nasr
- College of Health Sciences, QU Health, Qatar University, PO Box 2713, Doha, Qatar
| | - Ishita Gupta
- College of Medicine, QU Health, Qatar University, PO Box 2713, Doha, Qatar
| | - Hatem Zayed
- College of Health Sciences, QU Health, Qatar University, PO Box 2713, Doha, Qatar
| | - Ala-Eddin Al Moustafa
- College of Medicine, QU Health, Qatar University, PO Box 2713, Doha, Qatar
- Biomedical Research Center, Qatar University, PO Box 2713, Doha, Qatar
- Oncology Department, Faculty of Medicine, McGill University, Montreal, QC, H3G 2M1, Canada
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22
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Goel RK, Kim N, Lukong KE. Seeking a better understanding of the non-receptor tyrosine kinase, SRMS. Heliyon 2023; 9:e16421. [PMID: 37251450 PMCID: PMC10220380 DOI: 10.1016/j.heliyon.2023.e16421] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2023] [Revised: 05/14/2023] [Accepted: 05/16/2023] [Indexed: 05/31/2023] Open
Abstract
SRMS (Src-Related kinase lacking C-terminal regulatory tyrosine and N-terminal Myristoylation Sites) is a non-receptor tyrosine kinase first reported in a 1994 screen for genes regulating murine neural precursor cells. SRMS, pronounced "Shrims", lacks the C-terminal regulatory tyrosine critical for the regulation of the enzymatic activity of Src-family kinases (SFKs). Another remarkable characteristic of SRMS is its localization into distinct SRMS cytoplasmic punctae (SCPs) or GREL (Goel Raghuveera-Erique Lukong) bodies, a pattern not observed in the SFKs. This unique subcellular localization of SRMS could dictate its cellular targets, proteome, and potentially, substrates. However, the function of SRMS is still relatively unknown. Further, how is its activity regulated and by what cellular targets? Studies have emerged highlighting the potential role of SRMS in autophagy and in regulating the activation of BRK/PTK6. Potential novel cellular substrates have also been identified, including DOK1, vimentin, Sam68, FBKP51, and OTUB1. Recent studies have also demonstrated the potential role of the kinase in various cancers, including gastric and colorectal cancers and platinum resistance in ovarian cancer. This review discusses the advancements made in SRMS-related biology to date and the path to understanding the cellular and physiological significance of the kinase.
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Affiliation(s)
- Raghuveera Kumar Goel
- Center for Network Systems Biology, Boston University, Boston, MA, USA
- Department of Biochemistry, Boston University School of Medicine, Boston, MA, USA
| | - Nayoung Kim
- Department of Biochemistry, Microbiology, and Immunology, 107 Wiggins Road, Health Sciences Building, University of Saskatchewan, Saskatoon S7N 5E5, Saskatchewan, Canada
| | - Kiven Erique Lukong
- Department of Biochemistry, Microbiology, and Immunology, 107 Wiggins Road, Health Sciences Building, University of Saskatchewan, Saskatoon S7N 5E5, Saskatchewan, Canada
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23
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Reyes VE. Helicobacter pylori and Its Role in Gastric Cancer. Microorganisms 2023; 11:1312. [PMID: 37317287 PMCID: PMC10220541 DOI: 10.3390/microorganisms11051312] [Citation(s) in RCA: 37] [Impact Index Per Article: 18.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/17/2023] [Revised: 05/08/2023] [Accepted: 05/15/2023] [Indexed: 06/16/2023] Open
Abstract
Gastric cancer is a challenging public health concern worldwide and remains a leading cause of cancer-related mortality. The primary risk factor implicated in gastric cancer development is infection with Helicobacter pylori. H. pylori induces chronic inflammation affecting the gastric epithelium, which can lead to DNA damage and the promotion of precancerous lesions. Disease manifestations associated with H. pylori are attributed to virulence factors with multiple activities, and its capacity to subvert host immunity. One of the most significant H. pylori virulence determinants is the cagPAI gene cluster, which encodes a type IV secretion system and the CagA toxin. This secretion system allows H. pylori to inject the CagA oncoprotein into host cells, causing multiple cellular perturbations. Despite the high prevalence of H. pylori infection, only a small percentage of affected individuals develop significant clinical outcomes, while most remain asymptomatic. Therefore, understanding how H. pylori triggers carcinogenesis and its immune evasion mechanisms is critical in preventing gastric cancer and mitigating the burden of this life-threatening disease. This review aims to provide an overview of our current understanding of H. pylori infection, its association with gastric cancer and other gastric diseases, and how it subverts the host immune system to establish persistent infection.
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Affiliation(s)
- Victor E Reyes
- Department of Pediatrics and Microbiology & Immunology, University of Texas Medical Branch, 301 University Blvd., Galveston, TX 77555-0372, USA
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24
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Yamaguchi N, Sakaguchi T, Isomoto H, Inamine T, Tsukamoto R, Fukuda D, Ohnita K, Kanda T, Matsushima K, Hirayama T, Yashima K, Tsukamoto K. Polymorphism in autophagy-related genes LRP1 and CAPZA1 may promote gastric mucosal atrophy. Genes Environ 2023; 45:18. [PMID: 37198664 DOI: 10.1186/s41021-023-00274-5] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2023] [Accepted: 04/27/2023] [Indexed: 05/19/2023] Open
Abstract
BACKGROUND Helicobacter pylori secretes cytotoxin-associated gene A (CagA) into the gastric epithelium, causing gastric mucosal atrophy (GMA) and gastric cancer. In contrast, host cells degrade CagA via autophagy. However, the association between polymorphisms in autophagy-related genes and GMA must be fully elucidated. RESULTS We evaluated the association between single nucleotide polymorphisms (SNPs) in autophagy-related genes (low-density lipoprotein receptor-related protein 1, LRP1; capping actin protein of muscle Z-line alpha subunit 1, CAPAZ1; and lysosomal-associated membrane protein 1, LAMP1) and GMA in 200 H. pylori-positive individuals. The frequency of the T/T genotype at rs1800137 in LRP1 was significantly lower in the GMA group than in the non-GMA group (p = 0.018, odds ratio [OR] = 0.188). The frequencies of the G/A or A/A genotype at rs4423118 and T/A or A/A genotype at rs58618380 of CAPAZ1 in the GMA group were significantly higher than those in the non-GMA group (p = 0.029 and p = 0.027, respectively). Multivariate analysis revealed that C/C or C/T genotype at rs1800137, T/A or A/A genotype at rs58618380, and age were independent risk factors for GMA (p = 0.038, p = 0.023, and p = 0.006, respectively). Furthermore, individuals with the rs1800137 C/C or C/T genotype of LRP1 had a 5.3-fold higher susceptibility to GMA. These genetic tests may provide future directions for precision medicine for individuals more likely to develop GMA. CONCLUSION LRP1 and CAPZA1 polymorphisms may be associated with the development of GMA.
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Affiliation(s)
- Naoyuki Yamaguchi
- Department of Gastroenterology and Hepatology, Nagasaki University Graduate School of Biological Sciences, 1-7-1 Sakamoto, Nagasaki, 852-8501, Japan
| | - Takuki Sakaguchi
- Department of Gastroenterology and Nephrology, Faculty of Medicine, Tottori University, 36-1 Nishi-Cho, Yonago, 683-8504, Japan.
| | - Hajime Isomoto
- Department of Gastroenterology and Hepatology, Nagasaki University Graduate School of Biological Sciences, 1-7-1 Sakamoto, Nagasaki, 852-8501, Japan.
- Department of Gastroenterology and Nephrology, Faculty of Medicine, Tottori University, 36-1 Nishi-Cho, Yonago, 683-8504, Japan.
| | - Tatsuo Inamine
- Department of Pharmacotherapeutics, Nagasaki University Graduate School of Biomedical Sciences, 1-7-1 Sakamoto, Nagasaki, 852-8501, Japan
| | - Ryoya Tsukamoto
- Department of Pharmacotherapeutics, Nagasaki University Graduate School of Biomedical Sciences, 1-7-1 Sakamoto, Nagasaki, 852-8501, Japan
| | - Daisuke Fukuda
- Department of Gastroenterology and Hepatology, Nagasaki University Graduate School of Biological Sciences, 1-7-1 Sakamoto, Nagasaki, 852-8501, Japan
- Department of Surgical Oncology, Nagasaki University Graduate School of Biological Sciences, 1-7-1 Sakamoto, Nagasaki, 852-8501, Japan
- Fukuda Yutaka Clinic, 3-5 Hamaguchi-machi, Nagasaki, 852-8107, Japan
| | - Ken Ohnita
- Department of Gastroenterology and Hepatology, Nagasaki University Graduate School of Biological Sciences, 1-7-1 Sakamoto, Nagasaki, 852-8501, Japan
- Shunkaikai Inoue Hospital, 6-12 Takara-machi, Nagasaki, 850-0045, Japan
| | - Tsutomu Kanda
- Department of Gastroenterology and Hepatology, Nagasaki University Graduate School of Biological Sciences, 1-7-1 Sakamoto, Nagasaki, 852-8501, Japan
- Department of Gastroenterology and Nephrology, Faculty of Medicine, Tottori University, 36-1 Nishi-Cho, Yonago, 683-8504, Japan
| | - Kayoko Matsushima
- Department of Gastroenterology and Hepatology, Nagasaki University Graduate School of Biological Sciences, 1-7-1 Sakamoto, Nagasaki, 852-8501, Japan
| | - Tatsuro Hirayama
- Department of Pharmacotherapeutics, Nagasaki University Graduate School of Biomedical Sciences, 1-7-1 Sakamoto, Nagasaki, 852-8501, Japan
| | - Kazuo Yashima
- Department of Gastroenterology and Nephrology, Faculty of Medicine, Tottori University, 36-1 Nishi-Cho, Yonago, 683-8504, Japan
| | - Kazuhiro Tsukamoto
- Department of Pharmacotherapeutics, Nagasaki University Graduate School of Biomedical Sciences, 1-7-1 Sakamoto, Nagasaki, 852-8501, Japan
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25
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Thrift AP, Wenker TN, El-Serag HB. Global burden of gastric cancer: epidemiological trends, risk factors, screening and prevention. Nat Rev Clin Oncol 2023; 20:338-349. [PMID: 36959359 DOI: 10.1038/s41571-023-00747-0] [Citation(s) in RCA: 257] [Impact Index Per Article: 128.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 02/21/2023] [Indexed: 03/25/2023]
Abstract
Gastric cancer remains a major cause of cancer-related mortality worldwide. The temporal trends for this malignancy, however, are dynamic, and reports from the past decade indicate important declines in some regions and demographic groups, as well as a few notable exceptions in which gastric cancer rates are either stable or increasing. Two main anatomical subtypes of gastric cancer exist, non-cardia and cardia, with different temporal trends and risk factors (such as obesity and reflux for cardia gastric cancer and Helicobacter pylori infection for non-cardia gastric cancer). Shifts in the distribution of anatomical locations have been detected in several high-incidence regions. H. pylori is an important aetiological factor for gastric cancer; importantly, the anticipated long-term findings from studies examining the effect of H. pylori eradication on the risk of (re)developing gastric cancer have emerged in the past few years. In this Review, we highlight the latest trends in incidence and mortality using an evidence-based approach. We make the best possible inferences, including clinical and public health inference, on the basis of the quality of the evidence available, and highlight burning questions as well as gaps in knowledge and public health practice that need to be addressed to reduce gastric cancer burden worldwide.
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Affiliation(s)
- Aaron P Thrift
- Section of Epidemiology and Population Sciences, Department of Medicine, Baylor College of Medicine, Houston, TX, USA
- Dan L Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, TX, USA
| | - Theresa Nguyen Wenker
- Section of Gastroenterology and Hepatology, Department of Medicine, Baylor College of Medicine, Houston, TX, USA
- Center for Innovations in Quality, Effectiveness and Safety (IQuESt), Michael E. DeBakey Veterans Affairs Medical Center, Houston, TX, USA
| | - Hashem B El-Serag
- Section of Gastroenterology and Hepatology, Department of Medicine, Baylor College of Medicine, Houston, TX, USA.
- Center for Innovations in Quality, Effectiveness and Safety (IQuESt), Michael E. DeBakey Veterans Affairs Medical Center, Houston, TX, USA.
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26
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Innate immune activation and modulatory factors of Helicobacter pylori towards phagocytic and nonphagocytic cells. Curr Opin Immunol 2023; 82:102301. [PMID: 36933362 DOI: 10.1016/j.coi.2023.102301] [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: 11/22/2022] [Accepted: 02/17/2023] [Indexed: 03/18/2023]
Abstract
Helicobacter pylori is an intriguing obligate host-associated human pathogen with a specific host interaction biology, which has been shaped by thousands of years of host-pathogen coevolution. Molecular mechanisms of interaction of H. pylori with the local immune cells in the human system are less well defined than epithelial cell interactions, although various myeloid cells, including neutrophils and other phagocytes, are locally present or attracted to the sites of infection and interact with H. pylori. We have recently addressed the question of novel bacterial innate immune stimuli, including bacterial cell envelope metabolites, that can activate and modulate cell responses via the H. pylori Cag type IV secretion system. This review article gives an overview of what is currently known about the interaction modes and mechanisms of H. pylori with diverse human cell types, with a focus on bacterial metabolites and cells of the myeloid lineage including phagocytic and antigen-presenting cells.
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27
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Helicobacter pylori and Gastric Cancer: Pathogenetic Mechanisms. Int J Mol Sci 2023; 24:ijms24032895. [PMID: 36769214 PMCID: PMC9917787 DOI: 10.3390/ijms24032895] [Citation(s) in RCA: 80] [Impact Index Per Article: 40.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2022] [Revised: 01/27/2023] [Accepted: 01/31/2023] [Indexed: 02/05/2023] Open
Abstract
Gastric cancer is the sixth most commonly diagnosed cancer and the fourth leading cause of cancer death worldwide. Helicobacter pylori (H. pylori) is one of the main risk factors for this type of neoplasia. Carcinogenetic mechanisms associated with H. pylori are based, on the one hand, on the onset of chronic inflammation and, on the other hand, on bacterial-specific virulence factors that can damage the DNA of gastric epithelial cells and promote genomic instability. Here, we review and discuss the major pathogenetic mechanisms by which H. pylori infection contributes to the onset and development of gastric cancer.
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28
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Pandey H, Tang DWT, Wong SH, Lal D. Gut Microbiota in Colorectal Cancer: Biological Role and Therapeutic Opportunities. Cancers (Basel) 2023; 15:cancers15030866. [PMID: 36765824 PMCID: PMC9913759 DOI: 10.3390/cancers15030866] [Citation(s) in RCA: 58] [Impact Index Per Article: 29.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/29/2022] [Revised: 01/23/2023] [Accepted: 01/24/2023] [Indexed: 02/03/2023] Open
Abstract
Colorectal cancer (CRC) is the second-leading cause of cancer-related deaths worldwide. While CRC is thought to be an interplay between genetic and environmental factors, several lines of evidence suggest the involvement of gut microbiota in promoting inflammation and tumor progression. Gut microbiota refer to the ~40 trillion microorganisms that inhabit the human gut. Advances in next-generation sequencing technologies and metagenomics have provided new insights into the gut microbial ecology and have helped in linking gut microbiota to CRC. Many studies carried out in humans and animal models have emphasized the role of certain gut bacteria, such as Fusobacterium nucleatum, enterotoxigenic Bacteroides fragilis, and colibactin-producing Escherichia coli, in the onset and progression of CRC. Metagenomic studies have opened up new avenues for the application of gut microbiota in the diagnosis, prevention, and treatment of CRC. This review article summarizes the role of gut microbiota in CRC development and its use as a biomarker to predict the disease and its potential therapeutic applications.
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Affiliation(s)
- Himani Pandey
- Redcliffe Labs, Electronic City, Noida 201301, India
| | - Daryl W. T. Tang
- School of Biological Sciences, Nanyang Technological University, Singapore 308232, Singapore
| | - Sunny H. Wong
- Centre for Microbiome Medicine, Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore 308232, Singapore
- Correspondence: (S.H.W.); (D.L.)
| | - Devi Lal
- Department of Zoology, Ramjas College, University of Delhi, Delhi 110007, India
- Correspondence: (S.H.W.); (D.L.)
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29
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Senda M, Senda T. Crystal Structure Analysis of SH2 Domains in Complex with Phosphotyrosine Peptides. Methods Mol Biol 2023; 2705:39-58. [PMID: 37668968 DOI: 10.1007/978-1-0716-3393-9_3] [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: 09/06/2023]
Abstract
While the number of tertiary structures solved by cryoelectron microscopy has rapidly increased, X-ray crystallography is still a popular method to determine the tertiary structure of proteins at atomic resolution. However, there are still problems associated with X-ray crystallography, including crystallization and crystal twinning. Indeed, we encountered crystallization and twinning problems in the crystal structure analysis of the SH2 domains complexed with a phosphorylated peptide derived from the oncoprotein CagA. In this chapter, we describe the methods used to overcome these problems. In addition, we provide details of the optimization of the crystallization conditions and cryo-conditions, which are usually not given in published crystal structure analyses.
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Affiliation(s)
- Miki Senda
- Structural Biology Research Center, Institute of Materials Structure Science, High Energy Accelerator Research Organization (KEK), Tsukuba, Ibaraki, Japan
| | - Toshiya Senda
- Structural Biology Research Center, Institute of Materials Structure Science, High Energy Accelerator Research Organization (KEK), Tsukuba, Ibaraki, Japan.
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30
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Wang H, Zhao M, Shi F, Zheng S, Xiong L, Zheng L. A review of signal pathway induced by virulent protein CagA of Helicobacter pylori. Front Cell Infect Microbiol 2023; 13:1062803. [PMID: 37124036 PMCID: PMC10140366 DOI: 10.3389/fcimb.2023.1062803] [Citation(s) in RCA: 12] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/06/2022] [Accepted: 03/24/2023] [Indexed: 05/02/2023] Open
Abstract
Gastric cancer (GC), a common and high-mortality disease, still occupies an important position in current cancer research, and Helicobacter pylori (H. pylori) infection as its important risk factor has been a hot and challenging research area. Among the numerous pathogenic factors of H. pylori, the virulence protein CagA has been widely studied as the only bacterial-derived oncoprotein. It was found that CagA entering into gastric epithelial cells (GECs) can induce the dysregulation of multiple cellular pathways such as MAPK signaling pathway, PI3K/Akt signaling pathway, NF-κB signaling pathway, Wnt/β-catenin signaling pathway, JAK-STAT signaling pathway, Hippo signaling pathway through phosphorylation and non-phosphorylation. These disordered pathways cause pathological changes in morphology, adhesion, polarity, proliferation, movement, and other processes of GECs, which eventually promotes the occurrence of GC. With the deepening of H. pylori-related research, the research on CagA-induced abnormal signaling pathway has been updated and deepened to some extent, so the key signaling pathways activated by CagA are used as the main stem to sort out the pathogenesis of CagA in this paper, aiming to provide new strategies for the H. pylori infection and treatment of GC in the future.
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Affiliation(s)
- Haiqiang Wang
- Department of Internal Medicine, First Affiliated Hospital, Heilongjiang University of Chinese Medicine, Harbin, China
| | - Mei Zhao
- Graduate School of Heilongjiang University of Chinese Medicine, Harbin, China
| | - Fan Shi
- Graduate School of Heilongjiang University of Chinese Medicine, Harbin, China
| | - Shudan Zheng
- Graduate School of Heilongjiang University of Chinese Medicine, Harbin, China
| | - Li Xiong
- Graduate School of Heilongjiang University of Chinese Medicine, Harbin, China
| | - Lihong Zheng
- Department of Internal Medicine, Fourth Affiliated Hospital, Heilongjiang University of Chinese Medicine, Harbin, China
- *Correspondence: Lihong Zheng,
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31
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New CagL Amino Acid Polymorphism Patterns of Helicobacter pylori in Peptic Ulcer and Non-Ulcer Dyspepsia. Medicina (B Aires) 2022; 58:medicina58121738. [PMID: 36556940 PMCID: PMC9782086 DOI: 10.3390/medicina58121738] [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: 10/07/2022] [Revised: 11/06/2022] [Accepted: 11/24/2022] [Indexed: 11/29/2022] Open
Abstract
Background and Objectives: Helicobacter pylori infection is associated with chronic gastritis, ulcers, and gastric cancer. The H. pylori Type 4 secretion system (T4SS) translocates the CagA protein into host cells and plays an essential role in initiating gastric carcinogenesis. The CagL protein is a component of the T4SS. CagL amino acid polymorphisms are correlated with clinical outcomes. We aimed to study the association between CagL amino acid polymorphisms and peptic ulcer disease (PUD) and non-ulcer dyspepsia (NUD). Materials and Methods: A total of 99 patients (PUD, 46; NUD, 53) were enrolled and screened for H. pylori by qPCR from antrum biopsy samples. The amino acid polymorphisms of CagL were analyzed using DNA sequencing, followed by the MAFFT sequence alignment program to match the amino acid sequences. Results: Antrum biopsy samples from 70 out of 99 (70.7%) patients were found to be H. pylori DNA-positive. A positive band for cagL was detected in 42 out of 70 samples (PUD, 23; NUD, 19), and following this, these 42 samples were sequenced. In total, 27 different polymorphisms were determined. We determined three CagL amino acid polymorphism combinations, which were determined to be associated with PUD and NUD. Pattern 1 (K35/N122/V134/T175/R194/E210) was only detected in PUD patient samples and was related to a 1.35-fold risk (p = 0.02). Patterns 2 (V41/I134) and 3 (V41/K122/A171/I174) were found only in NUD patient samples and were linked to a 1.26-fold increased risk (p = 0.03). Conclusions: We observed three new patterns associated with PUD and NUD. Pattern 1 is related to PUD, and the other two patterns (Patterns 2 and 3) are related to NUD. The patterns that we identified include the remote polymorphisms of the CagL protein, which is a new approach. These patterns may help to understand the course of H. pylori infection.
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32
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Immunohistochemical Differentiation between Western and East Asian Types of CagA-Positive Helicobacter pylori in Gastric Biopsy Samples. Can J Gastroenterol Hepatol 2022; 2022:1371089. [PMID: 36419567 PMCID: PMC9678484 DOI: 10.1155/2022/1371089] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/24/2022] [Revised: 10/09/2022] [Accepted: 10/13/2022] [Indexed: 11/13/2022] Open
Abstract
BACKGROUND Cag A-positive Helicobacter pylori isolated from human gastric mucosa is categorized as a Western or East Asian allele-type based on whether the cagA gene encodes an EPIYA-C or EPIYA-D motif. We aimed to differentiate between the 2 types of H. pylori by immunohistochemistry (IHC) using formalin-fixed paraffin-embedded (FFPE) gastric biopsy samples. MATERIALS AND METHODS We developed 2 monoclonal antibodies (mAbs) that detect either the EPIYA-C or EPIYA-D motif of the H. pylori CagA protein by IHC using FFPE tissues. FFPE tissue sections from 30 Japanese and 39 Brazilian gastric biopsy samples with H. pylori infection confirmed by Giemsa staining (moderate/severe in the Sydney classification system) were examined by IHC with the novel mAbs followed by polymerase chain reaction (PCR) for EPIYA-C or EPIYA-D using DNA extracted from adjacent tissue sections. RESULTS Differentiation among Western and East Asian types and CagA-negative H. pylori was successful in most (97%) samples by IHC with the novel mAbs and commercially available mAbs that react with a species-specific lipopolysaccharide or a common CagA motif of H. pylori. The detection status of EPIYA-C/D motifs by IHC with the novel mAbs was consistent with the PCR results in 61 (88%) of 69 samples: EPIYA-C(+)/D(-) in zero Japanese and 26 Brazilian samples, EPIYA-C(-)/D(+) in 26 Japanese and 1 Brazilian sample, and EPIYA-C(-)/D(-) in 1 Japanese and 7 Brazilian samples. The detection sensitivity and specificity of IHC with each novel mAb compared with the PCR results were, respectively, 84% and 97% for EPIYA-C, and 97% and 95% for EPIYA-D. CONCLUSIONS The novel mAbs specific to each EPIYA-C or EPIYA-D motif differentiated between Western and East Asian types of CagA-positive H. pylori by IHC using FFPE tissues. Applying these novel mAbs to large numbers of archived pathology samples will contribute to elucidating the association of these allele types with gastric cancer.
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33
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Zhang L, Chen X, Ren B, Zhou X, Cheng L. Helicobacter pylori in the Oral Cavity: Current Evidence and Potential Survival Strategies. Int J Mol Sci 2022; 23:ijms232113646. [PMID: 36362445 PMCID: PMC9657019 DOI: 10.3390/ijms232113646] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/12/2022] [Revised: 11/03/2022] [Accepted: 11/05/2022] [Indexed: 11/11/2022] Open
Abstract
Helicobacter pylori (H. pylori) is transmitted primarily through the oral–oral route and fecal–oral route. The oral cavity had therefore been hypothesized as an extragastric reservoir of H. pylori, owing to the presence of H. pylori DNA and particular antigens in distinct niches of the oral cavity. This bacterium in the oral cavity may contribute to the progression of periodontitis and is associated with a variety of oral diseases, gastric eradication failure, and reinfection. However, the conditions in the oral cavity do not appear to be ideal for H. pylori survival, and little is known about its biological function in the oral cavity. It is critical to clarify the survival strategies of H. pylori to better comprehend the role and function of this bacterium in the oral cavity. In this review, we attempt to analyze the evidence indicating the existence of living oral H. pylori, as well as potential survival strategies, including the formation of a favorable microenvironment, the interaction between H. pylori and oral microorganisms, and the transition to a non-growing state. Further research on oral H. pylori is necessary to develop improved therapies for the prevention and treatment of H. pylori infection.
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Affiliation(s)
- Lin Zhang
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu 610041, China
- Department of Operative Dentistry and Endodontics, West China School of Stomatology, Sichuan University, Chengdu 610041, China
| | - Xi Chen
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu 610041, China
- Department of Operative Dentistry and Endodontics, West China School of Stomatology, Sichuan University, Chengdu 610041, China
| | - Biao Ren
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu 610041, China
| | - Xuedong Zhou
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu 610041, China
- Department of Operative Dentistry and Endodontics, West China School of Stomatology, Sichuan University, Chengdu 610041, China
| | - Lei Cheng
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu 610041, China
- Department of Operative Dentistry and Endodontics, West China School of Stomatology, Sichuan University, Chengdu 610041, China
- Correspondence:
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Garg A, Singhal N, Kumar M. Investigating the eukaryotic host-like SLiMs in microbial mimitopes and their potential as novel drug targets for treating autoimmune diseases. Front Microbiol 2022; 13:1039188. [DOI: 10.3389/fmicb.2022.1039188] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2022] [Accepted: 10/17/2022] [Indexed: 11/06/2022] Open
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Karpiński TM, Ożarowski M, Stasiewicz M. Carcinogenic microbiota and its role in colorectal cancer development. Semin Cancer Biol 2022; 86:420-430. [PMID: 35090978 DOI: 10.1016/j.semcancer.2022.01.004] [Citation(s) in RCA: 38] [Impact Index Per Article: 12.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/27/2021] [Revised: 12/30/2021] [Accepted: 01/13/2022] [Indexed: 02/06/2023]
Abstract
Colorectal cancer (CRC) is one of the most common malignancies worldwide. The main risk factors for CRC are family history of colon or rectal cancer, familial polyposis syndrome or hereditary nonpolyposis, and chronic inflammatory bowel diseases (ulcerative colitis and Crohn's disease). Recent studies show that the gastrointestinal microbiota play a significant role in colorectal carcinogenesis. In this review we present the microorganisms, whose influence on the development of CRC has been proven: Bacteroides fragilis, Clostridioides and Clostridium spp., Enterococcus faecalis, Escherichia coli, Fusobacterium nucleatum, Helicobacter pylori, Peptostreptococcus anaerobius, Streptococcus bovis group, and sulfate-reducing bacteria. Moreover, the carcinogenic mechanisms of action mediated by the above bacteria are laid out.
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Affiliation(s)
- Tomasz M Karpiński
- Chair and Department of Medical Microbiology, Poznań University of Medical Sciences, Wieniawskiego 3, 61-712 Poznań, Poland.
| | - Marcin Ożarowski
- Department of Biotechnology, Institute of Natural Fibres and Medicinal Plants - National Research Institute, Wojska Polskiego 71b, 60-630 Poznań, Poland.
| | - Mark Stasiewicz
- Research Group of Medical Microbiology, Chair and Department of Medical Microbiology, Poznań University of Medical Sciences, Wieniawskiego 3, 61-712 Poznań, Poland.
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Ishioka M, Osawa H, Hirasawa T, Kawachi H, Nakano K, Fukushima N, Sakaguchi M, Tada T, Kato Y, Shibata J, Ozawa T, Tajiri H, Fujisaki J. Performance of an artificial intelligence-based diagnostic support tool for early gastric cancers: Retrospective study. Dig Endosc 2022; 35:483-491. [PMID: 36239483 DOI: 10.1111/den.14455] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/13/2022] [Accepted: 10/12/2022] [Indexed: 02/08/2023]
Abstract
OBJECTIVES Endoscopists' abilities to diagnose early gastric cancers (EGCs) vary, especially between specialists and nonspecialists. We developed an artificial intelligence (AI)-based diagnostic support tool "Tango" to differentiate EGCs and compared its performance with that of endoscopists. METHODS The diagnostic performances of Tango and endoscopists (34 specialists, 42 nonspecialists) were compared using still images of 150 neoplastic and 165 non-neoplastic lesions. Neoplastic lesions included EGCs and adenomas. The primary outcome was to show the noninferiority of Tango (based on sensitivity) over specialists. The secondary outcomes were the noninferiority of Tango (based on accuracy) over specialists and the superiority of Tango (based on sensitivity and accuracy) over nonspecialists. The lower limit of the 95% confidence interval (CI) of the difference between Tango and the specialists for sensitivity was calculated, with >-10% defined as noninferiority and >0% defined as superiority in the primary outcome. The comparable differences between Tango and the endoscopists for each performance were calculated, with >10% defined as superiority and >0% defined as noninferiority in the secondary outcomes. RESULTS Tango achieved superiority over the specialists based on sensitivity (84.7% vs. 65.8%, difference 18.9%, 95% CI 12.3-25.3%) and demonstrated noninferiority based on accuracy (70.8% vs. 67.4%). Tango achieved superiority over the nonspecialists based on sensitivity (84.7% vs. 51.0%) and accuracy (70.8% vs. 58.4%). CONCLUSIONS The AI-based diagnostic support tool for EGCs demonstrated a robust performance and may be useful to reduce misdiagnosis.
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Affiliation(s)
- Mitsuaki Ishioka
- Department of Gastroenterology, Cancer Institute Hospital of the Japanese Foundation for Cancer Research, Tokyo, Japan
| | - Hiroyuki Osawa
- Division of Gastroenterology, Department of Medicine, Jichi Medical University, Tochigi, Japan
| | - Toshiaki Hirasawa
- Department of Gastroenterology, Cancer Institute Hospital of the Japanese Foundation for Cancer Research, Tokyo, Japan
| | - Hiroshi Kawachi
- Department of Pathology, Cancer Institute Hospital of the Japanese Foundation for Cancer Research, Tokyo, Japan
| | - Kaoru Nakano
- Department of Pathology, Cancer Institute Hospital of the Japanese Foundation for Cancer Research, Tokyo, Japan
| | | | - Mio Sakaguchi
- Department of Pathology, Jichi Medical University, Tochigi, Japan
| | - Tomohiro Tada
- AI Medical Service Inc., Tokyo, Japan.,Department of Surgical Oncology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.,Tada Tomohiro Institute of Gastroenterology and Proctology, Saitama, Japan
| | | | - Junichi Shibata
- AI Medical Service Inc., Tokyo, Japan.,Tada Tomohiro Institute of Gastroenterology and Proctology, Saitama, Japan
| | - Tsuyoshi Ozawa
- AI Medical Service Inc., Tokyo, Japan.,Department of Surgical Oncology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
| | - Hisao Tajiri
- The Jikei University School of Medicine, Tokyo, Japan
| | - Junko Fujisaki
- Department of Gastroenterology, Cancer Institute Hospital of the Japanese Foundation for Cancer Research, Tokyo, Japan
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Sukri A, Hanafiah A, Kosai NR, Mohammed Taher M, Mohamed R. New insight on the role of Helicobacter pylori cagA in the expression of cell surface antigens with important biological functions in gastric carcinogenesis. Helicobacter 2022; 27:e12913. [PMID: 35848223 DOI: 10.1111/hel.12913] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/21/2022] [Revised: 06/17/2022] [Accepted: 06/28/2022] [Indexed: 12/20/2022]
Abstract
BACKGROUND Expression of cluster of differentiation (CD) antigens changes according to disease status and inflammation. Profiles of CD antigens expression in gastric cancer patients are different based on the status of H. pylori infection. AIMS We conducted this study to profile CD antigen markers in gastric adenocarcinoma cells (AGS cell line) infected with distinct cytotoxin-associated gene A (cagA) genotypes of H. pylori clinical isolates. METHODS The AGS cells were infected with H. pylori isolates with different cagA genotypes, and CD antigens expression was determined using DotScan™ antibody microarray. Formation of "hummingbird" phenotype was determined, and the percentage was calculated. RESULTS H. pylori strains harboring cagA upregulated the expression of CD antigen involved in cancer stem cell formation (CD55), but downregulated CD antigens involved in immune regulation (CD40 and CD186) and cell adhesion (CD44). CD54 (neutrophil adhesion) and CD71 (iron transfer) were highly downregulated in the gastric cells infected with Western cagA isolates compared with East Asian isolates. CD antigen expression was different in the cells infected with H. pylori harboring different CagA EPIYA (Glu-Pro-Ile-Tyr-Ala) numbers, in which higher repression of CD54 and CD15 (Lewis x antigen) were observed in the isolate with the highest number of EPIYA motif. Furthermore, higher downregulation of CD15 was observed in the infected gastric cells with high percentage of "hummingbird" phenotype than that of low percentage of "hummingbird" phenotype. CONCLUSION Our study demonstrated the critical roles of CD antigens in the CagA pathogenesis and should be investigated further.
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Affiliation(s)
- Asif Sukri
- Integrative Pharmacogenomics Institute (iPROMISE), Universiti Teknologi MARA, Bandar Puncak Alam, Malaysia
| | - Alfizah Hanafiah
- Department of Medical Microbiology & Immunology, Faculty of Medicine, Universiti Kebangsaan Malaysia, Kuala Lumpur, Malaysia
| | - Nik Ritza Kosai
- Department of Surgery, Faculty of Medicine, Universiti Kebangsaan Malaysia, Kuala Lumpur, Malaysia
| | - Mustafa Mohammed Taher
- Department of Surgery, Faculty of Medicine, Universiti Kebangsaan Malaysia, Kuala Lumpur, Malaysia
| | - Ramelah Mohamed
- Department of Medical Microbiology & Immunology, Faculty of Medicine, Universiti Kebangsaan Malaysia, Kuala Lumpur, Malaysia
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Ansari S, Yamaoka Y. Helicobacter pylori Infection, Its Laboratory Diagnosis, and Antimicrobial Resistance: a Perspective of Clinical Relevance. Clin Microbiol Rev 2022; 35:e0025821. [PMID: 35404105 PMCID: PMC9491184 DOI: 10.1128/cmr.00258-21] [Citation(s) in RCA: 33] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
Abstract
Despite the recent decrease in overall prevalence of Helicobacter pylori infection, morbidity and mortality rates associated with gastric cancer remain high. The antimicrobial resistance developments and treatment failure are fueling the global burden of H. pylori-associated gastric complications. Accurate diagnosis remains the opening move for treatment and eradication of infections caused by microorganisms. Although several reports have been published on diagnostic approaches for H. pylori infection, most lack the data regarding diagnosis from a clinical perspective. Therefore, we provide an intensive, comprehensive, and updated description of the currently available diagnostic methods that can help clinicians, infection diagnosis professionals, and H. pylori researchers working on infection epidemiology to broaden their understanding and to select appropriate diagnostic methods. We also emphasize appropriate diagnostic approaches based on clinical settings (either clinical diagnosis or mass screening), patient factors (either age or other predisposing factors), and clinical factors (either upper gastrointestinal bleeding or partial gastrectomy) and appropriate methods to be considered for evaluating eradication efficacy. Furthermore, to cope with the increasing trend of antimicrobial resistance, a better understanding of its emergence and current diagnostic approaches for resistance detection remain inevitable.
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Affiliation(s)
- Shamshul Ansari
- Department of Environmental and Preventive Medicine, Oita University Faculty of Medicine, Yufu City, Oita, Japan
| | - Yoshio Yamaoka
- Department of Environmental and Preventive Medicine, Oita University Faculty of Medicine, Yufu City, Oita, Japan
- Department of Medicine, Gastroenterology and Hepatology Section, Baylor College of Medicine, Houston, Texas, USA
- Institute of Tropical Disease, Universitas Airlangga, Surabaya, Indonesia
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Takeuchi H, Okamoto A. Helicobacter pylori Infection and Chronic Immune Thrombocytopenia. J Clin Med 2022; 11:jcm11164822. [PMID: 36013059 PMCID: PMC9410305 DOI: 10.3390/jcm11164822] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2022] [Revised: 08/15/2022] [Accepted: 08/15/2022] [Indexed: 12/13/2022] Open
Abstract
Approximately half of the world’s population is infected with Helicobacter pylori, which causes gastric disease. Recent systematic reviews and meta-analyses have reported that H. pylori may also have extragastric manifestations such as hematologic diseases, including chronic immune thrombocytopenia (cITP). However, the molecular mechanisms by which H. pylori induces cITP remain unclear, and may involve the host immune response, bacterial strain diversity, and delivery of bacterial molecules to the host blood vessels. This review discusses the important pathophysiological mechanisms by which H. pylori potentially contributes to the development of cITP in infected patients.
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Zhang J, Wang W, Yan S, Li J, Wei H, Zhao W. CagA and VacA inhibit gastric mucosal epithelial cell autophagy and promote the progression of gastric precancerous lesions. ZHONG NAN DA XUE XUE BAO. YI XUE BAN = JOURNAL OF CENTRAL SOUTH UNIVERSITY. MEDICAL SCIENCES 2022; 47:942-951. [PMID: 36039592 PMCID: PMC10930283 DOI: 10.11817/j.issn.1672-7347.2022.210779] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Subscribe] [Scholar Register] [Received: 12/27/2021] [Indexed: 06/15/2023]
Abstract
Cytotoxin-associated gene A (CagA) and vacuolating cytotoxin A (VacA) are the keys to the pathogenic role of Helicobacter pylori and the high-risk factors for the progression of gastric precancerous lesions. Autophagy can stabilize the intracellular environment, resist Helicobacter pylori infection, prevent the accumulation of damaged DNA, and inhibit the proliferation of gastric precancerous variant cells. However, CagA and VacA can inhibit the activation of upstream signals of autophagy and the maturation of autophagy-lysosomes in various ways, thus inhibiting the autophagy of gastric mucosal cells in precancerous lesions of gastric cancer. This change can cause Helicobacter pylori to be unable to be effectively cleared by autophagy, so CagA and VacA can persist and promote the inflammation, oxidative stress, apoptosis of gastric mucosal tissue cells, and the glycolytic activity and proliferation of variant cells in gastric precancerous lesions and a series of malignant biological processes. In recent years, the research on drugs specifically inhibiting the activities of CagA and VacA has become a new direction for the prevention and treatment of Helicobacter pylori-related severe gastric diseases, and a variety of drugs or components that can precisely and effectively regulate the factors for the treatment of gastric precancerous lesions are emerged, which opens a new strategy for the treatment of gastric precancerous lesions in the future.
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Affiliation(s)
- Jiaxiang Zhang
- Basic Medical College, Shaanxi University of Traditional Chinese Medicine, Xianyang Shaanxi 712046.
| | - Wenba Wang
- Basic Medical College, Shaanxi University of Traditional Chinese Medicine, Xianyang Shaanxi 712046
| | - Shuguang Yan
- Basic Medical College, Shaanxi University of Traditional Chinese Medicine, Xianyang Shaanxi 712046.
| | - Jingtao Li
- Department of Hepatology, Affiliated Hospital of Shaanxi University of Traditional Chinese Medicine, Xianyang Shaanxi 712000
| | - Hailiang Wei
- Department of Hepatology, Affiliated Hospital of Shaanxi University of Traditional Chinese Medicine, Xianyang Shaanxi 712000
| | - Weihan Zhao
- Department of Gastroenterology, Affiliated Hospital of Shaanxi University of Traditional Chinese Medicine, Xianyang Shaanxi 712000, China
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Yang H, Zhou X, Hu B. The 'reversibility' of chronic atrophic gastritis after the eradication of Helicobacter pylori. Postgrad Med 2022; 134:474-479. [PMID: 35382697 DOI: 10.1080/00325481.2022.2063604] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Gram-negative bacterium Helicobacter pylori (H. pylori) infection is lifelong and usually acquired in childhood, which is etiologically linked to gastric cancer (GC). H. pylori gastritis is defined as an infectious disease with varying severity in virtually all infected subjects. Chronic atrophic gastritis (CAG) is the precancerous condition with the decrease or the loss of gastric glands, which can further be replaced by metaplasia or fibrosis. Patients with advanced stages of CAG are at higher risk of GC and should be followed up with a high-quality endoscopy every 3 years. H. pylori infection is the most common cause and its eradication is recommended, which may contribute to the regression of CAG. However, it is controversial whether CAG is reversible after eradication therapy. In the review, we discuss recent studies which provide important insights into whether CAG is 'reversibility' and when it may progress into GC after eradicating H. pylori.
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Affiliation(s)
- Hang Yang
- Department of Gastroenterology, West China Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Xinyue Zhou
- Department of Gastroenterology, West China Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Bing Hu
- Department of Gastroenterology, West China Hospital, Sichuan University, Chengdu, Sichuan, China
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El Hafa F, Wang T, Ndifor VM, Jin G. Association between Helicobacter pylori antibodies determined by multiplex serology and gastric cancer risk: A meta-analysis. Helicobacter 2022; 27:e12881. [PMID: 35212073 DOI: 10.1111/hel.12881] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/01/2021] [Revised: 01/17/2022] [Accepted: 01/30/2022] [Indexed: 12/11/2022]
Abstract
BACKGROUND AND AIMS Previous studies have reported the association between limited number of Helicobacter pylori (H. pylori) antigens and gastric cancer (GC) risk. The present study evaluated the association between serum antibodies against 15 different H. pylori proteins measured by using multiplex serology assay and GC risk. METHODS We searched PubMed databases, Embase, Web of Science, and Cochrane Library for relevant articles. A meta-analysis was used to pool studies and to estimate odds ratios (ORs) with 95% confidence intervals (95%CIs) of different H. pylori antigens associated with GC risk. Heterogeneity was investigated using Cochran's Q test and I-squared statistic. RESULTS Nine studies were identified, with a total of 3209 GC cases and 6964 controls. Five H. pylori virulence factors were significantly associated with non-cardia GC risk at p-value <0.0033 including: CagA (OR = 3.22, 95%CI: 2.10-4.94), HP0305 (OR = 1.72, 95%CI: 1.32-2.25), HyuA (OR = 1.42, 95%CI: 1.13-1.79), Omp (OR = 1.83, 95%CI: 1.30-2.58), and VacA (OR = 2.05, 95%CI: 1.67-2.52). However, none of the 15 antigens was associated with cardia GC risk. In subgroup analysis by ethnicity, we identified 7 antigens associated with the risk of non-cardia GC among East Asian while only two antigens were identified in European population. Nevertheless, CagA and GroEL showed a stronger association in Caucasian (CagA OR = 5.83, 95%CI: 3.31-10.26; GroEL OR = 3.66, 95%CI: 1.58-8.50) compared with East Asian (CagA OR = 2.20, 95% CI: 1.85-2.61; GroEL OR = 1.47, 95%CI: 1.29-1.68). CONCLUSIONS This study determined that H. pylori infection increases the risk of non-cardia GC with differential effects by its virulence factors and with different patterns among East Asian and European populations. These results advance the understanding of the effect of H. pylori on GC.
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Affiliation(s)
- Fadoua El Hafa
- Department of Epidemiology, Center for Global Health, School of Public Health, Nanjing Medical University, Nanjing, China
| | - Tianpei Wang
- Department of Epidemiology, Center for Global Health, School of Public Health, Nanjing Medical University, Nanjing, China.,Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center for Cancer Personalized Medicine and China International Cooperation Center for Environment and Human Health, Nanjing Medical University, Nanjing, China.,Public Health Institute of Gusu School, The Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou, China
| | - Valerie Mbuhnwi Ndifor
- Department of Epidemiology, Center for Global Health, School of Public Health, Nanjing Medical University, Nanjing, China
| | - Guangfu Jin
- Department of Epidemiology, Center for Global Health, School of Public Health, Nanjing Medical University, Nanjing, China.,Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center for Cancer Personalized Medicine and China International Cooperation Center for Environment and Human Health, Nanjing Medical University, Nanjing, China.,Public Health Institute of Gusu School, The Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou, China.,Jiangsu Key Laboratory of Molecular and Translational Cancer Research, Jiangsu Cancer Hospital, Jiangsu Institute of Cancer Research, The Affiliated Cancer Hospital of Nanjing Medical University, Nanjing, China
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Nath AN, Retnakumar RJ, Francis A, Chhetri P, Thapa N, Chattopadhyay S. Peptic Ulcer and Gastric Cancer: Is It All in the Complex Host-Microbiome Interplay That Is Encoded in the Genomes of "Us" and "Them"? Front Microbiol 2022; 13:835313. [PMID: 35547123 PMCID: PMC9083406 DOI: 10.3389/fmicb.2022.835313] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2021] [Accepted: 03/18/2022] [Indexed: 11/13/2022] Open
Abstract
It is increasingly being recognized that severe gastroduodenal diseases such as peptic ulcer and gastric cancer are not just the outcomes of Helicobacter pylori infection in the stomach. Rather, both diseases develop and progress due to the perfect storms created by a combination of multiple factors such as the expression of different H. pylori virulence proteins, consequent human immune responses, and dysbiosis in gastrointestinal microbiomes. In this mini review, we have discussed how the genomes of H. pylori and other gastrointestinal microbes as well as the genomes of different human populations encode complex and variable virulome–immunome interplay, which influences gastroduodenal health. The heterogeneities that are encrypted in the genomes of different human populations and in the genomes of their respective resident microbes partly explain the inconsistencies in clinical outcomes among the H. pylori-infected people.
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Affiliation(s)
- Angitha N Nath
- Rajiv Gandhi Centre for Biotechnology, Trivandrum, India
| | - R J Retnakumar
- Rajiv Gandhi Centre for Biotechnology, Trivandrum, India.,Manipal Academy of Higher Education, Manipal, India
| | - Ashik Francis
- Rajiv Gandhi Centre for Biotechnology, Trivandrum, India
| | - Prakash Chhetri
- Department of Zoology, Biotech Hub, Nar Bahadur Bhandari Degree College, Tadong, India
| | - Namrata Thapa
- Department of Zoology, Biotech Hub, Nar Bahadur Bhandari Degree College, Tadong, India
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Wang Y, Li H. Gut microbiota modulation: a tool for the management of colorectal cancer. J Transl Med 2022; 20:178. [PMID: 35449107 PMCID: PMC9022293 DOI: 10.1186/s12967-022-03378-8] [Citation(s) in RCA: 21] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/07/2022] [Accepted: 04/03/2022] [Indexed: 12/19/2022] Open
Abstract
Colorectal cancer (CRC) is the second cause of cancer death and the third most frequently diagnosed cancer. Besides the lifestyle, genetic and epigenetic alterations, and environmental factors, gut microbiota also plays a vital role in CRC development. The interruption of the commensal relationship between gut microbiota and the host could lead to an imbalance in the bacteria population, in which the pathogenic bacteria become the predominant population in the gut. Different therapeutic strategies have been developed to modify the gut immune system, prevent pathogen colonization, and alter the activity and composition of gut microbiota, such as prebiotics, probiotics, postbiotics, antibiotics, and fecal microbiota transplantation (FMT). Even though the employed strategies exhibit promising results, their translation into the clinic requires evaluating potential implications and risks, as well as assessment of their long-term effects. This study was set to review the gut microbiota imbalances and their relationship with CRC and their effects on CRC therapy, including chemotherapy and immunotherapy. More importantly, we reviewed the strategies that have been used to modulate gut microbiota, their impact on the treatment of CRC, and the challenges of each strategy.
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Affiliation(s)
- Yan Wang
- Department of Gastroenterology, Shengjing Hospital of China Medical University, Shenyang, 110004, China
| | - Hui Li
- Department of Gastroenterology, Shengjing Hospital of China Medical University, Shenyang, 110004, China.
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Jaramillo-Trujillo G, Otero-Regino WA, Estrada-Orozco KP. Efectividad y seguridad del uso de probióticos como adyuvantes en la erradicación de Helicobacter pylori. Revisión sistemática y metaanálisis. REVISTA DE LA FACULTAD DE MEDICINA 2022; 71:e98018. [DOI: 10.15446/revfacmed.v71n2.98018] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/04/2025] Open
Abstract
Introducción. Se ha propuesto agregar probióticos a las terapias triples y cuádruples para mejorar su efectividad en la curación de Helicobacter pylori, pero existe controversia sobre su utilidad.
Objetivo. Evaluar la efectividad y seguridad del uso adyuvante de probióticos en la terapia triple o cuádruple para la curación de H. pylori en adultos.
Materiales y métodos. Revisión sistemática y metanálisis. Se realizó una búsqueda en Embase, Ovid Medline, Cochrane Library y LILACS de ensayos clínicos aleatorizados (ECA) publicados en inglés o español entre enero de 2010 y mayo de 2020 que evalúan la efectividad y seguridad de usar probióticos como terapia coadyuvante en combinación con la terapia triple o cuádruple en la curación de H. pylori en adultos. En el metanálisis se utilizó un modelo de efectos fijos para calcular la medida combinada (OR y RR) de efectividad y seguridad de los probióticos coadyuvantes en terapia triple y cuádruple.
Resultados: Se incluyeron 12 ECA (1091 pacientes en total): 9 evaluaron terapia triple; 2, terapia cuádruple, y 1, terapia triple y cuádruple. En la terapia triple el uso coadyuvante de probióticos fue más efectivo que el uso de placebo: 79.4% vs. 71.1% (OR=1.42; IC95%:1.05-2.09), pero en la terapia cuádruple, su uso no aumentó la efectividad. El probiótico más utilizado fue Lactobacillus reuteri, con una tasa de curación de 77.9% (IC95%:70.5-84.19) versus 66.8% (IC95%:58.8–74.2) del placebo. Los probióticos disminuyeron la ocurrencia de efectos adversos tanto en terapia triple (OR=0.50; IC95%:0.28-0.90) como en cuádruple (OR=0.26; IC95%:0.09-0.74).
Conclusiones. El uso coadyuvante de probióticos mejora la efectividad de la terapia triple para erradicar H. Pylori en un 8.5%, pero la efectividad final es <90%. Además, su uso no aumenta la efectividad de la terapia cuádruple. No obstante, el uso de estos microorganismos disminuye los efectos adversos de estas terapias.
Materiales y métodos: Se analizaron los ensayos clínicos aleatorizados (ECA) que evaluaron los efectos de los probióticos en la erradicación de H. Pylori. Se siguieron las recomendaciones del Manual Cochrane y la declaración Preferred Reporting Items for Systematic Review and Meta-Analysis (PRISMA). Se evaluaron los riesgos de sesgo y la calidad general de la evidencia se evaluó mediante el enfoque Grades of Recommendations Assessment, Development, and Evaluation (GRADE). Resultados: Se identificaron 12 ECA que incluyeron 1091 pacientes. Nueve evaluaron terapia triple, dos terapia cuádruple y uno terapia triple y cuádruple. En las terapias triples los probióticos fueron más efectivos que placebo 79.4% vs 71.1%, (OR=1.42; IC95%=1.05-2.09; I2=0%). En cuádruple no aumentaron la efectividad. El probiótico más utilizado fue Lactobacillus reuteri, con éxito en erradicación de 77.9% (CI95%= 70.5-84.19) versus 66.8% (IC95%= 58.8–74.2). Los probióticos disminuyeron efectos adversos en terapias triples (OR= 0.50; IC95%= 0.28-0.90; I2=0%) y cuádruples (OR= 0.26; IC95%= 0.09-0.74; I2=0%). Conclusión: Los probióticos mejoran en 8.5% la efectividad de las terapias triple, pero el éxito final en alcanzar la erradicación de H. Pylori sigue siendo pobre (<90%). No aumenta la efectividad de terapias cuádruples. Significativamente disminuyen efectos adversos.
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Altanbayar O, Amgalanbaatar A, Battogtokh C, Bayarjargal N, Belick D, Kohns Vasconcelos M, Mackenzie CR, Pfeffer K, Henrich B. Characterization of the cagA-gene in Helicobacter pylori in Mongolia and detection of two EPIYA-A enriched CagA types. Int J Med Microbiol 2022; 312:151552. [DOI: 10.1016/j.ijmm.2022.151552] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2021] [Revised: 01/28/2022] [Accepted: 02/22/2022] [Indexed: 11/30/2022] Open
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Murata-Kamiya N, Hatakeyama M. Helicobacter pylori-induced DNA double-strand break in the development of gastric cancer. Cancer Sci 2022; 113:1909-1918. [PMID: 35359025 PMCID: PMC9207368 DOI: 10.1111/cas.15357] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2021] [Revised: 03/22/2022] [Accepted: 03/30/2022] [Indexed: 01/10/2023] Open
Abstract
Infection with cagA-positive Helicobacter pylori strains plays an etiological role in the development of gastric cancer. The CagA protein is injected into gastric epithelial cells through a bacterial Type IV secretion system. Inside the host cells, CagA promiscuously associates with multiple host cell proteins including the prooncogenic phosphatase SHP2 that is required for full activation of the RAS-ERK pathway. CagA-SHP2 interaction aberrantly activates SHP2 and thereby deregulates RAS-ERK signaling. Cancer is regarded as a disease of the genome, indicating that H. pylori-mediated gastric carcinogenesis is also associated with genomic alterations in the host cell. Indeed, accumulating evidence has indicated that H. pylori infection provokes DNA double-strand breaks (DSBs) by both CagA-dependent and -independent mechanisms. DSBs are repaired by either error-free homologous recombination (HR) or error-prone non-homologous end joining (NHEJ) or microhomology-mediated end joining (MMEJ). Infection with cagA-positive H. pylori inhibits RAD51 expression while dampening cytoplasmic-to-nuclear translocalization of BRCA1, causing replication fork instability and HR defects (known as "BRCAness"), which collectively provoke genomic hypermutation via non-HR-mediated DSB repair. H. pylori also subverts multiple DNA damage responses including DNA repair systems. Infection with H. pylori additionally inhibits the function of the p53 tumor suppressor, thereby dampening DNA damage-induced apoptosis while promoting proliferation of CagA-delivered cells. Thus, H. pylori cagA-positive strains promote abnormal expansion of cells with BRCAness, which dramatically increases the chance of generating driver gene mutations in the host cells. Once such driver mutations are acquired, H. pylori CagA is no longer required for subsequent gastric carcinogenesis (Hit-and-Run carcinogenesis).
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Affiliation(s)
- Naoko Murata-Kamiya
- Department of Microbiology, Graduate School of Medicine, The University of Tokyo, Tokyo, 113-0033, Japan
| | - Masanori Hatakeyama
- Department of Microbiology, Graduate School of Medicine, The University of Tokyo, Tokyo, 113-0033, Japan
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Helicobacter pylori in Native Americans in Northern Arizona. Diseases 2022; 10:diseases10020019. [PMID: 35466189 PMCID: PMC9036257 DOI: 10.3390/diseases10020019] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2022] [Revised: 03/11/2022] [Accepted: 03/13/2022] [Indexed: 02/04/2023] Open
Abstract
Background: In Arizona Helicobacter pylori prevalence of infection among Navajo adults is about 62% and gastric cancer incidence rate is 3–4 times higher than that of the non-Hispanic White population. Aim: The aim of this study was to estimate the prevalence of specific H. pylori virulence factors (cagA and vacA) among Navajo patients undergoing and their association with gastric disease. Methods: Virulence genes, cagA and vacA, in H. pylori were investigated in gastric biopsies from 96 Navajo patients over age 18 who were undergoing esophagogastroduodenoscopy. Biopsies from the antrum and fundus were used for molecular characterization to determine cagA type and number of EPIYA motifs and presence of alleles in the signal (s) and medium (m) regions of the vacA gene. Results: H. pylori infection was found in 22.9% of the biopsy samples. The cagA gene amplified in 57.6% of samples and showed a predominant “Western cagA” type, with the EPIYA-ABC motif (45.4%), most prevalent. The vacA allele s1bm1 was the most prevalent (54.5%). Conclusions: H. pylori genotypes were predominantly cagA Western-type and ABC EPIYA motifs. The vacA s1bm1 genotype was the most prevalent and seemed to be associated with gastritis. American Indian/Alaska Native populations are at higher risk for gastric cancer. It is important to identify genotypes of H. pylori and virulence factors involved in the high prevalence of H. pylori and associated disease among the Navajo population.
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Sharndama HC, Mba IE. Helicobacter pylori: an up-to-date overview on the virulence and pathogenesis mechanisms. Braz J Microbiol 2022; 53:33-50. [PMID: 34988937 PMCID: PMC8731681 DOI: 10.1007/s42770-021-00675-0] [Citation(s) in RCA: 83] [Impact Index Per Article: 27.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/10/2021] [Accepted: 12/24/2021] [Indexed: 02/06/2023] Open
Abstract
Helicobacter pylori is an organism associated with ulcer disease and gastric cancer. The latter is one of the most prevalent malignancies and currently the fourth major cause of cancer-related deaths globally. The pathogen infects about 50% of the world population, and currently, no treatment ensures its total elimination. There has been an increase in our understanding of the pathophysiology and pathogenesis mechanisms of H. pylori over the years. H. pylori can induce several genetic alterations, express numerous virulence factors, and trigger diverse adaptive mechanisms during its adherence and colonization. For successful colonization and infection establishment, several effector proteins/toxins are released by the organism. Evidence is also available reporting spiral to coccoid transition as a unique tactic H. pylori uses to survive in the host's gastrointestinal tract (GIT). Thus, the virulence and pathogenicity of H. pylori are under the control of complex interplay between the virulence factors, host, and environmental factors. Expounding the role of the various virulence factors in H. pylori pathogenesis and clinical outcomes is crucial for vaccine development and in providing and developing a more effective therapeutic intervention. Here we critically reflect on H. pylori infection and delineate what is currently known about the virulence and pathogenesis mechanisms of H. pylori.
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Affiliation(s)
| | - Ifeanyi Elibe Mba
- Department of Microbiology, University of Nigeria, Nsukka, Enugu, Nigeria.
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You Y, Thorell K, He L, Yahara K, Yamaoka Y, Cha JH, Murakami K, Katsura Y, Kobayashi I, Falush D, Zhang J. Genomic differentiation within East Asian Helicobacter pylori. Microb Genom 2022; 8. [PMID: 35188454 PMCID: PMC8942036 DOI: 10.1099/mgen.0.000676] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/23/2022] Open
Abstract
The East Asian region, including China, Japan and Korea, accounts for half of gastric cancer deaths. However, different areas have contrasting gastric cancer incidences and the population structure of Helicobacter pylori in this ethnically diverse region is yet unknown. We aimed to investigate genomic differences in H. pylori between these areas to identify sequence polymorphisms associated with increased cancer risk. We analysed 381 H. pylori genomes collected from different areas of the three countries using phylogenetic and population genetic tools to characterize population differentiation. The functional consequences of SNPs with a highest fixation index (Fst) between subpopulations were examined by mapping amino acid changes on 3D protein structure, solved or modelled. Overall, 329/381 genomes belonged to the previously identified hspEAsia population indicating that import of bacteria from other regions of the world has been uncommon. Seven subregional clusters were found within hspEAsia, related to subpopulations with various ethnicities, geographies and gastric cancer risks. Subpopulation-specific amino acid changes were found in multidrug exporters (hefC), transporters (frpB-4), outer membrane proteins (hopI) and several genes involved in host interaction, such as a catalase site, involved in H2O2 entrance, and a flagellin site mimicking host glycosylation. Several of the top hits, including frpB-4, hefC, alpB/hopB and hofC, have been found to be differentiated within the Americas in previous studies, indicating that a handful of genes may be key to local geographic adaptation. H. pylori within East Asia are not homogeneous but have become differentiated geographically at multiple loci that might have facilitated adaptation to local conditions and hosts. This has important implications for further evaluation of these changes in relation to the varying gastric cancer incidence between geographical areas in this region.
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Affiliation(s)
- Yuanhai You
- State Key Laboratory of Infectious Disease Prevention and Control, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, National Institute for Communicable Disease Control and Prevention, Chinese Center for Disease Control and Prevention, Beijing, PR China
| | - Kaisa Thorell
- Department of Clinical Microbiology, Sahlgrenska University Hospital, Västra Götaland 12 Region, Gothenburg, Sweden
- Department of Infectious Diseases, Sahlgrenska Academy, University of Gothenburg, Sweden
| | - Lihua He
- State Key Laboratory of Infectious Disease Prevention and Control, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, National Institute for Communicable Disease Control and Prevention, Chinese Center for Disease Control and Prevention, Beijing, PR China
| | - Koji Yahara
- Antimicrobial Resistance Research Center, National Institute of Infectious Diseases, Tokyo, Japan
| | - Yoshio Yamaoka
- Department of Environmental and Preventive Medicine, Oita University Faculty of Medicine, Oita, Japan
| | - Jeong-Heon Cha
- Department of Oral Biology, BK21 Plus Project, Yonsei University College of Dentistry, Seoul, Republic of Korea
| | - Kazunari Murakami
- Department of Gastroenterology, Faculty of Medicine, Oita University, Oita, Japan
| | - Yukako Katsura
- Primate Research Institute, Kyoto University, Inuyama, Japan
| | - Ichizo Kobayashi
- Department of Computational Biology and Medical Sciences (formerly Department of Medical Genome Sciences), Graduate School of Frontier Sciences, University of Tokyo, Tokyo, Japan
- Department of Infectious Diseases, Kyorin University School of Medicine, Mitaka-shi, Tokyo, Japan
- I2BC, University of Paris-Saclay, Gif-sur-Yvette, France
- Research Center for Micro-Nano Technology, Hosei University, Koganei-shi, Tokyo, Japan
- Institute of Medical Science, University of Tokyo, Minato-ku, Tokyo, Japan
| | - Daniel Falush
- The Center for Microbes, Development and Health, Key Laboratory of Molecular Virology and Immunology, Institut Pasteur of Shanghai, Chinese Academy of Sciences, Shanghai, PR China
| | - Jianzhong Zhang
- State Key Laboratory of Infectious Disease Prevention and Control, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, National Institute for Communicable Disease Control and Prevention, Chinese Center for Disease Control and Prevention, Beijing, PR China
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