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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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2
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Kim JH, Kim JM, Park B, Lim SG, Shin SJ, Lee KM, Lee GH, Noh CK. The Potential Role of the Rapid Urease Test with the Sweeping Method in the Gray Zone of the Urea Breath Test after Helicobacter pylori Eradication. Gut Liver 2025; 19:355-363. [PMID: 40169396 DOI: 10.5009/gnl240470] [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: 10/13/2024] [Revised: 01/03/2025] [Accepted: 01/15/2025] [Indexed: 04/03/2025] Open
Abstract
Background/Aims Although the urea breath test (UBT) is widely used as a representative monitoring test after Helicobacter pylori eradication, false-negative results can occur because of the gray zone related to its cutoff value. This study aimed to compare the diagnostic performances of the rapid urease test (RUT), the RUT with sweeping method, and the UBT, and to investigate the role of the sweeping method in the gray zone of UBT values. Methods We retrospectively reviewed 216 patients who received standard first-line H. pylori eradication treatments (n=216). All participants underwent to testing using the sweeping method and UBT on the same day. The sensitivity, specificity, and accuracy were analyzed to compare the two methods. Results The sensitivity (0.537 vs 0.806, p=0.002) and accuracy (0.843 vs 0.870, p=0.026) of the UBT were inferior to those of the sweeping method. A total of 31 individuals tested positive for H. pylori according to the UBT, whereas 54 individuals tested positive according to the sweeping method. In the group for which the gold standard definition indicated H. pylori positivity but UBT results were negative (n=31), all individuals had a UBT value under 2.5‰. In the multivariate logistic regression model, a UBT value of 1.4‰ to 2.5‰ increased the risk of false-negative results by 6.5 times (odds ratio, 6.5; 95% confidence interval, 2.077 to 20.288; p=0.001). Conclusions After H. pylori eradication, false-negative results can occur for individuals undergoing the UBT, primarily for values below the UBT cutoff. The RUT with the sweeping method can potentially help detect H. pylori in the gray zone of the UBT, improving diagnostic accuracy.
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Affiliation(s)
- Ji Hyun Kim
- Department of Gastroenterology, Ajou University School of Medicine, Suwon, Korea
| | - Ji Min Kim
- Department of Biomedical Informatics, Ajou University School of Medicine, Suwon, Korea
| | - Bumhee Park
- Department of Biomedical Informatics, Ajou University School of Medicine, Suwon, Korea
| | - Sun Gyo Lim
- Department of Gastroenterology, Ajou University School of Medicine, Suwon, Korea
| | - Sung Jae Shin
- Department of Gastroenterology, Ajou University School of Medicine, Suwon, Korea
| | - Kee Myung Lee
- Department of Gastroenterology, Ajou University School of Medicine, Suwon, Korea
| | - Gil Ho Lee
- Department of Gastroenterology, Ajou University School of Medicine, Suwon, Korea
| | - Choong-Kyun Noh
- Department of Gastroenterology, Ajou University School of Medicine, Suwon, Korea
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3
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Wizenty J, Sigal M. Helicobacter pylori, microbiota and gastric cancer - principles of microorganism-driven carcinogenesis. Nat Rev Gastroenterol Hepatol 2025; 22:296-313. [PMID: 40011753 DOI: 10.1038/s41575-025-01042-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 01/16/2025] [Indexed: 02/28/2025]
Abstract
The demonstration that Helicobacter pylori is a pathogenic bacterium with marked carcinogenic potential has paved the way for new preventive approaches for gastric cancer. Although decades of research have uncovered complex interactions of H. pylori with epithelial cells, current insights have refined our view on H. pylori-associated carcinogenesis. Specifically, the cell-type-specific effects on gastric stem and progenitor cells deep in gastric glands provide a new view on the ability of the bacteria to colonize long-term, manipulate host responses and promote gastric pathology. Furthermore, new, large-scale epidemiological data have shed light on factors that determine why only a subset of carriers progress to gastric cancer. Currently, technological advances have brought yet another revelation: H. pylori is far from the only microorganism able to colonize the stomach. Instead, the stomach is colonized by a diverse gastric microbiota, and there is emerging evidence for the occurrence and pathological effect of dysbiosis resulting from an aberrant interplay between H. pylori and the gastric mucosa. With the weight of this evidence mounting, here we consider how the lessons learned from H. pylori research inform and synergize with this emerging field to bring a more comprehensive understanding of the role of microbes in gastric carcinogenesis.
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Affiliation(s)
- Jonas Wizenty
- Department of Hepatology and Gastroenterology, Charité - Universitätsmedizin Berlin, Berlin, Germany
- Berlin Institute of Health at Charité - Universitätsmedizin Berlin, BIH Biomedical Innovation Academy and BIH Charité Clinician Scientist Program, Berlin, Germany
| | - Michael Sigal
- Department of Hepatology and Gastroenterology, Charité - Universitätsmedizin Berlin, Berlin, Germany.
- Berlin Institute for Medical Systems Biology, Max Delbrück Center for Molecular Medicine in the Helmholtz Association, Berlin, Germany.
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Fares M, Imberty A, Titz A. Bacterial lectins: multifunctional tools in pathogenesis and possible drug targets. Trends Microbiol 2025:S0966-842X(25)00083-6. [PMID: 40307096 DOI: 10.1016/j.tim.2025.03.007] [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: 01/30/2025] [Revised: 02/27/2025] [Accepted: 03/14/2025] [Indexed: 05/02/2025]
Abstract
Glycans are vital macromolecules with diverse biological roles, decoded by lectins - specialized carbohydrate-binding proteins crucial in pathogenesis. The WHO identifies bacterial antimicrobial resistance (AMR) as a critical global health challenge, necessitating innovative strategies that also target non-antibiotic pathways. Recent studies highlight bacterial lectins as key players in pathogenesis and promising therapeutic targets, with early clinical success using glycomimetics and vaccines to treat and prevent AMR-related infections. This review covers the current knowledge on bacterial lectins, their classifications, and roles in host recognition and adhesion, biofilm formation, cytotoxicity, and host immune evasion, with examples of well-characterized lectins. It also explores their therapeutic potential and highlights novel lectins with unknown functions, encouraging further research.
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Affiliation(s)
- Mario Fares
- Helmholtz Institute for Pharmaceutical Research Saarland (HIPS), Helmholtz Centre for Infection Research, D-66123 Saarbrücken, Germany; Deutsches Zentrum für Infektionsforschung (DZIF), Standort Hannover-Braunschweig, Germany; Department of Chemistry, PharmaScienceHub (PSH), Saarland University, D-66123 Saarbrücken, Germany
| | - Anne Imberty
- University Grenoble Alpes, CNRS, CERMAV, 601 rue de la chimie, Grenoble 38000, France
| | - Alexander Titz
- Helmholtz Institute for Pharmaceutical Research Saarland (HIPS), Helmholtz Centre for Infection Research, D-66123 Saarbrücken, Germany; Deutsches Zentrum für Infektionsforschung (DZIF), Standort Hannover-Braunschweig, Germany; Department of Chemistry, PharmaScienceHub (PSH), Saarland University, D-66123 Saarbrücken, Germany.
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Chen D, Wang W, Chen X, Liang N, Li J, Ding W, Zhang H, Yang Z, Zhao H, Liu Z. Plant-derived extracts or compounds for Helicobacter-associated gastritis: a systematic review of their anti-Helicobacter activity and anti-inflammatory effect in animal experiments. Chin Med 2025; 20:53. [PMID: 40264171 PMCID: PMC12013188 DOI: 10.1186/s13020-025-01093-2] [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: 06/21/2024] [Accepted: 03/10/2025] [Indexed: 04/24/2025] Open
Abstract
BACKGROUND Helicobacter infection, which is the leading cause of gastritis and stomach cancer, has become common worldwide. Almost all Helicobacter-infected patients have chronic active gastritis, also known as Helicobacter-associated gastritis (HAG). However, the eradication rate of Helicobacter is decreasing due to the poor efficacy of current medications, which causes infection to recur, inflammation to persist, and stomach cancer to develop. Natural components have robust antibacterial activity and anti-inflammatory capacity, as confirmed by many studies of alternative natural medicines. PURPOSE This article aimed to conduct a comprehensive search and meta-analysis to evaluate the efficacy of anti-Helicobacter and anti-inflammatory activities of plant-derived extracts or compounds that can treat HAG in animal experiments. We intended to provide detailed preclinical-research foundation including plant and compound information, as well as the mechanisms by which these plant-derived substances inhibit the progression of Helicobacter infection, gastritis and neoplasms for future study. METHODS The systematic review is aligned with the guidelines outlined in the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement, and the protocol was registered in PROSPERO (CRD42024527889). An extensive search was performed across multiple databases, including PubMed, Scopus, Web of Science, Embase, China National Knowledge Infrastructure (CNKI), the Chinese Scientific Journal database (VIP), the Wanfang database, and the China biomedical literature service system (SinoMed), up until November 2023. Meta-analysis on Review Manager software (RevMan 5.4) estimating anti-Helicobacter and anti-inflammatory activity was performed. We used the Systematic Review Center for Laboratory Animal Experimentation (SYRCLE) risk of bias tool to evaluate the risk of bias of each study included. RESULTS Our study encompassed 61 researches, comprised 36 extracts and 37 compounds improving HAG by inhibiting Helicobacter infection, the inflammatory response, oxidative stress, and regulating apoptosis and proliferation. Sixteen families especially Asteraceae, Fabaceae and Rosaceae and nine classes including Terpenoids, Alkaloids, Phenols, and Flavonoids may be promising directions for valuable new drugs. The Meta-analyse demonstrated the plant-base substance treatments possess significant anti-Helicobacter and anti-inflammation activity comparing to control groups. The included plants and compounds confirmed that signaling pathways NF-κB, JAK2/STAT3, MAPK, TLR4/MyD88, PI3K/AKT, NLRP3/Caspase-1 and NRF2/HO-1 play a key role in the progression of HAG. CONCLUSION Plant-derived extracts or compounds actively improve HAG by modulating relevant mechanisms and signaling pathways, particularly through the anti-Helicobacter and inflammatory regulation ways. Further researches to apply these treatments in humans are needed, which will provide direction for the future development of therapeutic drugs to increase eradication rate and alleviate gastritis.
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Affiliation(s)
- Danni Chen
- College of Traditional Chinese Medicine, Beijing University of Chinese Medicine, No. 11 Bei San Huan Dong Lu, Chaoyang District, Beijing, 100029, China
| | - Wenlai Wang
- Institute of Basic Theory for Chinese Medicine, China Academy of Chinese Medical Sciences, No. 16 Nanxiaojie, Dongzhimen Nei, Dongcheng District, Beijing, 100700, China
| | - Xiangyun Chen
- College of Traditional Chinese Medicine, Beijing University of Chinese Medicine, No. 11 Bei San Huan Dong Lu, Chaoyang District, Beijing, 100029, China
| | - Ning Liang
- Institute of Basic Research in Clinical Medicine, China Academy of Chinese Medical Sciences, Beijing, 100700, China
| | - Jiawang Li
- College of Traditional Chinese Medicine, Beijing University of Chinese Medicine, No. 11 Bei San Huan Dong Lu, Chaoyang District, Beijing, 100029, China
| | - Wei Ding
- College of Traditional Chinese Medicine, Beijing University of Chinese Medicine, No. 11 Bei San Huan Dong Lu, Chaoyang District, Beijing, 100029, China
| | - Hongrui Zhang
- Dongzhimen Hospital, Beijing University of Chinese Medicine, No. 5 Haiyuncang, Dongcheng District, Beijing, 100700, China
- Institute for Brain Disorders, Beijing University of Chinese Medicine, Beijing, 100700, China
| | - Zhen Yang
- College of Traditional Chinese Medicine, Beijing University of Chinese Medicine, No. 11 Bei San Huan Dong Lu, Chaoyang District, Beijing, 100029, China.
| | - Hongxia Zhao
- Institute of Basic Theory for Chinese Medicine, China Academy of Chinese Medical Sciences, No. 16 Nanxiaojie, Dongzhimen Nei, Dongcheng District, Beijing, 100700, China.
| | - Zhenhong Liu
- Dongzhimen Hospital, Beijing University of Chinese Medicine, No. 5 Haiyuncang, Dongcheng District, Beijing, 100700, China.
- Institute for Brain Disorders, Beijing University of Chinese Medicine, Beijing, 100700, China.
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Gebrehiwot NT, Liu Y, Li J, Liu HM. Molecular Alterations in Gastric Intestinal Metaplasia Shed Light on Alteration of Methionine Metabolism: Insight into New Diagnostic and Treatment Approaches. Biomedicines 2025; 13:964. [PMID: 40299656 PMCID: PMC12025106 DOI: 10.3390/biomedicines13040964] [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: 02/23/2025] [Revised: 04/03/2025] [Accepted: 04/08/2025] [Indexed: 05/01/2025] Open
Abstract
Gastric intestinal metaplasia (GIM) is a precancerous lesion and the key risk factor in the development of gastric cancer (GC), but early detection and treatment remain challenging. The traditional endoscopic diagnosis of metaplastic lesions is complicated by an increased rate of inappropriateness and false negativity. Although early interventions with H. pylori eradication, as well as endoscopic therapy results, were promising, there is still a significant unmet need to control GIM progression and recurrences. Molecular alterations, such as an increased DNA methylation index, have been identified as a crucial factor in the downregulation of tumor suppressor genes, such as the caudal-type homeobox (CDX2) gene, which regulates epithelial cell proliferation and GIM progression and is associated with treatment failure. CDX2 is downregulated by promoter hypermethylation in the colonic-type epithelium, in which the methylation was correlated with reduced intake of dietary folate sources. Tumor cells alter to dietary methionine sources in the biosynthesis of S-Adenosylmethionine, a universal methyl donor for transmethylation, under the conditions of limited folate and B12 availability. The gut microbiota also exhibited a shift in microbial composition, which could influence the host's dietary methionine metabolism. Meanwhile, activated oncogenic signaling via the PI3K/Akt/mTORC1/c-MYC pathway could promotes rewiring dietary methionine and cellular proliferation. Tumor methionine dependence is a metabolic phenotype that could be helpful in predictive screening of tumorigenesis and as a target for preventive therapy to enhance precision oncology. This review aimed to discuss the molecular alterations in GIM to shed light on the alteration of methionine metabolism, with insight into new diagnostic and treatment approaches and future research directions.
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Affiliation(s)
- Nigatu Tadesse Gebrehiwot
- School of Pharmaceutical Sciences, Institute of Drug Discovery and Development, Zhengzhou University, Zhengzhou 450001, China;
- Key Laboratory of Advanced Drug Preparation Technologies, Zhengzhou University, Ministry of Education, Zhengzhou 450001, China
| | - Ying Liu
- The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, China;
| | - Juan Li
- School of Pharmaceutical Sciences, Institute of Drug Discovery and Development, Zhengzhou University, Zhengzhou 450001, China;
- Key Laboratory of Advanced Drug Preparation Technologies, Zhengzhou University, Ministry of Education, Zhengzhou 450001, China
| | - Hong-Min Liu
- School of Pharmaceutical Sciences, Institute of Drug Discovery and Development, Zhengzhou University, Zhengzhou 450001, China;
- Key Laboratory of Advanced Drug Preparation Technologies, Zhengzhou University, Ministry of Education, Zhengzhou 450001, China
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Hofer M, Kim Y, Broguiere N, Gorostidi F, Klein JA, Amieva MR, Lutolf MP. Accessible homeostatic gastric organoids reveal secondary cell type-specific host-pathogen interactions in Helicobacter pylori infections. Nat Commun 2025; 16:2767. [PMID: 40113752 PMCID: PMC11926186 DOI: 10.1038/s41467-025-57131-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/29/2024] [Accepted: 02/12/2025] [Indexed: 03/22/2025] Open
Abstract
Despite the high prevalence of gastric diseases like gastric cancer and peptic ulcer disease attributed to Helicobacter pylori infections, there is still only a limited understanding of the underlying mechanisms. Existing in vitro models are either two-dimensional systems lacking the structural complexity of the gastric architecture, or complex three-dimensional systems that pose challenges for experimental access. In this study, we introduce a patterned homeostatic human gastric organoid-on-a-chip system with bilateral access that is capable of modeling H. pylori niche establishment and persistent colonization of the gastric epithelium. We show that in physiological apical acidic conditions, our organ-on-a-chip can generate pit cells of higher maturity in contrast to traditionally grown organoids. Upon infection with H. pylori for up to 6 days, these mature pit cells exhibit a distinctive response from other cell types, which was previously uncharacterized. Beyond its application in studying H. pylori infection, the increased structural and functional relevance of our model offers broader significance as a versatile platform for advancing our understanding of gastric epithelial cell interactions, gastric mucosal immunity, and host-pathogen interactions.
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Affiliation(s)
- Moritz Hofer
- Laboratory of Stem Cell Bioengineering, École Polytechnique Fédérale de Lausanne (EPFL), Lausanne, Switzerland
| | - Youlim Kim
- Department of Microbiology and Immunology, Stanford University School of Medicine, Stanford, CA, United States of America
| | - Nicolas Broguiere
- Laboratory of Stem Cell Bioengineering, École Polytechnique Fédérale de Lausanne (EPFL), Lausanne, Switzerland
| | - François Gorostidi
- Service d'oto-rhino-laryngologie et de chirurgie cervico-faciale, Centre hospitalier universitaire vaudois (CHUV), Lausanne, Switzerland
| | - Jessica A Klein
- Department of Pediatrics, Stanford University School of Medicine, Stanford, CA, United States of America
- Complex In Vitro Systems, Translational Safety, Genentech Inc., South San Francisco, CA, United States of America
| | - Manuel R Amieva
- Department of Microbiology and Immunology, Stanford University School of Medicine, Stanford, CA, United States of America
- Department of Pediatrics, Stanford University School of Medicine, Stanford, CA, United States of America
| | - Matthias P Lutolf
- Laboratory of Stem Cell Bioengineering, École Polytechnique Fédérale de Lausanne (EPFL), Lausanne, Switzerland.
- Institute of Human Biology (IHB), Roche Pharma Research and Early Development, F. Hoffmann-La Roche, Basel, Switzerland.
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Dessenne C, Mariller C, Vidal O, Huvent I, Guerardel Y, Elass-Rochard E, Rossez Y. Glycan-mediated adhesion mechanisms in antibiotic-resistant bacteria. BBA ADVANCES 2025; 7:100156. [PMID: 40207210 PMCID: PMC11979486 DOI: 10.1016/j.bbadva.2025.100156] [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: 11/29/2024] [Revised: 03/10/2025] [Accepted: 03/13/2025] [Indexed: 04/11/2025] Open
Abstract
Bacterial adhesins play a central role in host-pathogen interactions, with many specifically targeting glycans to mediate bacterial colonization, influence infection dynamics, and evade host immune responses. In this review, we focus on bacterial pathogens identified by the World Health Organization as critical threats to public health and in urgent need of new treatments. We summarize glycoconjugate targets identified in the literature across 19 bacterial genera and species. This comprehensive review provides a foundation for the development of innovative therapeutic strategies to effectively combat these pathogens.
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Affiliation(s)
- Clara Dessenne
- Université Lille, CNRS, UMR 8576-UGSF-Unité de Glycobiologie Structurale et Fonctionnelle, Lille, France
| | - Christophe Mariller
- Université Lille, CNRS, UMR 8576-UGSF-Unité de Glycobiologie Structurale et Fonctionnelle, Lille, France
| | - Olivier Vidal
- Université Lille, CNRS, UMR 8576-UGSF-Unité de Glycobiologie Structurale et Fonctionnelle, Lille, France
| | - Isabelle Huvent
- Université Lille, CNRS, UMR 8576-UGSF-Unité de Glycobiologie Structurale et Fonctionnelle, Lille, France
| | - Yann Guerardel
- Université Lille, CNRS, UMR 8576-UGSF-Unité de Glycobiologie Structurale et Fonctionnelle, Lille, France
- Institute for Glyco-core Research (iGCORE), Gifu University, Gifu, Japan
| | - Elisabeth Elass-Rochard
- Université Lille, CNRS, UMR 8576-UGSF-Unité de Glycobiologie Structurale et Fonctionnelle, Lille, France
| | - Yannick Rossez
- Université Lille, CNRS, UMR 8576-UGSF-Unité de Glycobiologie Structurale et Fonctionnelle, Lille, France
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Yi M, Chen S, Yi X, Zhang F, Zhou X, Zeng M, Song H. Helicobacter pylori infection process: from the molecular world to clinical treatment. Front Microbiol 2025; 16:1541140. [PMID: 40083792 PMCID: PMC11903457 DOI: 10.3389/fmicb.2025.1541140] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2024] [Accepted: 02/10/2025] [Indexed: 03/16/2025] Open
Abstract
Helicobacter pylori is a gram-negative microaerophilic microorganism intricately associated with chronic gastrointestinal disorders and gastric cancer. H. pylori can cause various upper digestive tract diseases, including chronic gastritis, peptic ulcer, gastroesophageal reflux disease, and gastric cancer. The bacterium exhibits a variety of pathogenic mechanisms, including colonization, the expression of virulence factors, and the development of drug resistance. This article presents a comprehensive review of H. pylori pathogenesis, emphasizing recent research advancements concerning the cytotoxin-associated gene A, vacuolating cytotoxin, outer membrane proteins, and other virulence factors. Additionally, it examines the molecular mechanisms underlying drug resistance and evaluates the efficacy of conventional therapeutic approaches. Recently, researchers have attempted novel therapeutic regimens, including probiotics and Chinese medicine-assisted therapies, to enhance therapeutic effects. This article aimed to offer an overview of the academic community's comprehension of H. pylori infection and to highlight the current treatment options.
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Affiliation(s)
- Meijing Yi
- School of Traditional Chinese Medicine, Hunan University of Chinese Medicine, Changsha, China
- Hunan Provincial Key Laboratory of Traditional Chinese Medicine Diagnostics, Hunan University of Chinese Medicine, Changsha, China
| | - Silan Chen
- School of Traditional Chinese Medicine, Hunan University of Chinese Medicine, Changsha, China
- Hunan Provincial Key Laboratory of Traditional Chinese Medicine Diagnostics, Hunan University of Chinese Medicine, Changsha, China
| | - Xinying Yi
- School of Traditional Chinese Medicine, Hunan University of Chinese Medicine, Changsha, China
- Hunan Provincial Key Laboratory of Traditional Chinese Medicine Diagnostics, Hunan University of Chinese Medicine, Changsha, China
| | - Fan Zhang
- School of Traditional Chinese Medicine, Hunan University of Chinese Medicine, Changsha, China
- Hunan Provincial Key Laboratory of Traditional Chinese Medicine Diagnostics, Hunan University of Chinese Medicine, Changsha, China
| | - Xuan Zhou
- School of Traditional Chinese Medicine, Hunan University of Chinese Medicine, Changsha, China
- Hunan Provincial Key Laboratory of Traditional Chinese Medicine Diagnostics, Hunan University of Chinese Medicine, Changsha, China
| | - Meiyan Zeng
- School of Traditional Chinese Medicine, Hunan University of Chinese Medicine, Changsha, China
| | - Houpan Song
- School of Traditional Chinese Medicine, Hunan University of Chinese Medicine, Changsha, China
- Hunan Provincial Key Laboratory of Traditional Chinese Medicine Diagnostics, Hunan University of Chinese Medicine, Changsha, China
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Bao X, Wu J. Natural anti-adhesive components against pathogenic bacterial adhesion and infection in gastrointestinal tract: case studies of Helicobacter pylori, Salmonella enterica, Clostridium difficile, and diarrheagenic Escherichia coli. Crit Rev Food Sci Nutr 2024:1-46. [PMID: 39666022 DOI: 10.1080/10408398.2024.2436139] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2024]
Abstract
Antimicrobial resistance (AMR) poses a global public health concern. Recognizing the critical role of bacterial adhesion in pathogenesis of infection, anti-adhesive therapy emerges as a promising approach to impede initial bacterial attachment, thus preventing pathogenic colonization and infection. Natural anti-adhesive agents derived from food sources are generally safe and have the potential to inhibit the emergence of resistant bacteria. This comprehensive review explored diverse natural dietary components exhibiting anti-adhesive activities against several model enteric pathogens, including Helicobacter pylori, Salmonella enterica, Clostridium difficile, and three key diarrheagenic Escherichia coli (i.e., enterotoxigenic E. coli, enteropathogenic E. coli, and enterohemorrhagic E. coli). Investigating various anti-adhesive products will advance our understanding of current research of the field and inspire further development of these agents as potential nutraceuticals or adjuvants to improve the efficacy of conventional antibiotics.
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Affiliation(s)
- Xiaoyu Bao
- Department of Agricultural, Food and Nutritional Science, University of Alberta, Edmonton, Alberta, Canada
| | - Jianping Wu
- Department of Agricultural, Food and Nutritional Science, University of Alberta, Edmonton, Alberta, Canada
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Xu L, Li X, Han S, Mu C, Zhu W. Galacto-oligosaccharides regulate intestinal mucosal sialylation to counteract antibiotic-induced mucin dysbiosis. Food Funct 2024; 15:12016-12032. [PMID: 39563647 DOI: 10.1039/d4fo04626a] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2024]
Abstract
Intestinal mucin offers a physical barrier to maintain host-commensal homeostasis. Glycosylation is essential for the appropriate functioning of mucin. Galacto-oligosaccharides (GOS) have been used as a prebiotic with proven intestinal benefits, while their regulatory mechanism on mucin remains unclear. This study employed an antibiotic-treated rat model to mimic gut dysbiosis and attempted to restore gut dysbiosis using GOS. The gut microbiome and intestinal mucus O-glycosylations (O-glycans) in the small intestine were profiled by high-throughput sequencing and glycomics. The sialic acid phenotype at the end of O-glycans was further validated with lectin staining. Expressions of key enzymes in sialic acid metabolism and epithelial morphology were determined as well. Antibiotics significantly increased the relative abundance of Escherichia/Shigella and decreased the relative abundance of Lactobacillus. This was accompanied by decreased microbial sialidase activity and increased sialic acid in the digesta, as well as an increase in epithelial sialidase activity. Analysis of key sialylation enzymes showed the upregulation of α 2,6 sialylation (e.g. ST6GALNACs) and downregulation of α 2,3 sialylation (e.g. ST3GALs) after antibiotic treatment. The glycomics results revealed that antibiotics increased core 4 and α 2,6 sialylated O-glycans and decreased core 1, core 3 and α 2,3 sialylated O-glycans in the intestinal mucus of rats, which was further confirmed by lectin staining. Intestinal histology results demonstrated that antibiotic treatment led to the dysbiosis of intestinal mucus homeostasis. To further test the role of microbiota in regulating intestinal mucus sialylation, we supplemented GOS with antibiotics. The results showed that GOS reversed the effects of antibiotics on the gut microbiota and intestinal mucus O-glycans (especially sialylated O-glycans), characterized by an increase of Lactobacillus and α 2,3 sialylated O-glycans and a decrease of Escherichia/Shigella and α 2,6 sialylated O-glycans. What's more, GOS reduced the stimulation of the intestinal mucosa by lipopolysaccharide (LPS) by increasing α 2,3 sialylated intestinal alkaline phosphatase (IAP) to enhance IAP activity, thereby restoring intestinal mucus homeostasis. Overall, GOS counteracts antibiotic-induced mucin deficiency by remedying the gut ecology and changing the mucin sialylation pattern, as reflected by the increase of α 2,3 sialylated O-glycans and the decrease of α 2,6 sialylated O-glycans.
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Affiliation(s)
- Laipeng Xu
- Laboratory of Gastrointestinal Microbiology, Jiangsu Key Laboratory of Gastrointestinal Nutrition and Animal Health, College of Animal Science and Technology, Nanjing Agricultural University, Nanjing 210095, China.
- National Center for International Research on Animal Gut Nutrition, Nanjing Agricultural University, Nanjing 210095, China
| | - Xuan Li
- Laboratory of Gastrointestinal Microbiology, Jiangsu Key Laboratory of Gastrointestinal Nutrition and Animal Health, College of Animal Science and Technology, Nanjing Agricultural University, Nanjing 210095, China.
- National Center for International Research on Animal Gut Nutrition, Nanjing Agricultural University, Nanjing 210095, China
| | - Shuibing Han
- Laboratory of Gastrointestinal Microbiology, Jiangsu Key Laboratory of Gastrointestinal Nutrition and Animal Health, College of Animal Science and Technology, Nanjing Agricultural University, Nanjing 210095, China.
- National Center for International Research on Animal Gut Nutrition, Nanjing Agricultural University, Nanjing 210095, China
| | - Chunlong Mu
- Department of Biochemistry and Molecular Biology, Cumming School of Medicine, University of Calgary, Calgary, AB., Canada.
| | - Weiyun Zhu
- Laboratory of Gastrointestinal Microbiology, Jiangsu Key Laboratory of Gastrointestinal Nutrition and Animal Health, College of Animal Science and Technology, Nanjing Agricultural University, Nanjing 210095, China.
- National Center for International Research on Animal Gut Nutrition, Nanjing Agricultural University, Nanjing 210095, China
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12
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Xiao Y, Zhang B, Zhang H, Zhang Z, Meng F, Zhao X, Zhang J, Xiao D. Study of the relationships among known virulence genes, coccoid transformation and cytotoxicity of Helicobacter pylori in different clinical diseases. Virulence 2024; 15:2418407. [PMID: 39420787 PMCID: PMC11497995 DOI: 10.1080/21505594.2024.2418407] [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: 01/23/2024] [Revised: 07/31/2024] [Accepted: 08/13/2024] [Indexed: 10/19/2024] Open
Abstract
BACKGROUND Helicobacter pylori (H. pylori) has infected approximately 4.4 billion individuals worldwide. The known virulence genes and the existing H. pylori typing methods have not been shown to have a recognized correlation with its infectivity. The aim of this study was to elucidate the relationships among known important virulence genes, coccoid transformation, and cytotoxicity of H. pylori isolated from individuals with different clinical diseases to provide guidance for the development of new virulence typing methods for H. pylori. METHODS The known important virulence genes of 35 H. pylori strains were identified by whole-gene next-generation sequencing (WGS) and polymerase chain reaction (PCR). The chronological changes in the proportion of coccoid forms of H. pylori and their ultramicroscopic structures were observed chronologically using transmission electron microscopy. Human gastric mucosal epithelial cells (GES-1) were infected with H. pylori strains in vitro to evaluate cytotoxicity of H. pylori. RESULTS There were no significant correlations among the known important virulence genes, coccoid transformation and cytotoxicity of H. pylori isolated from patients with different clinical diseases. We developed a new virulence classification based on the defensive and offensive abilities of H. pylori. CONCLUSIONS Coccoid transformation and virulence are two independent characteristics of H. pylori that reflect its defensive and offensive abilities, respectively. These two abilities work synergistically, warranting the construction of a new virulence typing method for H. pylori. However, the correlation between the new virulence classification and pathogenic ability still needs to be further verified.
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Affiliation(s)
- Yao Xiao
- National Key Laboratory of Intelligent Tracking and Forecasting for Infectious Diseases, National Institute for Communicable Disease Control and Prevention, Chinese Center for Disease Control and Prevention, Beijing, China
| | - Binghua Zhang
- National Key Laboratory of Intelligent Tracking and Forecasting for Infectious Diseases, National Institute for Communicable Disease Control and Prevention, Chinese Center for Disease Control and Prevention, Beijing, China
| | - Huifang Zhang
- National Key Laboratory of Intelligent Tracking and Forecasting for Infectious Diseases, National Institute for Communicable Disease Control and Prevention, Chinese Center for Disease Control and Prevention, Beijing, China
| | - Zehui Zhang
- National Key Laboratory of Intelligent Tracking and Forecasting for Infectious Diseases, National Institute for Communicable Disease Control and Prevention, Chinese Center for Disease Control and Prevention, Beijing, China
| | - Fanliang Meng
- National Key Laboratory of Intelligent Tracking and Forecasting for Infectious Diseases, National Institute for Communicable Disease Control and Prevention, Chinese Center for Disease Control and Prevention, Beijing, China
| | - Xin Zhao
- National Key Laboratory of Intelligent Tracking and Forecasting for Infectious Diseases, National Institute for Communicable Disease Control and Prevention, Chinese Center for Disease Control and Prevention, Beijing, China
| | - Jianzhong Zhang
- National Key Laboratory of Intelligent Tracking and Forecasting for Infectious Diseases, National Institute for Communicable Disease Control and Prevention, Chinese Center for Disease Control and Prevention, Beijing, China
| | - Di Xiao
- National Key Laboratory of Intelligent Tracking and Forecasting for Infectious Diseases, National Institute for Communicable Disease Control and Prevention, Chinese Center for Disease Control and Prevention, Beijing, China
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13
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Kővári B, Carneiro F, Lauwers GY. Epithelial tumours of the stomach. MORSON AND DAWSON'S GASTROINTESTINAL PATHOLOGY 2024:227-286. [DOI: 10.1002/9781119423195.ch13] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/04/2025]
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14
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Linz B, Sticht H, Tegtmeyer N, Backert S. Cancer-associated SNPs in bacteria: lessons from Helicobacter pylori. Trends Microbiol 2024; 32:847-857. [PMID: 38485609 DOI: 10.1016/j.tim.2024.02.001] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2023] [Revised: 02/01/2024] [Accepted: 02/02/2024] [Indexed: 09/06/2024]
Abstract
Several single-nucleotide polymorphisms (SNPs) in human chromosomes are known to predispose to cancer. However, cancer-associated SNPs in bacterial pathogens were unknown until discovered in the stomach pathogen Helicobacter pylori. Those include an alanine-threonine polymorphism in the EPIYA-B phosphorylation motif of the injected effector protein CagA that affects cancer risk by modifying inflammatory responses and loss of host cell polarity. A serine-to-leucine change in serine protease HtrA is associated with boosted proteolytic cleavage of epithelial junction proteins and introduction of DNA double-strand breaks (DSBs) in host chromosomes, which co-operatively elicit malignant alterations. In addition, H. pylori genome-wide association studies (GWAS) identified several other SNPs potentially associated with increased gastric cancer (GC) risk. Here we discuss the clinical importance, evolutionary origin, and functional advantage of the H. pylori SNPs. These exciting new data highlight cancer-associated SNPs in bacteria, which should be explored in more detail in future studies.
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Affiliation(s)
- Bodo Linz
- Department of Biology, Division of Microbiology, Friedrich-Alexander-Universität Erlangen-Nürnberg, Staudtstr. 5, 91058 Erlangen, Germany
| | - Heinrich Sticht
- Division of Bioinformatics, Institute of Biochemistry, Friedrich-Alexander-Universität Erlangen-Nürnberg; 91054 Erlangen, Germany
| | - Nicole Tegtmeyer
- Department of Biology, Division of Microbiology, Friedrich-Alexander-Universität Erlangen-Nürnberg, Staudtstr. 5, 91058 Erlangen, Germany
| | - Steffen Backert
- Department of Biology, Division of Microbiology, Friedrich-Alexander-Universität Erlangen-Nürnberg, Staudtstr. 5, 91058 Erlangen, Germany.
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15
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Singh S, Sharma AK, Som A, Gehlot V, Mahant S, Sharma P, Das K, Das R. Molecular characterization and phylogenetic analysis of babA gene of Helicobacter pylori isolated from Indian patients with gastrointestinal diseases. Gene 2024; 920:148526. [PMID: 38703866 DOI: 10.1016/j.gene.2024.148526] [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: 03/29/2024] [Revised: 04/16/2024] [Accepted: 05/01/2024] [Indexed: 05/06/2024]
Abstract
INTRODUCTION Outer membrane protein (OMP) of Helicobacter pylori (H. pylori) i.e., blood group antigen binding adhesin (babA) is responsible for the attachment of H. pylori in the gastric epithelium. Its adherence is causative for gastric pathology such as gastritis, peptic ulcer disease (PUD), or digestive tract disorders like erosive reflux disease (ERD) and (NERD) non-erosive reflux disease and together called Gastroesophageal reflux disease (GERD). BabA manifests rapid and varied selection via substitution of amino acid in its Leb-carbohydrate binding domain (CBD) which enables better binding preferences for distinct human populations and ABO blood group phenotypes. The positive evolutionary selection of the pathogenic factor of this genetically diverse bacterium has enabled it to adapt to the host gastric environment. Analyzing the association of virulent genes (cagA, vacA) and babA will help us better understand bacteria's pathogenicity. METHOD 109 H. pylori strains from patients with distinct gastrointestinal diseases were genotyped using Polymerase Chain Reaction(PCR) for cagA, vacA, and babA followed by Sanger sequencing and phylogenetic analysis. RESULT In the babA + ve genotype, a statistically significant association with p = 0.04 and < 0.0001 is seen in gastritis and ERD respectively. A significant association of genotype vacAs1m2 (p = 0.0002) was seen in gastritis, vacAs1m1 (p = 0.02) in NERD, vacAs1m1 (p < 0.0001) and vacAs1m2 (p = 0.002) in ERD. This relationship helps to detect gastritis or ERD where BabA gene can be used as an independent marker for detecting their presence. CONCLUSION The appearance of variants within distinct disease categories is due to local genetic variation.
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Affiliation(s)
- Sarika Singh
- Centre for Medical Biotechnology, Amity Institute of Biotechnology, Amity University, Noida 201301, UP, India.
| | - Amresh Kumar Sharma
- Centre of Bioinformatics, Institute of Interdisciplinary Studies, University of Allahabad, Prayagraj 211002, UP, India.
| | - Anup Som
- Centre of Bioinformatics, Institute of Interdisciplinary Studies, University of Allahabad, Prayagraj 211002, UP, India.
| | - Valentina Gehlot
- Centre for Medical Biotechnology, Amity Institute of Biotechnology, Amity University, Noida 201301, UP, India.
| | - Shweta Mahant
- Centre for Medical Biotechnology, Amity Institute of Biotechnology, Amity University, Noida 201301, UP, India.
| | - Prateek Sharma
- Centre for Medical Biotechnology, Amity Institute of Biotechnology, Amity University, Noida 201301, UP, India.
| | - Kunal Das
- Department of Gastroenterology, Yashoda super specialty Hospital, Ghaziabad, 201001, U.P, India.
| | - Rajashree Das
- Centre for Medical Biotechnology, Amity Institute of Biotechnology, Amity University, Noida 201301, UP, India.
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Hegde M, Girisa S, Aswani BS, Alqahtani MS, Abbas M, Sethi G, Kunnumakkara AB. Harnessing potential role of gangliosides in immunomodulation and cancer therapeutics. Life Sci 2024; 351:122786. [PMID: 38848944 DOI: 10.1016/j.lfs.2024.122786] [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: 01/20/2024] [Revised: 05/01/2024] [Accepted: 06/04/2024] [Indexed: 06/09/2024]
Abstract
Gangliosides represent glycolipids containing sialic acid residues, present on the cell membrane with glycan residues exposed to the extracellular matrix (ECM), while the ceramides are anchored within the membrane. These molecules play a critical role in pathophysiological processes such as host-pathogen interactions, cell-cell recognition, signal transduction, cell adhesion, motility, and immunomodulation. Accumulated evidence suggests the overexpression of gangliosides on tumor tissues in comparison to healthy human tissues. These tumor-associated gangliosides have been implicated in various facets of tumor biology, including cell motility, differentiation, signaling, immunosuppression, angiogenesis, and metastasis. Consequently, these entities emerge as attractive targets for immunotherapeutic interventions. Notably, the administration of antibodies targeting gangliosides has demonstrated cytotoxic effects on cancer cells that exhibit an overexpression of these glycolipids. Passive immunotherapy approaches utilizing murine or murine/human chimeric anti-ganglioside antibodies have been explored as potential treatments for diverse cancer types. Additionally, vaccination strategies employing tumor-associated gangliosides in conjunction with adjuvants have entered the realm of promising techniques currently undergoing clinical trials. The present comprehensive review encapsulates the multifaceted roles of gangliosides in tumor initiation, progression, immunosuppression, and metastasis. Further, an overview is provided of the correlation between the expression status of gangliosides in normal and tumor cells and its impact on cancer patient survival. Furthermore, the discussion extends to ongoing and completed clinical trials employing diverse strategies to target gangliosides, elucidating their effectiveness in treating cancers. This emerging discipline is expected to supply substantial impetus for the establishment of novel therapeutic strategies.
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Affiliation(s)
- Mangala Hegde
- Cancer Biology Laboratory, Department of Biosciences and Bioengineering, Indian Institute of Technology Guwahati (IITG), Guwahati, Assam 781039, India
| | - Sosmitha Girisa
- Cancer Biology Laboratory, Department of Biosciences and Bioengineering, Indian Institute of Technology Guwahati (IITG), Guwahati, Assam 781039, India
| | - Babu Santha Aswani
- Cancer Biology Laboratory, Department of Biosciences and Bioengineering, Indian Institute of Technology Guwahati (IITG), Guwahati, Assam 781039, India
| | - Mohammed S Alqahtani
- Radiological Sciences Department, College of Applied Medical Sciences, King Khalid University, Abha 61421, Saudi Arabia; BioImaging Unit, Space Research Centre, Michael Atiyah Building, University of Leicester, Leicester LE1 7RH, UK
| | - Mohamed Abbas
- Electrical Engineering Department, College of Engineering, King Khalid University, Abha 61421, Saudi Arabia
| | - Gautam Sethi
- Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117600, Singapore; NUS Center for Cancer Research, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117699, Singapore.
| | - Ajaikumar B Kunnumakkara
- Cancer Biology Laboratory, Department of Biosciences and Bioengineering, Indian Institute of Technology Guwahati (IITG), Guwahati, Assam 781039, India.
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Benktander J, Sundh H, Sundell K, Sharba S, Teneberg S, Lindén SK. Characterization of the rainbow trout (Oncorhynchus mykiss) mucosal glycosphingolipid repertoire and Aeromonas salmonicida binding to neutral glycosphingolipids. Glycobiology 2024; 34:cwae055. [PMID: 39107988 PMCID: PMC11303275 DOI: 10.1093/glycob/cwae055] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2023] [Revised: 07/02/2024] [Indexed: 08/10/2024] Open
Abstract
Infections pose a challenge for the fast growing aquaculture sector. Glycosphingolipids are cell membrane components that pathogens utilize for attachment to the host to initiate infection. Here, we characterized rainbow trout glycosphingolipids from five mucosal tissues using mass spectrometry and nuclear magnetic resonance and investigated binding of radiolabeled Aeromonas salmonicida to the glycosphingolipids on thin-layer chromatograms. 12 neutral and 14 acidic glycosphingolipids were identified. The glycosphingolipids isolated from the stomach and intestine were mainly neutral, whereas glycosphingolipids isolated from the skin, gills and pyloric caeca were largely acidic. Many of the acidic structures were poly-sialylated with shorter glycan structures in the skin compared to the other tissues. The sialic acids found were Neu5Ac and Neu5Gc. Most of the glycosphingolipids had isoglobo and ganglio core chains, or a combination of these. The epitopes on the rainbow trout glycosphingolipid glycans differed between epithelial sites leading to differences in pathogen binding. A major terminal epitope was fucose, that occurred attached to GalNAc in a α1-3 linkage but also in the form of HexNAc-(Fuc-)HexNAc-R. A. salmonicida were shown to bind to neutral glycosphingolipids from the gill and intestine. This study is the first to do a comprehensive investigation of the rainbow trout glycosphingolipids and analyze binding of A. salmonicida to glycosphingolipids. The structural information paves the way for identification of ways of interfering in pathogen colonization processes to protect against infections in aquaculture and contributes towards understanding A. salmonicida infection mechanisms.
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Affiliation(s)
- John Benktander
- Department of Medical Biochemistry and Cell Biology, Institute of Biomedicine, Sahlgrenska Academy, University of Gothenburg, Box 440, Medicinaregatan 9C, Gothenburg 405 30, Sweden
| | - Henrik Sundh
- Department of Biological and Environmental Sciences, Box 463, Medicinareg 7B, University of Gothenburg, Gothenburg 405 30, Sweden
| | - Kristina Sundell
- Department of Biological and Environmental Sciences, Box 463, Medicinareg 7B, University of Gothenburg, Gothenburg 405 30, Sweden
| | - Sinan Sharba
- Department of Medical Biochemistry and Cell Biology, Institute of Biomedicine, Sahlgrenska Academy, University of Gothenburg, Box 440, Medicinaregatan 9C, Gothenburg 405 30, Sweden
| | - Susann Teneberg
- Department of Medical Biochemistry and Cell Biology, Institute of Biomedicine, Sahlgrenska Academy, University of Gothenburg, Box 440, Medicinaregatan 9C, Gothenburg 405 30, Sweden
| | - Sara K Lindén
- Department of Medical Biochemistry and Cell Biology, Institute of Biomedicine, Sahlgrenska Academy, University of Gothenburg, Box 440, Medicinaregatan 9C, Gothenburg 405 30, Sweden
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18
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Zhou S, Zheng Z, Wang L, Song W, Xia Y, Shao L, Liang X. Correlation of FUT3 and FUT6 Gene Polymorphisms With Helicobacter pylori Infection. Helicobacter 2024; 29:e13122. [PMID: 39108208 DOI: 10.1111/hel.13122] [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: 06/11/2024] [Revised: 07/24/2024] [Accepted: 07/25/2024] [Indexed: 09/17/2024]
Abstract
BACKGROUND Helicobacter pylori infection is a significant pathogen in gastrointestinal diseases. Previous studies have identified single-nucleotide polymorphisms (SNPs) are factors associated with H. pylori infection. Notably, Leb and Sialyl-Lex antigens, regulated by the FUT3 and FUT6 genes, play a crucial role in H. pylori infection. This study aimed to investigate the correlation between FUT3 and FUT6 gene polymorphisms and H. pylori infection in the Han population of northern China. MATERIALS AND METHODS An immunoturbidimetric assay was employed to detect H. pylori infection, categorizing subjects into infected and noninfected groups. Gene variants were identified through sequencing. Finally, FUT3 and FUT6 gene polymorphisms were analyzed to assess their association with H. pylori infection. RESULTS The frequency of the T allele (rs778805) and the G allele (rs61147939) in the infection group was significantly higher than that in the noninfection group (63.4% vs. 55.1%, p = 0.045; 55.2% vs. 47.0%, p = 0.042, respectively). In the infection group, the frequency of the AA genotype (rs3745635) in the recessive model, the TT genotype (rs778805) in the recessive model, and the GG genotype (rs61147939) in the recessive model were significantly higher than the noninfection group (5.8% vs. 2.3%, p = 0.042; 41.9% vs. 29.3%, p = 0.022; 34.9% vs. 20.5%, p = 0.0068, respectively). The frequency of the A13 haplotype and the A13/A13 diplotype of the FUT6 gene was significantly higher in the infection group than in the noninfection group (55.56% vs. 46.32%, p = 0.019; 34.94% vs. 20.30%, p = 0.045, respectively). The rs778805-rs17855739-rs28362459-rs3745635 combination was identified as the best interaction model (p < 0.05). CONCLUSIONS This study suggests that FUT3 and FUT6 gene polymorphisms are significantly associated with H. pylori infection in the Han Chinese from northern China.
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Affiliation(s)
| | - Ziwei Zheng
- College of Laboratory Medicine, Dalian Medical University, Dalian, China
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Tohumcu E, Kaitsas F, Bricca L, Ruggeri A, Gasbarrini A, Cammarota G, Ianiro G. Helicobacter pylori and the Human Gastrointestinal Microbiota: A Multifaceted Relationship. Antibiotics (Basel) 2024; 13:584. [PMID: 39061266 PMCID: PMC11274338 DOI: 10.3390/antibiotics13070584] [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: 05/17/2024] [Revised: 06/17/2024] [Accepted: 06/20/2024] [Indexed: 07/28/2024] Open
Abstract
Helicobacter pylori is a type of Gram-negative bacteria belonging to the Proteobacteria phylum which is known to cause gastrointestinal disorders such as gastritis and gastric ulcers. Its treatment is based on current eradication regimens, which are composed of combinations of antibiotics such as clarithromycin, metronidazole, levofloxacin and amoxicillin, often combined with a proton pump inhibitor (PPI). With the development of sequencing technologies, it has been demonstrated that not only does the colonization of the gastric and gut environment by H. pylori cause microbial changes, but also the treatment regimens used for its eradication have a significant altering effect on both the gastric and gut microbiota. Here, we review current knowledge on microbiota modulations of current therapies in both environments. We also summarize future perspectives regarding H. pylori infection, the integration of probiotics into therapy and what challenges are being faced on a global basis when we talk about eradication.
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Affiliation(s)
- Ege Tohumcu
- Department of Translational Medicine and Surgery, Università Cattolica del Sacro Cuore, Largo A. Gemelli 8, 00168 Rome, Italy; (E.T.); (F.K.); (A.R.); (A.G.); (G.C.)
- Department of Medical and Surgical Sciences, UOC Gastroenterologia, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, 00168 Rome, Italy
- Department of Medical and Surgical Sciences, UOC CEMAD Centro Malattie dell’Apparato Digerente, Medicina Interna e Gastroenterologia, Fondazione Policlinico Universitario Gemelli IRCCS, 00168 Rome, Italy
| | - Francesco Kaitsas
- Department of Translational Medicine and Surgery, Università Cattolica del Sacro Cuore, Largo A. Gemelli 8, 00168 Rome, Italy; (E.T.); (F.K.); (A.R.); (A.G.); (G.C.)
- Department of Medical and Surgical Sciences, UOC Gastroenterologia, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, 00168 Rome, Italy
- Department of Medical and Surgical Sciences, UOC CEMAD Centro Malattie dell’Apparato Digerente, Medicina Interna e Gastroenterologia, Fondazione Policlinico Universitario Gemelli IRCCS, 00168 Rome, Italy
| | - Ludovica Bricca
- Department of Surgical, Oncological and Gastroenterological Sciences (DiSCOG), Padua Univeristy, 35123 Padova, Italy;
| | - Alessandro Ruggeri
- Department of Translational Medicine and Surgery, Università Cattolica del Sacro Cuore, Largo A. Gemelli 8, 00168 Rome, Italy; (E.T.); (F.K.); (A.R.); (A.G.); (G.C.)
- Department of Medical and Surgical Sciences, UOC Gastroenterologia, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, 00168 Rome, Italy
- Department of Medical and Surgical Sciences, UOC CEMAD Centro Malattie dell’Apparato Digerente, Medicina Interna e Gastroenterologia, Fondazione Policlinico Universitario Gemelli IRCCS, 00168 Rome, Italy
| | - Antonio Gasbarrini
- Department of Translational Medicine and Surgery, Università Cattolica del Sacro Cuore, Largo A. Gemelli 8, 00168 Rome, Italy; (E.T.); (F.K.); (A.R.); (A.G.); (G.C.)
- Department of Medical and Surgical Sciences, UOC Gastroenterologia, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, 00168 Rome, Italy
- Department of Medical and Surgical Sciences, UOC CEMAD Centro Malattie dell’Apparato Digerente, Medicina Interna e Gastroenterologia, Fondazione Policlinico Universitario Gemelli IRCCS, 00168 Rome, Italy
| | - Giovanni Cammarota
- Department of Translational Medicine and Surgery, Università Cattolica del Sacro Cuore, Largo A. Gemelli 8, 00168 Rome, Italy; (E.T.); (F.K.); (A.R.); (A.G.); (G.C.)
- Department of Medical and Surgical Sciences, UOC Gastroenterologia, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, 00168 Rome, Italy
- Department of Medical and Surgical Sciences, UOC CEMAD Centro Malattie dell’Apparato Digerente, Medicina Interna e Gastroenterologia, Fondazione Policlinico Universitario Gemelli IRCCS, 00168 Rome, Italy
| | - Gianluca Ianiro
- Department of Translational Medicine and Surgery, Università Cattolica del Sacro Cuore, Largo A. Gemelli 8, 00168 Rome, Italy; (E.T.); (F.K.); (A.R.); (A.G.); (G.C.)
- Department of Medical and Surgical Sciences, UOC Gastroenterologia, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, 00168 Rome, Italy
- Department of Medical and Surgical Sciences, UOC CEMAD Centro Malattie dell’Apparato Digerente, Medicina Interna e Gastroenterologia, Fondazione Policlinico Universitario Gemelli IRCCS, 00168 Rome, Italy
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Åberg A, Gideonsson P, Bhat A, Ghosh P, Arnqvist A. Molecular insights into the fine-tuning of pH-dependent ArsR-mediated regulation of the SabA adhesin in Helicobacter pylori. Nucleic Acids Res 2024; 52:5572-5595. [PMID: 38499492 PMCID: PMC11162790 DOI: 10.1093/nar/gkae188] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2023] [Revised: 02/28/2024] [Accepted: 03/12/2024] [Indexed: 03/20/2024] Open
Abstract
Adaptation to variations in pH is crucial for the ability of Helicobacter pylori to persist in the human stomach. The acid responsive two-component system ArsRS, constitutes the global regulon that responds to acidic conditions, but molecular details of how transcription is affected by the ArsR response regulator remains poorly understood. Using a combination of DNA-binding studies, in vitro transcription assays, and H. pylori mutants, we demonstrate that phosphorylated ArsR (ArsR-P) forms an active protein complex that binds DNA with high specificity in order to affect transcription. Our data showed that DNA topology is key for DNA binding. We found that AT-rich DNA sequences direct ArsR-P to specific sites and that DNA-bending proteins are important for the effect of ArsR-P on transcription regulation. The repression of sabA transcription is mediated by ArsR-P with the support of Hup and is affected by simple sequence repeats located upstream of the sabA promoter. Here stochastic events clearly contribute to the fine-tuning of pH-dependent gene regulation. Our results reveal important molecular aspects for how ArsR-P acts to repress transcription in response to acidic conditions. Such transcriptional control likely mediates shifts in bacterial positioning in the gastric mucus layer.
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Affiliation(s)
- Anna Åberg
- Department of Medical Biochemistry and Biophysics, Umeå University, SE-90187 Umeå, Sweden
| | - Pär Gideonsson
- Department of Medical Biochemistry and Biophysics, Umeå University, SE-90187 Umeå, Sweden
| | - Abhayprasad Bhat
- Department of Medical Biochemistry and Biophysics, Umeå University, SE-90187 Umeå, Sweden
| | - Prachetash Ghosh
- Department of Medical Biochemistry and Biophysics, Umeå University, SE-90187 Umeå, Sweden
| | - Anna Arnqvist
- Department of Medical Biochemistry and Biophysics, Umeå University, SE-90187 Umeå, Sweden
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Druffner SR, Venkateshwaraprabu S, Khadka S, Duncan BC, Morris MT, Sen-Kilic E, Damron FH, Liechti GW, Busada JT. Comparison of gastric inflammation and metaplasia induced by Helicobacter pylori or Helicobacter felis colonization in mice. Microbiol Spectr 2024; 12:e0001524. [PMID: 38682907 PMCID: PMC11237807 DOI: 10.1128/spectrum.00015-24] [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: 01/04/2024] [Accepted: 03/18/2024] [Indexed: 05/01/2024] Open
Abstract
Gastric cancer is the fifth most diagnosed cancer in the world. Infection by the bacteria Helicobacter pylori (HP) is associated with approximately 75% of gastric cancer cases. HP infection induces chronic gastric inflammation, damaging the stomach and fostering carcinogenesis. Most mechanistic studies on gastric cancer initiation are performed in mice and utilize either mouse-adapted strains of HP or the natural mouse pathogen Helicobacter felis (HF). Here, we identified the differences in gastric inflammation, atrophy, and metaplasia associated with HP and HF infection in mice. PMSS1 HP strain or the CS1 HF strain were co-cultured with mouse peritoneal macrophages to assess their immunostimulatory effects. HP and HF induced similar cytokine production from cultured mouse peritoneal macrophages revealing that both bacteria exhibit similar immunostimulatory effects in vitro. Next, C57BL/6J mice were infected with HP or HF and were assessed 2 months post-infection. HP-infected mice caused modest inflammation within both the gastric corpus and antrum, and did not induce significant atrophy within the gastric corpus. In contrast, HF induced significant inflammation throughout the gastric corpus and antrum. Moreover, HF infection was associated with significant atrophy of the chief and parietal cell compartments and induced the expression of pyloric metaplasia (PM) markers. HP is poorly immunogenic compared to HF. HF induces dramatic CD4+ T cell activation, which is associated with increased gastric cancer risk in humans. Thus, HP studies in mice are better suited for studies on colonization, while HF is more strongly suited for studies on the effects of gastric inflammation on tumorigenesis. . IMPORTANCE Mouse infection models with Helicobacter species are widely used to study Helicobacter pathogenesis and gastric cancer initiation. However, Helicobacter pylori is not a natural mouse pathogen, and mouse-adapted H. pylori strains are poorly immunogenic. In contrast, Helicobacter felis is a natural mouse pathogen that induces robust gastric inflammation and is often used in mice to investigate gastric cancer initiation. Although both bacterial strains are widely used, their disease pathogenesis in mice differs dramatically. However, few studies have directly compared the pathogenesis of these bacterial species in mice, and the contrasting features of these two models are not clearly defined. This study directly compares the gastric inflammation, atrophy, and metaplasia development triggered by the widely used PMSS1 H. pylori and CS1 H. felis strains in mice. It serves as a useful resource for researchers to select the experimental model best suited for their studies.
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Affiliation(s)
- Sara R. Druffner
- Department of Microbiology, Immunology and Cell Biology, West Virginia University School of Medicine, Morgantown, West Virginia, USA
| | - Shrinidhi Venkateshwaraprabu
- Department of Microbiology, Immunology and Cell Biology, West Virginia University School of Medicine, Morgantown, West Virginia, USA
| | - Stuti Khadka
- Department of Microbiology, Immunology and Cell Biology, West Virginia University School of Medicine, Morgantown, West Virginia, USA
| | - Benjamin C. Duncan
- Department of Microbiology, Immunology and Cell Biology, West Virginia University School of Medicine, Morgantown, West Virginia, USA
| | - Maeve T. Morris
- Department of Microbiology, Immunology and Cell Biology, West Virginia University School of Medicine, Morgantown, West Virginia, USA
| | - Emel Sen-Kilic
- Department of Microbiology, Immunology and Cell Biology, West Virginia University School of Medicine, Morgantown, West Virginia, USA
| | - Fredrick H. Damron
- Department of Microbiology, Immunology and Cell Biology, West Virginia University School of Medicine, Morgantown, West Virginia, USA
| | - George W. Liechti
- Department of Microbiology and Immunology, Uniformed Services University of the Health Sciences, Bethesda, Maryland, USA
| | - Jonathan T. Busada
- Department of Microbiology, Immunology and Cell Biology, West Virginia University School of Medicine, Morgantown, West Virginia, USA
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Santacroce L, Topi S, Bottalico L, Charitos IA, Jirillo E. Current Knowledge about Gastric Microbiota with Special Emphasis on Helicobacter pylori-Related Gastric Conditions. Curr Issues Mol Biol 2024; 46:4991-5009. [PMID: 38785567 PMCID: PMC11119845 DOI: 10.3390/cimb46050299] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2024] [Revised: 05/06/2024] [Accepted: 05/14/2024] [Indexed: 05/25/2024] Open
Abstract
The gastric milieu, because of its very low acidic pH, is very harsh for bacterial growth. The discovery of Helicobacter pylori (H.p.) has opened a new avenue for studies on the gastric microbiota, thus indicating that the stomach is not a sterile environment. Nowadays, new technologies of bacterial identification have demonstrated the existence of other microorganisms in the gastric habitat, which play an important role in health and disease. This bacterium possesses an arsenal of compounds which enable its survival but, at the same time, damage the gastric mucosa. Toxins, such as cytotoxin-associated gene A, vacuolar cytotoxin A, lipopolysaccharides, and adhesins, determine an inflammatory status of the gastric mucosa which may become chronic, ultimately leading to a gastric carcinoma. In the initial stage, H.p. persistence alters the gastric microbiota with a condition of dysbiosis, predisposing to inflammation. Probiotics and prebiotics exhibit beneficial effects on H.p. infection, and, among them, anti-inflammatory, antioxidant, and antibacterial activities are the major ones. Moreover, the association of probiotics with prebiotics (synbiotics) to conventional anti-H.p. therapy contributes to a more efficacious eradication of the bacterium. Also, polyphenols, largely present in the vegetal kingdom, have been demonstrated to alleviate H.p.-dependent pathologies, even including the inhibition of tumorigenesis. The gastric microbiota composition in health and disease is described. Then, cellular and molecular mechanisms of H.p.-mediated damage are clarified. Finally, the use of probiotics, prebiotics, and polyphenols in experimental models and in patients infected with H.p. is discussed.
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Affiliation(s)
- Luigi Santacroce
- Section of Microbiology and Virology, Interdisciplinary Department of Medicine, School of Medicine, University of Bari ‘Aldo Moro’, 70124 Bari, Italy;
| | - Skender Topi
- Department of Clinical Disciplines, University ‘Alexander Xhuvani’ of Elbasan, 3001 Elbasan, Albania; (S.T.)
| | - Lucrezia Bottalico
- Department of Clinical Disciplines, University ‘Alexander Xhuvani’ of Elbasan, 3001 Elbasan, Albania; (S.T.)
| | - Ioannis Alexandros Charitos
- Istituti Clinici Scientifici Maugeri IRCCS, Pneumology and Respiratory Rehabilitation Unit, Institute of Bari, 70124 Bari, Italy;
| | - Emilio Jirillo
- Section of Microbiology and Virology, Interdisciplinary Department of Medicine, School of Medicine, University of Bari ‘Aldo Moro’, 70124 Bari, Italy;
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23
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Sedarat Z, Taylor-Robinson AW. Helicobacter pylori Outer Membrane Proteins and Virulence Factors: Potential Targets for Novel Therapies and Vaccines. Pathogens 2024; 13:392. [PMID: 38787244 PMCID: PMC11124246 DOI: 10.3390/pathogens13050392] [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: 02/26/2024] [Revised: 04/12/2024] [Accepted: 05/07/2024] [Indexed: 05/25/2024] Open
Abstract
Helicobacter pylori is a gastric oncopathogen that infects over half of the world's human population. It is a Gram-negative, microaerophilic, helix-shaped bacterium that is equipped with flagella, which provide high motility. Colonization of the stomach is asymptomatic in up to 90% of people but is a recognized risk factor for developing various gastric disorders such as gastric ulcers, gastric cancer and gastritis. Invasion of the human stomach occurs via numerous virulence factors such as CagA and VacA. Similarly, outer membrane proteins (OMPs) play an important role in H. pylori pathogenicity as a means to adapt to the epithelial environment and thereby facilitate infection. While some OMPs are porins, others are adhesins. The epithelial cell receptors SabA, BabA, AlpA, OipA, HopQ and HopZ have been extensively researched to evaluate their epidemiology, structure, role and genes. Moreover, numerous studies have been performed to seek to understand the complex relationship between these factors and gastric diseases. Associations exist between different H. pylori virulence factors, the co-expression of which appears to boost the pathogenicity of the bacterium. Improved knowledge of OMPs is a major step towards combatting this global disease. Here, we provide a current overview of different H. pylori OMPs and discuss their pathogenicity, epidemiology and correlation with various gastric diseases.
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Affiliation(s)
- Zahra Sedarat
- Cellular & Molecular Research Centre, Shahrekord University of Medical Sciences, Shahrekord 8813833435, Iran;
| | - Andrew W. Taylor-Robinson
- College of Health Sciences, VinUniversity, Gia Lam District, Hanoi 67000, Vietnam
- Center for Global Health, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 1904, USA
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24
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Zhang SZ, Lobo A, Li PF, Zhang YF. Sialylated glycoproteins and sialyltransferases in digestive cancers: Mechanisms, diagnostic biomarkers, and therapeutic targets. Crit Rev Oncol Hematol 2024; 197:104330. [PMID: 38556071 DOI: 10.1016/j.critrevonc.2024.104330] [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: 10/11/2023] [Revised: 03/12/2024] [Accepted: 03/19/2024] [Indexed: 04/02/2024] Open
Abstract
Sialic acid (SA), as the ultimate epitope of polysaccharides, can act as a cap at the end of polysaccharide chains to prevent their overextension. Sialylation is the enzymatic process of transferring SA residues onto polysaccharides and is catalyzed by a group of enzymes known as sialyltransferases (SiaTs). It is noteworthy that the sialylation level of glycoproteins is significantly altered when digestive cancer occurs. And this alteration exhibits a close correlation with the progression of these cancers. In this review, from the perspective of altered SiaTs expression levels and changed glycoprotein sialylation patterns, we summarize the pathogenesis of gastric cancer (GC), colorectal cancer (CRC), pancreatic ductal adenocarcinoma (PDAC), and hepatocellular carcinoma (HCC). Furthermore, we propose potential early diagnostic biomarkers and prognostic indicators for different digestive cancers. Finally, we summarize the therapeutic value of sialylation in digestive system cancers.
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Affiliation(s)
- Shao-Ze Zhang
- Institute for Translational Medicine, The Affiliated Hospital of Qingdao University, College of Medicine, Qingdao University, Qingdao 266021, China
| | - Amara Lobo
- Department of Critical Care Medicine Holy Family Hospital, St Andrew's Road, Bandra (West), Mumbai 400050, India
| | - Pei-Feng Li
- Institute for Translational Medicine, The Affiliated Hospital of Qingdao University, College of Medicine, Qingdao University, Qingdao 266021, China.
| | - Yin-Feng Zhang
- Institute for Translational Medicine, The Affiliated Hospital of Qingdao University, College of Medicine, Qingdao University, Qingdao 266021, China.
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25
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Asmah RH, Archampong T, King G, Eyison B, Teye AK, Adjei C, Amegatcher G, Aidoo EK, Attoh S. Characterization of Helicobacter pylori iceA and babA2 virulence genes in dyspeptic patients at a teaching hospital in Ghana. Pan Afr Med J 2024; 47:204. [PMID: 39247779 PMCID: PMC11380614 DOI: 10.11604/pamj.2024.47.204.39135] [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: 01/31/2023] [Accepted: 02/25/2024] [Indexed: 09/10/2024] Open
Abstract
Introduction Helicobacter pylori (H. pylori) infection is endemic in Africa. It is a major aetiological factor in the development of peptic ulcer disease and distal gastric cancers. Existing data shows that clinical outcomes are dependent on the virulence of the infecting strain, host´s susceptibility, and environmental factors. In Ghana, a previous study showed that the majority of symptomatic individuals harboured cagA and vacA virulent strains. The main objective of this study was to characterize and assess the significance of other virulence factors, specifically iceA and babA2 in Ghana. Methods H. pylori iceA and babA2 genes were investigated in dyspeptic patients at the Korle Bu Teaching Hospital (KBTH), Accra, Ghana. The study employed a cross-sectional design consecutively recruiting patients with upper gastrointestinal symptoms for endoscopy. Nucleic acid was extracted from gastric biopsies using a commercial kit (QIAGEN DNeasy tissue kit). H. pylori babA2 and iceA genes were amplified using extracted deoxyribonucleic acid (DNA) and primers by polymerase chain reaction (PCR). Results majority, (71.1%), of the study participants, were H. pylori positive when tested with urease-campylobacter-like organism (CLO). In total, 46 H. pylori urease CLO-positive samples were randomly analyzed by PCR for iceA, of which, 12 (26%) and 7 (15%) were found to have iceA1 and iceA2 respectively. Of the CLO-positive samples, 9 were randomly analysed for babA2 by PCR. Three samples were babA2 positive and 6 were babA2 negative. Conclusion in Ghana, although H. pylori is endemic, iceA prevalence is rather low and probably exerts a limited effect on bacterial virulence. Further evaluation would be required, not only to determine association with other virulence factors but more importantly, inter-relationships with wider host and environmental factors that impact on disease pathogenesis.
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Affiliation(s)
- Richard Harry Asmah
- Department of Biomedical Sciences, School of Basic and Biomedical Sciences, University of Health and Allied Sciences, Ho, Ghana
| | - Timothy Archampong
- Department of Medicine and Therapeutics, University of Ghana Medical School, Accra, Ghana
| | - Gabriel King
- Department of Biomedical Sciences, School of Basic and Biomedical Sciences, University of Health and Allied Sciences, Ho, Ghana
| | - Benjamin Eyison
- Department of Medical Laboratory Sciences, School of Biomedical and Allied Health Sciences, University of Ghana, Accra, Ghana
| | - Andrew Kwablah Teye
- Department of Medical Laboratory Sciences, School of Biomedical and Allied Health Sciences, University of Ghana, Accra, Ghana
| | - Christopher Adjei
- Department of Biomedical Sciences, School of Basic and Biomedical Sciences, University of Health and Allied Sciences, Ho, Ghana
| | - Gloria Amegatcher
- Department of Medical Laboratory Sciences, School of Biomedical and Allied Health Sciences, University of Ghana, Accra, Ghana
| | | | - Seth Attoh
- Division of Pathology, Military Hospital, Accra, Ghana
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26
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Sijmons D, Collett S, Soliman C, Guy AJ, Scott AM, Durrant LG, Elbourne A, Walduck AK, Ramsland PA. Probing the expression and adhesion of glycans involved in Helicobacter pylori infection. Sci Rep 2024; 14:8587. [PMID: 38615147 PMCID: PMC11016089 DOI: 10.1038/s41598-024-59234-w] [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: 12/19/2023] [Accepted: 04/08/2024] [Indexed: 04/15/2024] Open
Abstract
Helicobacter pylori infects approximately half the human population and has an unusual infective niche of the human stomach. Helicobacter pylori is a major cause of gastritis and has been classified as a group 1 carcinogen by the WHO. Treatment involves triple or quadruple antibiotic therapy, but antibiotic resistance is becoming increasingly prevalent. Helicobacter pylori expresses certain blood group related antigens (Lewis system) as a part of its lipopolysaccharide (LPS), which is thought to assist in immune evasion. Additionally, H. pylori LPS participates in adhesion to host cells alongside several adhesion proteins. This study profiled the carbohydrates of H. pylori reference strains (SS1 and 26695) using monoclonal antibodies (mAbs) and lectins, identifying interactions between two carbohydrate-targeting mAbs and multiple lectins. Atomic force microscopy (AFM) scans were used to probe lectin and antibody interactions with the bacterial surfaces. The selected mAb and lectins displayed an increased adhesive force over the surface of the curved H. pylori rods. Furthermore, this study demonstrates the ability of anti-carbohydrate antibodies to reduce the adhesion of H. pylori 26695 to human gastric adenocarcinoma cells via AFM. Targeting bacterial carbohydrates to disrupt crucial adhesion and immune evasion mechanisms represents a promising strategy for combating H. pylori infection.
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Affiliation(s)
- Daniel Sijmons
- School of Science, RMIT University, Melbourne, VIC, 3000, Australia
| | - Simon Collett
- School of Science, RMIT University, Melbourne, VIC, 3000, Australia
- Department of Paediatrics, The University of Melbourne, Parkville, VIC, 3010, Australia
| | - Caroline Soliman
- School of Science, RMIT University, Melbourne, VIC, 3000, Australia
- Department of Microbiology and Immunology, Peter Doherty Institute for Infection and Immunity, The University of Melbourne, Melbourne, VIC, 3000, Australia
| | - Andrew J Guy
- School of Science, RMIT University, Melbourne, VIC, 3000, Australia
- ZiP Diagnostics, Collingwood, VIC, 3066, Australia
| | - Andrew M Scott
- Olivia Newton-John Cancer Research Institute and School of Cancer Medicine, La Trobe University, Melbourne, VIC, Australia
- Department of Molecular Imaging and Therapy, Austin Health and Faculty of Medicine, The University of Melbourne, Melbourne, VIC, Australia
| | - Lindy G Durrant
- Scancell Limited, University of Nottingham Biodiscovery Institute, Nottingham, UK
- Division of Cancer and Stem Cells, School of Medicine, University of Nottingham Biodiscovery Institute, Nottingham, UK
| | - Aaron Elbourne
- School of Science, RMIT University, Melbourne, VIC, 3000, Australia
| | - Anna K Walduck
- School of Science, RMIT University, Melbourne, VIC, 3000, Australia.
- Rural Health Research Institute, Charles Sturt University, Orange, NSW, 2800, Australia.
| | - Paul A Ramsland
- School of Science, RMIT University, Melbourne, VIC, 3000, Australia.
- Department of Immunology, Monash University, Melbourne, VIC, 3004, Australia.
- Department of Surgery, Austin Health, The University of Melbourne, Heidelberg, VIC, 3084, Australia.
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27
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Bhattacharjee A, Sahoo OS, Sarkar A, Bhattacharya S, Chowdhury R, Kar S, Mukherjee O. Infiltration to infection: key virulence players of Helicobacter pylori pathogenicity. Infection 2024; 52:345-384. [PMID: 38270780 DOI: 10.1007/s15010-023-02159-9] [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: 09/08/2023] [Accepted: 12/13/2023] [Indexed: 01/26/2024]
Abstract
PURPOSE This study aims to comprehensively review the multifaceted factors underlying the successful colonization and infection process of Helicobacter pylori (H. pylori), a prominent Gram-negative pathogen in humans. The focus is on elucidating the functions, mechanisms, genetic regulation, and potential cross-interactions of these elements. METHODS Employing a literature review approach, this study examines the intricate interactions between H. pylori and its host. It delves into virulence factors like VacA, CagA, DupA, Urease, along with phase variable genes, such as babA, babC, hopZ, etc., giving insights about the bacterial perspective of the infection The association of these factors with the infection has also been added in the form of statistical data via Funnel and Forest plots, citing the potential of the virulence and also adding an aspect of geographical biasness to the virulence factors. The biochemical characteristics and clinical relevance of these factors and their effects on host cells are individually examined, both comprehensively and statistically. RESULTS H. pylori is a Gram-negative, spiral bacterium that successfully colonises the stomach of more than half of the world's population, causing peptic ulcers, gastric cancer, MALT lymphoma, and other gastro-duodenal disorders. The clinical outcomes of H. pylori infection are influenced by a complex interplay between virulence factors and phase variable genes produced by the infecting strain and the host genetic background. A meta-analysis of the prevalence of all the major virulence factors has also been appended. CONCLUSION This study illuminates the diverse elements contributing to H. pylori's colonization and infection. The interplay between virulence factors, phase variable genes, and host genetics determines the outcome of the infection. Despite biochemical insights into many factors, their comprehensive regulation remains an understudied area. By offering a panoramic view of these factors and their functions, this study enhances understanding of the bacterium's perspective, i.e. H. pylori's journey from infiltration to successful establishment within the host's stomach.
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Affiliation(s)
- Arghyadeep Bhattacharjee
- Department of Biotechnology, National Institute of Technology Durgapur, Durgapur, West Bengal, 713209, India
- Department of Microbiology, Kingston College of Science, Beruanpukuria, Barasat, West Bengal, 700219, India
| | - Om Saswat Sahoo
- Department of Biotechnology, National Institute of Technology Durgapur, Durgapur, West Bengal, 713209, India
| | - Ahana Sarkar
- Department of Biotechnology, National Institute of Technology Durgapur, Durgapur, West Bengal, 713209, India
| | - Saurabh Bhattacharya
- Department of Microbiology and Molecular Genetics, Institute for Medical Research Israel-Canada, The Hebrew University-Hadassah Medical School, The Hebrew University of Jerusalem, P.O.B. 12272, 9112001, Jerusalem, Israel
| | - Rukhsana Chowdhury
- School of Biological Sciences, RKM Vivekananda Educational and Research Institute Narendrapur, Kolkata, India
| | - Samarjit Kar
- Department of Mathematics, National Institute of Technology Durgapur, Durgapur, West Bengal, 713209, India
| | - Oindrilla Mukherjee
- Department of Biotechnology, National Institute of Technology Durgapur, Durgapur, West Bengal, 713209, India.
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Dyankov G, Eftimov T, Hikova E, Najdenski H, Kussovski V, Genova-Kalou P, Mankov V, Kisov H, Veselinov P, Ghaffari SS, Kovacheva-Slavova M, Vladimirov B, Malinowski N. SPR and Double Resonance LPG Biosensors for Helicobacter pylori BabA Antigen Detection. SENSORS (BASEL, SWITZERLAND) 2024; 24:2118. [PMID: 38610328 PMCID: PMC11014364 DOI: 10.3390/s24072118] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/04/2024] [Revised: 03/14/2024] [Accepted: 03/24/2024] [Indexed: 04/14/2024]
Abstract
Given the medical and social significance of Helicobacter pylori infection, timely and reliable diagnosis of the disease is required. The traditional invasive and non-invasive conventional diagnostic techniques have several limitations. Recently, opportunities for new diagnostic methods have appeared based on the recent advance in the study of H. pylori outer membrane proteins and their identified receptors. In the present study we assess the way in which outer membrane protein-cell receptor reactions are applicable in establishing a reliable diagnosis. Herein, as well as in other previous studies of ours, we explore the reliability of the binding reaction between the best characterized H. pylori adhesin BabA and its receptor, the blood antigen Leb. For the purpose we developed surface plasmon resonance (SPR) and double resonance long period grating (DR LPG) biosensors based on the BabA-Leb binding reaction for diagnosing H. pylori infection. In SPR detection, the sensitivity was estimated at 3000 CFU/mL-a much higher sensitivity than that of the RUT test. The DR LPG biosensor proved to be superior in terms of accuracy and sensitivity-concentrations as low as 102 CFU/mL were detected.
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Affiliation(s)
- Georgi Dyankov
- Institute of Optical Materials and Technologies “Acad. J. Malinowski” (IOMT), Bulgarian Academy of Sciences (BAS), 109 “Acad. G. Bonchev” Str., 1113 Sofia, Bulgaria; (G.D.); (V.M.); (H.K.); (P.V.); (N.M.)
- Central Laboratory of Applied Physics, Bulgarian Academy of Sciences, 61 Sankt Petersburg Blvd., 4000 Plovdiv, Bulgaria;
| | - Tinko Eftimov
- Central Laboratory of Applied Physics, Bulgarian Academy of Sciences, 61 Sankt Petersburg Blvd., 4000 Plovdiv, Bulgaria;
- Photonics Research Center, Université du Québec en Outaouais, Rue 101 St-Jean Bosco, Gatineau, QC J8X 3G5, Canada;
| | - Evdokiya Hikova
- Institute of Optical Materials and Technologies “Acad. J. Malinowski” (IOMT), Bulgarian Academy of Sciences (BAS), 109 “Acad. G. Bonchev” Str., 1113 Sofia, Bulgaria; (G.D.); (V.M.); (H.K.); (P.V.); (N.M.)
| | - Hristo Najdenski
- The Stephan Angeloff Institute of Microbiology, Bulgarian Academy of Sciences, 26 Acad. G. Bonchev Str., 1113 Sofia, Bulgaria; (H.N.); (V.K.)
| | - Vesselin Kussovski
- The Stephan Angeloff Institute of Microbiology, Bulgarian Academy of Sciences, 26 Acad. G. Bonchev Str., 1113 Sofia, Bulgaria; (H.N.); (V.K.)
| | - Petia Genova-Kalou
- National Center of Infectious and Parasitic Diseases, 44A “Gen. Stoletov” Blvd., 1233 Sofia, Bulgaria;
| | - Vihar Mankov
- Institute of Optical Materials and Technologies “Acad. J. Malinowski” (IOMT), Bulgarian Academy of Sciences (BAS), 109 “Acad. G. Bonchev” Str., 1113 Sofia, Bulgaria; (G.D.); (V.M.); (H.K.); (P.V.); (N.M.)
| | - Hristo Kisov
- Institute of Optical Materials and Technologies “Acad. J. Malinowski” (IOMT), Bulgarian Academy of Sciences (BAS), 109 “Acad. G. Bonchev” Str., 1113 Sofia, Bulgaria; (G.D.); (V.M.); (H.K.); (P.V.); (N.M.)
- Central Laboratory of Applied Physics, Bulgarian Academy of Sciences, 61 Sankt Petersburg Blvd., 4000 Plovdiv, Bulgaria;
| | - Petar Veselinov
- Institute of Optical Materials and Technologies “Acad. J. Malinowski” (IOMT), Bulgarian Academy of Sciences (BAS), 109 “Acad. G. Bonchev” Str., 1113 Sofia, Bulgaria; (G.D.); (V.M.); (H.K.); (P.V.); (N.M.)
| | - Sanaz Shoar Ghaffari
- Photonics Research Center, Université du Québec en Outaouais, Rue 101 St-Jean Bosco, Gatineau, QC J8X 3G5, Canada;
- Department of Electrical and Computer Engineering, University of Alberta, 116 St & 85 Ave, Edmonton, AB T6G 2R3, Canada
| | - Mila Kovacheva-Slavova
- Department of Gastroenterology, University Hospital Tsaritsa Ioanna-ISUL, Medical University Sofia, 8 “Byalo More” Str., 1527 Sofia, Bulgaria; (M.K.-S.); (B.V.)
| | - Borislav Vladimirov
- Department of Gastroenterology, University Hospital Tsaritsa Ioanna-ISUL, Medical University Sofia, 8 “Byalo More” Str., 1527 Sofia, Bulgaria; (M.K.-S.); (B.V.)
| | - Nikola Malinowski
- Institute of Optical Materials and Technologies “Acad. J. Malinowski” (IOMT), Bulgarian Academy of Sciences (BAS), 109 “Acad. G. Bonchev” Str., 1113 Sofia, Bulgaria; (G.D.); (V.M.); (H.K.); (P.V.); (N.M.)
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Zaman T, Haq A, Ahmad R, Sinha S, Chowdhury K, Parvin S, Imran M, Humayra ZU, Kumar S, Haque M. The Role of Probiotics in the Eradication of Helicobacter pylori and Overall Impact on Management of Peptic Ulcer: A Study Involving Patients Undergoing Triple Therapy in Bangladesh. Cureus 2024; 16:e56283. [PMID: 38495972 PMCID: PMC10944298 DOI: 10.7759/cureus.56283] [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] [Accepted: 03/16/2024] [Indexed: 03/19/2024] Open
Abstract
Background Helicobacter pylori infection has been identified to cause constantly recurring inflammation, leading to gastrointestinal tract disorders, including carcinoma. The standard triple therapy (STT), used to eradicate H. pylori, includes two antimicrobials and a proton pump inhibitor for two weeks. Other drug regimens have also been developed since H. pylori exhibits antimicrobial resistance. These regimens, including probiotics, have been shown to lower adverse drug reactions (ADR), improve drug adherence, exert bacteriostatic effect, and reduce inflammation. Objective This study intended to explore probiotic intervention for improving eradication rates and mitigating adverse effects while administrating STT. Methods This prospective study was conducted from May to December, 2021, in the Department of Gastroenterology of Ship International Hospital, Dhaka, Bangladesh, to observe the effects of probiotics inclusion along with STT on H. pylori eradication. A total of 100 patients aged ≥18 years who tested positive for H. pylori were included. The experimental group (n=50) was given STT and probiotics, and the control group (n=50) was given only STT without probiotics for 14 days. Necessary follow-up was done six weeks after treatment. An independent sample t-test, chi-square test, and multiple regression analysis were used for statistical analysis. Result The odds of getting rapid urease test (RUT) negative results from positive were 2.06 times higher (95%CI= 0.95, 3.22, p=0.054) in the experimental group. ADRs were crucially towering in the control group (p=0.045) compared to the probiotics group. The probiotics group had a lower risk of having adverse effects by 0.54 times (95%CI=0.19, 0.84, p=0.032) than the control group. Conclusion Using probiotics and STT together to eradicate H. pylori may lower ADR and improve treatment adherence. It may also help terminate H. pylori infection more effectively. More research is required as H. pylori is very contagious and can ultimately cause life-threatening gastric cancer.
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Affiliation(s)
- Taslima Zaman
- Department of Gastroenterology, United Hospital Ltd, Dhaka, BGD
| | - Ahsanul Haq
- Department of Biostatistics, RNA Biotech Limited, Dhaka, BGD
| | - Rahnuma Ahmad
- Department of Physiology, Medical College for Women & Hospital, Dhaka, BGD
| | - Susmita Sinha
- Department of Physiology, Khulna City Medical College and Hospital, Khulna, BGD
| | - Kona Chowdhury
- Department of Pediatrics, Gonoshasthaya Samaj Vittik Medical College, Dhaka, BGD
| | - Sultana Parvin
- Department of Medical Gastroenterology, Sheikh Russel National Gastroliver Institute & Hospital, Dhaka, BGD
| | - Mostofa Imran
- Department of Gastroenterology, Ibn Sina Medical College & Hospital, Dhaka, BGD
| | - Zaman U Humayra
- Department of Plastic and Reconstructive Surgery, Ship International Hospital, Dhaka, BGD
| | - Santosh Kumar
- Department of Periodontology and Implantology, Karnavati School of Dentistry, Karnavati University, Gandhinagar, IND
| | - Mainul Haque
- Karnavati Scientific Research Center (KSRC), Karnavati School of Dentistry, Karnavati University, Gandhinagar, IND
- Unit of Pharmacology and Therapeutics, National Defence University of Malaysia, Kuala Lumpur, MYS
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Engelsberger V, Gerhard M, Mejías-Luque R. Effects of Helicobacter pylori infection on intestinal microbiota, immunity and colorectal cancer risk. Front Cell Infect Microbiol 2024; 14:1339750. [PMID: 38343887 PMCID: PMC10853882 DOI: 10.3389/fcimb.2024.1339750] [Citation(s) in RCA: 22] [Impact Index Per Article: 22.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2023] [Accepted: 01/10/2024] [Indexed: 02/15/2024] Open
Abstract
Infecting about half of the world´s population, Helicobacter pylori is one of the most prevalent bacterial infections worldwide and the strongest known risk factor for gastric cancer. Although H. pylori colonizes exclusively the gastric epithelium, the infection has also been associated with various extragastric diseases, including colorectal cancer (CRC). Epidemiological studies reported an almost two-fold increased risk for infected individuals to develop CRC, but only recently, direct causal and functional links between the chronic infection and CRC have been revealed. Besides modulating the host intestinal immune response, H. pylori is thought to increase CRC risk by inducing gut microbiota alterations. It is known that H. pylori infection not only impacts the gastric microbiota at the site of infection but also leads to changes in bacterial colonization in the distal large intestine. Considering that the gut microbiome plays a driving role in CRC, H. pylori infection emerges as a key factor responsible for promoting changes in microbiome signatures that could contribute to tumor development. Within this review, we want to focus on the interplay between H. pylori infection, changes in the intestinal microbiota, and intestinal immunity. In addition, the effects of H. pylori antibiotic eradication therapy will be discussed.
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Affiliation(s)
| | | | - Raquel Mejías-Luque
- Institute for Medical Microbiology, Immunology and Hygiene, TUM School of Medicine and Health, Department Preclinical Medicine, Technical University of Munich, Munich, Germany
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Druffner SR, Venkateshwaraprabu S, Khadka S, Duncan BC, Morris MT, Sen-Kilic E, Damron FH, Liechti GW, Busada JT. Comparison of gastric inflammation and metaplasia induced by Helicobacter pylori or Helicobacter felis colonization in mice. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2023:2023.12.22.573128. [PMID: 38187587 PMCID: PMC10769338 DOI: 10.1101/2023.12.22.573128] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/09/2024]
Abstract
Background Gastric cancer is the fifth most diagnosed cancer in the world. Infection by the bacteria Helicobacter pylori (HP) is associated with approximately 75% of gastric cancer cases. HP infection induces chronic gastric inflammation, damaging the stomach and fostering carcinogenesis. Most mechanistic studies on Helicobacter- induced gastric cancer initiation are performed in mice and utilize either mouse-adapted strains of HP or the natural mouse pathogen Helicobacter felis (HF). Each of these infection models is associated with strengths and weaknesses. Here, we identified the differences in immunogenicity and gastric pathological changes associated with HP and HF infection in mice. Material and Methods PMSS1 HP strain or with the CS1 HF strain were co-cultured with mouse peritoneal macrophages to assess their immunostimulatory effects. C57BL/6J mice were infected with HP or HF, and gastric inflammation, atrophy, and metaplasia development were assessed 2 months post-infection. Results HP and HF induced similar cytokine production from cultured mouse peritoneal macrophages. HP-infected mice caused modest inflammation within both the gastric corpus and antrum and did not induce significant atrophy within the gastric corpus. In contrast, HF induced significant inflammation throughout the gastric corpus and antrum. Moreover, HF infection was associated with significant atrophy of the chief and parietal cell compartments and induced expression of pyloric metaplasia markers. Conclusions HP is poorly immunogenic compared to HF. HF induces dramatic CD4+ T cell activation, which is associated with increased gastric cancer risk in humans. Thus, HP studies in mice are better suited for studies on colonization, while HF is more strongly suited for pathogenesis and cancer initiation studies.
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Cai J, Wu H, Wang C, Chen Y, Zhang D, Guan S, Fu B, Jin Y, Qian C. Sec1 regulates intestinal mucosal immunity in a mouse model of inflammatory bowel disease. BMC Immunol 2023; 24:51. [PMID: 38066482 PMCID: PMC10704666 DOI: 10.1186/s12865-023-00578-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2023] [Accepted: 10/16/2023] [Indexed: 12/18/2023] Open
Abstract
Inflammatory bowel disease (IBD) is a common immune-mediated condition with its molecular pathogenesis remaining to be fully elucidated. This study aimed to deepen our understanding of the role of FUT2 in human IBD, by studying a new surrogate gene Sec1, a neighboring gene of Fut2 and Fut1 that co-encodes the α 1,2 fucosyltransferase in mice. CRISPR/Cas9 was used to prepare Sec1 knockout (Sec1-/-) mice. IBD was induced in mice using 3% w/v dextran sulphate sodium. Small interfering RNA (siRNA) was employed to silence Sec1 in murine colon cancer cell lines CT26.WT and CMT93. IBD-related symptoms, colonic immune responses, proliferation and apoptosis of colon epithelial cells were assessed respectively to determine the role of Sec1 in mouse IBD. Impact of Sec1 on the expression of death receptor 5 (DR5) and other apoptosis-associated proteins were determined. Sec1 knockout was found to be associated with deterioration of IBD in mice and elevated immune responses in the colonic mucosa. Silencing Sec1 in CT26.WT and CMT93 cells led to greater secretion of inflammatory cytokines IL-1β, IL-6 and TNF-α. Cell counting kit 8 (CCK8) assay, flow cytometry and TUNEL detection suggested that Sec1 expression promoted the proliferation of colon epithelial cells, inhibited cell apoptosis, reduced cell arrest in G0/G1 phase and facilitated repair of inflammatory injury. Over-expression of DR5 and several apoptosis-related effector proteins was noticed in Sec1-/- mice and Sec1-silenced CT26.WT and CMT93 cells, supporting a suppressive role of Sec1 in cell apoptosis. Our results depicted important regulatory roles of Sec1 in mouse IBD, further reflecting the importance of FUT2 in the pathogenesis of human IBD.
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Affiliation(s)
- Jing Cai
- Department of Gastroenterology, Sir Run Run Shaw Hospital, College of Medicine, Zhejiang University, Hangzhou, 310016, China
- Inflammatory Bowel Disease Center, Sir Run Run Shaw Hospital, College of Medicine, Zhejiang University, Hangzhou, 310016, China
- Department of Comprehensive Medicine, The Second, Wenzhou Central Hospital Medical Group, Affiliated Hospital of Shanghai University, Affiliated Dingli Clinical Institute of Wenzhou Medical University, Wenzhou, 325000, China
| | - Hao Wu
- Department of Gastroenterology, The Second Affiliated Hospital, Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, 325000, Zhejiang, China.
| | - Chenxing Wang
- Department of Gastroenterology, The Second Affiliated Hospital, Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, 325000, Zhejiang, China
| | - Yujiao Chen
- Department of Gastroenterology, The Second Affiliated Hospital, Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, 325000, Zhejiang, China
| | - Dingli Zhang
- Department of Gastroenterology, The Second Affiliated Hospital, Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, 325000, Zhejiang, China
| | - Shiwei Guan
- Department of Hepatobiliary Surgery, Wenzhou Central Hospital, The Dingli Clinical Institute of Wenzhou Medical University, Wenzhou, 325000, Zhejiang, P.R. China
| | - Beilei Fu
- Department of Gastroenterology, The Second Affiliated Hospital, Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, 325000, Zhejiang, China
| | - Yingli Jin
- Department of Gastroenterology, The Second Affiliated Hospital, Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, 325000, Zhejiang, China
| | - Cao Qian
- Department of Gastroenterology, Sir Run Run Shaw Hospital, College of Medicine, Zhejiang University, Hangzhou, 310016, China.
- Inflammatory Bowel Disease Center, Sir Run Run Shaw Hospital, College of Medicine, Zhejiang University, Hangzhou, 310016, China.
- Institute of Gastroenterology, Zhejiang University, Hangzhou, 310016, Zhejiang, China.
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Hulbert SW, Desai P, Jewett MC, DeLisa MP, Williams AJ. Glycovaccinology: The design and engineering of carbohydrate-based vaccine components. Biotechnol Adv 2023; 68:108234. [PMID: 37558188 DOI: 10.1016/j.biotechadv.2023.108234] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2023] [Revised: 07/12/2023] [Accepted: 08/05/2023] [Indexed: 08/11/2023]
Abstract
Vaccines remain one of the most important pillars in preventative medicine, providing protection against a wide array of diseases by inducing humoral and/or cellular immunity. Of the many possible candidate antigens for subunit vaccine development, carbohydrates are particularly appealing because of their ubiquitous presence on the surface of all living cells, viruses, and parasites as well as their known interactions with both innate and adaptive immune cells. Indeed, several licensed vaccines leverage bacterial cell-surface carbohydrates as antigens for inducing antigen-specific plasma cells secreting protective antibodies and the development of memory T and B cells. Carbohydrates have also garnered attention in other aspects of vaccine development, for example, as adjuvants that enhance the immune response by either activating innate immune responses or targeting specific immune cells. Additionally, carbohydrates can function as immunomodulators that dampen undesired humoral immune responses to entire protein antigens or specific, conserved regions on antigenic proteins. In this review, we highlight how the interplay between carbohydrates and the adaptive and innate arms of the immune response is guiding the development of glycans as vaccine components that act as antigens, adjuvants, and immunomodulators. We also discuss how advances in the field of synthetic glycobiology are enabling the design, engineering, and production of this new generation of carbohydrate-containing vaccine formulations with the potential to prevent infectious diseases, malignancies, and complex immune disorders.
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Affiliation(s)
- Sophia W Hulbert
- Biochemistry, Molecular and Cell Biology, Cornell University, Ithaca, NY 14853, USA
| | - Primit Desai
- Biochemistry, Molecular and Cell Biology, Cornell University, Ithaca, NY 14853, USA
| | - Michael C Jewett
- Department of Bioengineering, Stanford University, Stanford, CA 94305, USA
| | - Matthew P DeLisa
- Biochemistry, Molecular and Cell Biology, Cornell University, Ithaca, NY 14853, USA; Robert F. Smith School of Chemical and Biomolecular Engineering, Cornell University, Ithaca, NY 14853, USA; Cornell Institute of Biotechnology, Cornell University, Ithaca, NY 14853, USA.
| | - Asher J Williams
- Robert F. Smith School of Chemical and Biomolecular Engineering, Cornell University, Ithaca, NY 14853, USA; Department of Chemical Engineering, Columbia University, New York, NY 10027, USA.
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34
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Wang Y, Han W, Wang N, Han M, Ban M, Dai J, Dong Y, Sun T, Xu J. The role of microbiota in the development and treatment of gastric cancer. Front Oncol 2023; 13:1224669. [PMID: 37841431 PMCID: PMC10572359 DOI: 10.3389/fonc.2023.1224669] [Citation(s) in RCA: 13] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2023] [Accepted: 08/28/2023] [Indexed: 10/17/2023] Open
Abstract
The stomach was once considered a sterile organ until the discovery of Helicobacter pylori (HP). With the application of high-throughput sequencing technology and macrogenomics, researchers have identified fungi and fivemajor bacterial phyla within the stomachs of healthy individuals. These microbial communities exert regulatory influence over various physiological functions, including energy metabolism and immune responses. HP is a well-recognized risk factor for gastric cancer, significantly altering the stomach's native microecology. Currently, numerous studies are centered on the mechanisms by which HP contributes to gastric cancer development, primarily involving the CagA oncoprotein. However, aside from exogenous infections such as HP and EBV, certain endogenous dysbiosis can also lead to gastric cancer through multiple mechanisms. Additionally, gut microbiota and its metabolites significantly impact the development of gastric cancer. The role of microbial therapies, including diet, phages, probiotics and fecal microbiota transplantation, in treating gastric cancer should not be underestimated. This review aims to study the mechanisms involved in the roles of exogenous pathogen infection and endogenous microbiota dysbiosis in the development of gastric cancer. Also, we describe the application of microbiota therapy in the treatment and prognosis of gastric cancer.
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Affiliation(s)
- Yiwen Wang
- Department of Breast Medicine 1, Cancer Hospital of China Medical University, Liaoning Cancer Hospital, Shenyang, China
- Department of Pharmacology, Cancer Hospital of China Medical University, Liaoning Cancer Hospital, Shenyang, China
| | - Wenjie Han
- Department of Breast Medicine 1, Cancer Hospital of China Medical University, Liaoning Cancer Hospital, Shenyang, China
- Department of Pharmacology, Cancer Hospital of China Medical University, Liaoning Cancer Hospital, Shenyang, China
| | - Na Wang
- Department of Breast Medicine 1, Cancer Hospital of China Medical University, Liaoning Cancer Hospital, Shenyang, China
- Department of Pharmacology, Cancer Hospital of China Medical University, Liaoning Cancer Hospital, Shenyang, China
| | - Mengzhen Han
- Department of Breast Medicine 1, Cancer Hospital of China Medical University, Liaoning Cancer Hospital, Shenyang, China
- Department of Pharmacology, Cancer Hospital of China Medical University, Liaoning Cancer Hospital, Shenyang, China
| | - Meng Ban
- Department of Bioinformatics, Kanghui Biotechnology Co., Ltd., Shenyang, China
| | - Jianying Dai
- School of Bioengineering, Dalian University of Technology, Dalian, Liaoning, China
| | - Yuesheng Dong
- School of Bioengineering, Dalian University of Technology, Dalian, Liaoning, China
| | - Tao Sun
- Department of Breast Medicine 1, Cancer Hospital of China Medical University, Liaoning Cancer Hospital, Shenyang, China
- Department of Oncology Medicine, Key Laboratory of Liaoning Breast Cancer Research, Shenyang, Liaoning, China
| | - Junnan Xu
- Department of Breast Medicine 1, Cancer Hospital of China Medical University, Liaoning Cancer Hospital, Shenyang, China
- Department of Pharmacology, Cancer Hospital of China Medical University, Liaoning Cancer Hospital, Shenyang, China
- Department of Oncology Medicine, Key Laboratory of Liaoning Breast Cancer Research, Shenyang, Liaoning, China
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Gonciarz W, Chyb M, Chmiela M. Diminishing of Helicobacter pylori adhesion to Cavia porcellus gastric epithelial cells by BCG vaccine mycobacteria. Sci Rep 2023; 13:16305. [PMID: 37770504 PMCID: PMC10539345 DOI: 10.1038/s41598-023-43571-3] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2023] [Accepted: 09/26/2023] [Indexed: 09/30/2023] Open
Abstract
Mycobacterium bovis onco-BCG bacilli used in immunotherapy of bladder cancer are candidates for training of immune cells towards microbial pathogens. Increasing antibiotic resistance of gastric pathogen Helicobacter pylori (Hp) prompts the search for new anti-Hp and immunomodulatory formulations. Colonization of gastric mucosa by Hp through mucin 5 AC (MUC5AC) ligands could potentially be a therapeutic target. The aim of this study was to examine the ability of onco-BCG mycobacteria to reduce Hp adhesion to gastric epithelial cells using Cavia porcellus model. Animals were inoculated per os with 0.85% NaCl, Hp alone, onco-BCG alone or with onco-BCG and Hp. After 7/28 days Mucin5AC and Hp binding to gastric epithelium were assessed in gastric tissue specimens by staining with anti-Mucin5AC and anti-Hp antibodies, respectively, both fluorescently labeled. Primary gastric epithelial cells were treated ex vivo with live Hp or Hp surface antigens (glycine extract or lipopolysaccharide) alone or with onco-BCG. In such cells MUC5AC and Hp binding were determined as above. Mycobacteria reduced the amount of MUC5AC animals infected with Hp and in gastric epithelial cells pulsed in vitro with Hp components. Decrease of MUC5AC driven in cell cultures in vitro and in gastric tissue exposed ex vivo to mycobacteria was related to diminished adhesion of H. pylori bacilli. Vaccine mycobacteria by diminishing the amount of MUC5AC in gastric epithelial cells may reduce Hp adhesion.
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Affiliation(s)
- Weronika Gonciarz
- Department of Immunology and Infectious Biology, Institute of Microbiology, Biotechnology and Immunology, Faculty of Biology and Environmental Protection, University of Lodz, Banacha 12-16, 90-237, Lodz, Poland.
| | - Maciej Chyb
- Department of Molecular Microbiology, Faculty of Biology and Environmental Protection, University of Lodz, Lodz, Poland
- Bio-Med-Chem Doctoral School of the University of Lodz and Lodz Institutes of the Polish Academy of Sciences, Lodz, Poland
| | - Magdalena Chmiela
- Department of Immunology and Infectious Biology, Institute of Microbiology, Biotechnology and Immunology, Faculty of Biology and Environmental Protection, University of Lodz, Banacha 12-16, 90-237, Lodz, Poland.
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Wu S, Xu Y, Chen Z, Chen Y, Wei F, Xia C, Zhou Q, Li P, Gu Q. Lactiplantibacillus plantarum ZJ316 Reduces Helicobacter pylori Adhesion and Inflammation by Inhibiting the Expression of Adhesin and Urease Genes. Mol Nutr Food Res 2023; 67:e2300241. [PMID: 37485583 DOI: 10.1002/mnfr.202300241] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/18/2023] [Revised: 06/02/2023] [Indexed: 07/25/2023]
Abstract
SCOPE The present study aims to investigate the anti-Helicobacter pylori (H. pylori) effects of Lactiplantibacillus plantarum ZJ316 (L. plantarum ZJ316) both in vitro and in vivo. METHODS AND RESULTS This study finds that L. plantarum ZJ316 effectively suppresses H. pylori adhesion in inhibition (Pre-ZJ316), competition (Co-ZJ316), and displacement (Post-ZJ316) assays, and Pre-ZJ316 displaying the most potent inhibitory effect with an impressive inhibition ratio of 70.14%. Upon anti-adhesion, L. plantarum ZJ316 significantly downregulates the expression of H. pylori virulence genes, including ureA, ureB, flaA, and sabA, with inhibition ratios of 46.83%, 24.02%, 21.42%, and 62.38% at 2 h, respectively. In addition, L. plantarum ZJ316 is observed to reduce the level of interleukin 8 (IL-8) and improve cell viability in infected AGS cells. Furthermore, in vivo studies show that supplementation with L. plantarum ZJ316 effectively hinders H. pylori colonization and significantly suppresses the infiltration of immune cells and IL-8 production with H. pylori infection, protecting host from inflammatory damage. CONCLUSION L. plantarum ZJ316 exhibits excellent adhesion inhibition on H. pylori, and may be used as a probiotic candidate in the prevention or adjuvant therapy of gastric disease caused by H. pylori.
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Affiliation(s)
- Shiying Wu
- Key Laboratory for Food Microbial Technology of Zhejiang Province, College of Food Science and Biotechnology, Zhejiang Gongshang University, Hangzhou, Zhejiang, 310018, China
| | - Yang Xu
- Key Laboratory for Food Microbial Technology of Zhejiang Province, College of Food Science and Biotechnology, Zhejiang Gongshang University, Hangzhou, Zhejiang, 310018, China
| | - Ziqi Chen
- Key Laboratory for Food Microbial Technology of Zhejiang Province, College of Food Science and Biotechnology, Zhejiang Gongshang University, Hangzhou, Zhejiang, 310018, China
| | - Yongqiang Chen
- Key Laboratory for Food Microbial Technology of Zhejiang Province, College of Food Science and Biotechnology, Zhejiang Gongshang University, Hangzhou, Zhejiang, 310018, China
| | - Fangtong Wei
- Key Laboratory for Food Microbial Technology of Zhejiang Province, College of Food Science and Biotechnology, Zhejiang Gongshang University, Hangzhou, Zhejiang, 310018, China
| | - Chenlan Xia
- Key Laboratory for Food Microbial Technology of Zhejiang Province, College of Food Science and Biotechnology, Zhejiang Gongshang University, Hangzhou, Zhejiang, 310018, China
| | - Qingqing Zhou
- Key Laboratory for Food Microbial Technology of Zhejiang Province, College of Food Science and Biotechnology, Zhejiang Gongshang University, Hangzhou, Zhejiang, 310018, China
| | - Ping Li
- Key Laboratory for Food Microbial Technology of Zhejiang Province, College of Food Science and Biotechnology, Zhejiang Gongshang University, Hangzhou, Zhejiang, 310018, China
| | - Qing Gu
- Key Laboratory for Food Microbial Technology of Zhejiang Province, College of Food Science and Biotechnology, Zhejiang Gongshang University, Hangzhou, Zhejiang, 310018, China
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37
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Almorish MA, Al-Absi B, Elkhalifa AME, Elamin E, Elderdery AY, Alhamidi AH. ABO, Lewis blood group systems and secretory status with H.pylori infection in yemeni dyspeptic patients: a cross- sectional study. BMC Infect Dis 2023; 23:520. [PMID: 37553651 PMCID: PMC10408178 DOI: 10.1186/s12879-023-08496-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2023] [Accepted: 07/31/2023] [Indexed: 08/10/2023] Open
Abstract
BACKGROUND The ABO and Lewis blood group antigens are potential factors in susceptibility to H. pylori infection. This research aimed to examine the prevalence of Helicobater pylori (H.pylori) infection and its association with ABO, Lewis blood group systems, and secretory status in Yemeni symptomatic patients. METHODS In a cross-sectional study, 103 patients referred for endoscopy due to dyspepsia were included. H pylori infection was assessed using stool antigen and serum antibody rapid tests. ABO and Lewis blood group systems were examined using hemagglutination assay. Saliva samples were investigated for identification of the secretory phenotype using hemagglutination inhibition test. RESULTS The prevalence of H. pylori infection was (80.6%), with a higher rate of infection in females than males. The ABO blood groups were found to be significantly different between males and females (p = 0.047). The O blood group was prevalent among H. pylori patients, especially secretors. There was a significant association between ABO blood groups and H. pylori infection (p = 0.001). The Le (a + b+) phenotype was the most common, followed by Le (a + b-), Le (a-b+), and Le (a-b-). Lewis blood group systems and secretory status of symptomatic patients were not associated with H. pylori infection. The results showed that serum Ab test for H. pylori achieved poor sensitivity (68%), specificity of 55%; positive predictive value (PPV) 86%, negative predictive value (NPV) 29% and accuracy 65.1%. CONCLUSION The prevalence of H. pylori infection was high in Yemeni patients. This infection was linked to the O and Le (a + b+) secretor phenotype. The H. pylori stool Ag test is the most reliable noninvasive diagnostic method for detecting H. pylori infection.
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Affiliation(s)
| | - Boshra Al-Absi
- Department of Hematology, Faculty of Medicine and Health Sciences, Sana'a University, Sana'a, Yemen
| | - Ahmed M E Elkhalifa
- Public Heath Department, College of Health Sciences, Saudi Electronic University, Riyadh, Saudi Arabia
- Department of Hematology, Faculty of Medical Laboratory Sciences, University of El Imam El Mahdi, Kosti, 1158, Sudan
| | - Elham Elamin
- Department of Hematology, Faculty of Medical Laboratory Sciences, University of El Imam El Mahdi, Kosti, 1158, Sudan
| | - Abozer Y Elderdery
- Department of Clinical Laboratory Sciences, College of Applied Medical Science, Jouf University, Sakaka, Saudi Arabia
| | - Abdulaziz H Alhamidi
- Clinical Laboratory Sciences Department, College of Applied Medical Science, King Saud University, Riyadh, Saudi Arabia
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38
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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: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [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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Harduin-Lepers A. The vertebrate sialylation machinery: structure-function and molecular evolution of GT-29 sialyltransferases. Glycoconj J 2023; 40:473-492. [PMID: 37247156 PMCID: PMC10225777 DOI: 10.1007/s10719-023-10123-w] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2023] [Revised: 03/09/2023] [Accepted: 05/10/2023] [Indexed: 05/30/2023]
Abstract
Every eukaryotic cell is covered with a thick layer of complex carbohydrates with essential roles in their social life. In Deuterostoma, sialic acids present at the outermost positions of glycans of glycoconjugates are known to be key players in cellular interactions including host-pathogen interactions. Their negative charge and hydrophilic properties enable their roles in various normal and pathological states and their expression is altered in many diseases including cancers. Sialylation of glycoproteins and glycolipids is orchestrated by the regulated expression of twenty sialyltransferases in human tissues with distinct enzymatic characteristics and preferences for substrates and linkages formed. However, still very little is known on the functional organization of sialyltransferases in the Golgi apparatus and how the sialylation machinery is finely regulated to provide the ad hoc sialome to the cell. This review summarizes current knowledge on sialyltransferases, their structure-function relationships, molecular evolution, and their implications in human biology.
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Affiliation(s)
- Anne Harduin-Lepers
- Univ. Lille, CNRS, UMR 8576 - UGSF - Unité de Glycobiologie Structurale et Fonctionnelle, F-59000, Lille, France.
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40
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Bugaytsova JA, Piddubnyi A, Tkachenko I, Rakhimova L, Edlund JO, Thorell K, Marcotte H, Lundquist A, Schön K, Lycke N, Suerbaum S, Schulz C, Malfertheiner P, Hansen LM, Solnick JV, Moskalenko R, Hammarström L, Borén T. Vaccination with Helicobacter pylori attachment proteins protects against gastric cancer. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2023:2023.05.25.542131. [PMID: 37461695 PMCID: PMC10349987 DOI: 10.1101/2023.05.25.542131] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 07/24/2023]
Abstract
Most cases of gastric cancer are caused by chronic Helicobacter pylori infection, but the lack of early onco-diagnostics and a high risk for antibiotic resistance hampers early intervention through eradication of H. pylori infection by antibiotics. We reported on a protective mechanism where H. pylori gastric mucosal attachment can be reduced by natural antibodies that block the binding of its attachment protein BabA. Here we show that challenge infection with H. pylori induced response of such blocking antibodies in both human volunteers and in rhesus macaques, that mucosal vaccination with BabA protein antigen induced blocking antibodies in rhesus macaques, and that vaccination in a mouse model induced blocking antibodies that reduced gastric mucosal inflammation, preserved the gastric juice acidity, and fully protected the mice from gastric cancer caused by H. pylori.
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Affiliation(s)
- Jeanna A. Bugaytsova
- Department Medical Biochemistry and Biophysics, Umeå University, SE90187 Umeå, Sweden
- SUMEYA, The Ukrainian-Swedish Research Center, Sumy State University, 40022 Sumy, Ukraine
| | - Artem Piddubnyi
- Department Medical Biochemistry and Biophysics, Umeå University, SE90187 Umeå, Sweden
- SUMEYA, The Ukrainian-Swedish Research Center, Sumy State University, 40022 Sumy, Ukraine
- Department of Pathology, Medical Institute, Sumy State University, 40007 Sumy, Ukraine
| | - Iryna Tkachenko
- Department Medical Biochemistry and Biophysics, Umeå University, SE90187 Umeå, Sweden
- Department of Public Health, Medical Institute, Sumy State University, 40007 Sumy, Ukraine
| | - Lena Rakhimova
- Department Medical Biochemistry and Biophysics, Umeå University, SE90187 Umeå, Sweden
- Present address: Department of Odontology, Umea University, SE90187 Umeå, Sweden
| | - Johan Olofsson Edlund
- Department Medical Biochemistry and Biophysics, Umeå University, SE90187 Umeå, Sweden
- The Biochemical Imaging Center Umeå (BICU), Umeå University, SE90187 Umeå, Sweden
| | - Kaisa Thorell
- Department of Chemistry and Molecular Biology, University of Gothenburg, SE40530, Gothenburg, Sweden
| | - Harold Marcotte
- Department Medical Biochemistry and Biophysics, Umeå University, SE90187 Umeå, Sweden
- Department of Biosciences and Nutrition, Karolinska Institutet, SE14183, Huddinge, Sweden
| | - Anders Lundquist
- Department of Statistics, USBE, Umeå University, SE90187 Umeå, Sweden
- Umeå Center for Functional Brain Imaging, Umeå University, SE90187 Umeå, Sweden
| | - Karin Schön
- Department of Microbiology & Immunology, University of Gothenburg, Gothenburg, Sweden
| | - Nils Lycke
- Department of Microbiology & Immunology, University of Gothenburg, Gothenburg, Sweden
- Deceased, December 2022
| | - Sebastian Suerbaum
- Institute of Medical Microbiology and Hospital Epidemiology, Hannover Medical School, 30625 Hannover, Germany
- German Center for Infection Research (DZIF), Hannover-Braunschweig Site, 30625 Hannover, Germany
- Max von Pettenkofer Institute of Hygiene and Medical Microbiology, LMU Munich, 80336 Munich, Germany
- German Center for Infection Research (DZIF), Munich Site, 80336 Munich, Germany
| | - Christian Schulz
- Department of Gastroenterology, Hepatology and Infectious Diseases, Otto-von-Guericke University Magdeburg, Magdeburg, Germany
- Department of Medicine II, University Hospital, LMU Munich, Munich, Germany
| | - Peter Malfertheiner
- Department of Gastroenterology, Hepatology and Infectious Diseases, Otto-von-Guericke University Magdeburg, Magdeburg, Germany
- Department of Medicine II, University Hospital, LMU Munich, Munich, Germany
| | - Lori M. Hansen
- Departments of Medicine and Microbiology and Immunology, Center for Immunology and Infectious Disease, University of California Davis, Davis, CA 95616, USA
| | - Jay V. Solnick
- Departments of Medicine and Microbiology and Immunology, Center for Immunology and Infectious Disease, University of California Davis, Davis, CA 95616, USA
- California National Primate Research Center, University of California Davis School of Medicine, Davis, CA 95616, USA
| | - Roman Moskalenko
- SUMEYA, The Ukrainian-Swedish Research Center, Sumy State University, 40022 Sumy, Ukraine
- Department of Pathology, Medical Institute, Sumy State University, 40007 Sumy, Ukraine
| | - Lennart Hammarström
- Department of Biosciences and Nutrition, Karolinska Institutet, SE14183, Huddinge, Sweden
| | - Thomas Borén
- Department Medical Biochemistry and Biophysics, Umeå University, SE90187 Umeå, Sweden
- SUMEYA, The Ukrainian-Swedish Research Center, Sumy State University, 40022 Sumy, Ukraine
- Lead contact
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Zhou X, Zhu Y, Liu J, Liu J. Effects of Helicobacter pylori Infection on the Development of Chronic Gastritis. THE TURKISH JOURNAL OF GASTROENTEROLOGY : THE OFFICIAL JOURNAL OF TURKISH SOCIETY OF GASTROENTEROLOGY 2023; 34:700-713. [PMID: 37249580 PMCID: PMC10441145 DOI: 10.5152/tjg.2023.22316] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/10/2022] [Accepted: 09/25/2022] [Indexed: 05/31/2023]
Abstract
BACKGROUND/AIMS Based on the gene expression profiles of gastric epithelial tissue at different stages of Helicobacter pylori-infected gastritis, key long noncoding RNAs and genes in the development of Helicobacter pylori infection-induced gastritis were screened to provide a basis for early diagnosis and treatment. MATERIALS AND METHODS We downloaded 2 sets of sample data from the database, including gastric epithelial tissue samples from gastritis patients from Bhutan and Dominican, and screened mRNAs in the differentially expressed RNAs of the 2 regions. Mfuzz clustering algorithm was used to screen RNAs related to the 3 stages of chronic gastritis. The competing endogenous RNA (ceRNA) regulation network was constructed, and the selected key RNAs were verified. Samples from Bhutan and Dominican were subdivided into the chronic gastritis/ normal comparison groups, and the differentially expressed RNAs were screened to obtain 1067 overlapping RNAs, containing 21 long noncoding RNAs and 1046 mRNAs. RESULTS Thirty-eight significant gene ontology functional nodes and 6 expression pattern clusters were obtained. Two ceRNA regulatory networks were constructed, and 4 shared miRNAs (hsa-miR-320b, hsa-miR-320c, hsa-miR-320d, and hsa-miR-155-5p) were obtained. Eleven important long noncoding RNAs (AFAP1-AS1, MIR155HG, LINC00472, and FAM201A) and mRNAs (CASP10, SLC26A2, TRIB1, BMP2K, SCAMP1, TNKS1BP1, and MBOAT2) regulated by these 4 miRNAs were obtained. These results indicated that Helicobacter pylori infection had a certain influence on the development of gastritis. CONCLUSIONS The 11 key RNAs can provide a target for the early diagnosis and treatment of chronic gastritis following Helicobacter pylori infection.
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Affiliation(s)
| | | | - Jiayu Liu
- Nantong Hospital to Nanjing University of Chinese Medicine, Nantong, Jiangsu, China
| | - Jindi Liu
- Nantong Hospital to Nanjing University of Chinese Medicine, Nantong, Jiangsu, China
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Li ML, Hong XX, Zhang WJ, Liang YZ, Cai TT, Xu YF, Pan HF, Kang JY, Guo SJ, Li HW. Helicobacter pylori plays a key role in gastric adenocarcinoma induced by spasmolytic polypeptide-expressing metaplasia. World J Clin Cases 2023; 11:3714-3724. [PMID: 37383139 PMCID: PMC10294147 DOI: 10.12998/wjcc.v11.i16.3714] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/04/2023] [Revised: 03/01/2023] [Accepted: 04/23/2023] [Indexed: 06/02/2023] Open
Abstract
Heliobacter pylori (H. pylori), a group 1 human gastric carcinogen, is significantly associated with chronic gastritis, gastric mucosal atrophy, and gastric cancer. Approximately 20% of patients infected with H. pylori develop precancerous lesions, among which metaplasia is the most critical. Except for intestinal metaplasia (IM), which is characterized by goblet cells appearing in the stomach glands, one type of mucous cell metaplasia, spasmolytic polypeptide-expressing metaplasia (SPEM), has attracted much attention. Epidemiological and clinicopathological studies suggest that SPEM may be more strongly linked to gastric adenocarcinoma than IM. SPEM, characterized by abnormal expression of trefoil factor 2, mucin 6, and Griffonia simplicifolia lectin II in the deep glands of the stomach, is caused by acute injury or inflammation. Although it is generally believed that the loss of parietal cells alone is a sufficient and direct cause of SPEM, further in-depth studies have revealed the critical role of immunosignals. There is controversy regarding whether SPEM cells originate from the transdifferentiation of mature chief cells or professional progenitors. SPEM plays a functional role in the repair of gastric epithelial injury. However, chronic inflammation and immune responses caused by H. pylori infection can induce further progression of SPEM to IM, dysplasia, and adenocarcinoma. SPEM cells upregulate the expression of whey acidic protein 4-disulfide core domain protein 2 and CD44 variant 9, which recruit M2 macrophages to the wound. Studies have revealed that interleukin-33, the most significantly upregulated cytokine in macrophages, promotes SPEM toward more advanced metaplasia. Overall, more effort is needed to reveal the specific mechanism of SPEM malignant progression driven by H. pylori infection.
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Affiliation(s)
- Mian-Li Li
- Department of Gastroenterology, Shenzhen Hospital of Integrated, Traditional Chinese and Western Medicine, Shenzhen 518033, Guangdong Province, China
| | - Xin-Xin Hong
- Department of Gastroenterology, Shenzhen Traditional Chinese Medicine Hospital, Shenzhen 518033, Guangdong Province, China
| | - Wei-Jian Zhang
- Science and Technology Innovation Center, Guangzhou University of Traditional Chinese Medicine, Guangzhou 510405, Guangdong Province, China
| | - Yi-Zhong Liang
- Department of Gastroenterology, Shenzhen Traditional Chinese Medicine Hospital, Shenzhen 518033, Guangdong Province, China
| | - Tian-Tian Cai
- Department of Gastroenterology, Shenzhen Traditional Chinese Medicine Hospital, Shenzhen 518033, Guangdong Province, China
| | - Yi-Fei Xu
- Department of Gastroenterology, Shenzhen Traditional Chinese Medicine Hospital, Shenzhen 518033, Guangdong Province, China
| | - Hua-Feng Pan
- Science and Technology Innovation Center, Guangzhou University of Traditional Chinese Medicine, Guangzhou 510405, Guangdong Province, China
| | - Jian-Yuan Kang
- Department of Gastroenterology, Shenzhen Traditional Chinese Medicine Hospital, Shenzhen 518033, Guangdong Province, China
| | - Shao-Ju Guo
- Department of Gastroenterology, Shenzhen Traditional Chinese Medicine Hospital, Shenzhen 518033, Guangdong Province, China
| | - Hai-Wen Li
- Department of Gastroenterology, Shenzhen Traditional Chinese Medicine Hospital, Shenzhen 518033, Guangdong Province, China
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Gupta N, Kumar A, Verma VK. Strategies adopted by gastric pathogen Helicobacter pylori for a mature biofilm formation: Antimicrobial peptides as a visionary treatment. Microbiol Res 2023; 273:127417. [PMID: 37267815 DOI: 10.1016/j.micres.2023.127417] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/13/2023] [Revised: 05/15/2023] [Accepted: 05/21/2023] [Indexed: 06/04/2023]
Abstract
Enormous efforts in recent past two decades to eradicate the pathogen that has been prevalent in half of the world's population have been problematic. The biofilm formed by Helicobacter pylori provides resistance towards innate immune cells, various combinatorial antibiotics, and human antimicrobial peptides, despite the fact that these all are potent enough to eradicate it in vitro. Biofilm provides the opportunity to secrete various virulence factors that strengthen the interaction between host and pathogen helping in evading the innate immune system and ultimately leading to persistence. To our knowledge, this review is the first of its kind to explain briefly the journey of H. pylori starting with the chemotaxis, the mechanism for selecting the site for colonization, the stress faced by the pathogen, and various adaptations to evade these stress conditions by forming biofilm and the morphological changes acquired by the pathogen in mature biofilm. Furthermore, we have explained the human GI tract antimicrobial peptides and the reason behind the failure of these AMPs, and how encapsulation of Pexiganan-A(MSI-78A) in a chitosan microsphere increases the efficiency of eradication.
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Affiliation(s)
- Nidhi Gupta
- Department of Microbiology, University of Delhi South Campus, Benito Juarez Marg, New Delhi 110021, India.
| | - Atul Kumar
- Department of Microbiology, University of Delhi South Campus, Benito Juarez Marg, New Delhi 110021, India
| | - Vijay Kumar Verma
- Department of Microbiology, University of Delhi South Campus, Benito Juarez Marg, New Delhi 110021, India.
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Bugaytsova JA, Moonens K, Piddubnyi A, Schmidt A, Edlund JO, Lisiutin G, Brännström K, Chernov YA, Thorel K, Tkachenko I, Sharova O, Vikhrova I, Butsyk A, Shubin P, Chyzhma R, Johansson DX, Marcotte H, Sjöström R, Shevtsova A, Bylund G, Rakhimova L, Lundquist A, Berhilevych O, Kasianchuk V, Loboda A, Ivanytsia V, Hultenby K, Persson MAA, Gomes J, Matos R, Gartner F, Reis CA, Whitmire JM, Merrell DS, Pan-Hammarström Q, Landström M, Oscarson S, D’Elios MM, Agreus L, Ronkainen J, Aro P, Engstrand L, Graham DY, Kachkovska V, Mukhopadhyay A, Chaudhuri S, Karmakar BC, Paul S, Kravets O, Camorlinga M, Torres J, Berg DE, Moskalenko R, Haas R, Remaut H, Hammarström L, Borén T. Helicobacter pylori attachment-blocking antibodies protect against duodenal ulcer disease. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2023:2023.05.24.542096. [PMID: 37292721 PMCID: PMC10245814 DOI: 10.1101/2023.05.24.542096] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/10/2023]
Abstract
The majority of the world population carry the gastric pathogen Helicobacter pylori. Fortunately, most individuals experience only low-grade or no symptoms, but in many cases the chronic inflammatory infection develops into severe gastric disease, including duodenal ulcer disease and gastric cancer. Here we report on a protective mechanism where H. pylori attachment and accompanying chronic mucosal inflammation can be reduced by antibodies that are present in a vast majority of H. pylori carriers. These antibodies block binding of the H. pylori attachment protein BabA by mimicking BabA's binding to the ABO blood group glycans in the gastric mucosa. However, many individuals demonstrate low titers of BabA blocking antibodies, which is associated with an increased risk for duodenal ulceration, suggesting a role for these antibodies in preventing gastric disease.
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Affiliation(s)
- Jeanna A. Bugaytsova
- Department of Medical Biochemistry and Biophysics, Umeå University, SE90187 Umeå, Sweden
- SUMEYA, The Ukrainian-Swedish Research Center, Sumy State University, 40022 Sumy, Ukraine
| | - Kristof Moonens
- Structural and Molecular Microbiology, VIB Department of Structural Biology, VIB, 1050 Brussels, Belgium
- Structural Biology Brussels, Vrije Universiteit Brussel, 1050 Brussels, Belgium
- Present address: Ablynx, a Sanofi Company, Technologiepark 21, 9052 Zwijnaarde, Belgium
| | - Artem Piddubnyi
- Department of Medical Biochemistry and Biophysics, Umeå University, SE90187 Umeå, Sweden
- SUMEYA, The Ukrainian-Swedish Research Center, Sumy State University, 40022 Sumy, Ukraine
- Department of Pathology, Medical Institute, Sumy State University, 40007 Sumy, Ukraine
| | - Alexej Schmidt
- Department of Medical Biochemistry and Biophysics, Umeå University, SE90187 Umeå, Sweden
- Division of Clinical Immunology and Transfusion Medicine, Karolinska Institutet at Karolinska University Hospital, SE14186 Huddinge, Sweden
- Present address: Department of Medical Biosciences, Umeå University, SE90185 Umeå, Sweden
| | - Johan Olofsson Edlund
- Department of Medical Biochemistry and Biophysics, Umeå University, SE90187 Umeå, Sweden
- The Biochemical Imaging Center Umeå (BICU), Umeå University, SE90187 Umeå, Sweden
| | - Gennadii Lisiutin
- Department of Medical Biochemistry and Biophysics, Umeå University, SE90187 Umeå, Sweden
- Department of Microbiology, Virology and Biotechnology, Odesa Mechnikov National University, 65082 Odesa, Ukraine
| | - Kristoffer Brännström
- Department of Medical Biochemistry and Biophysics, Umeå University, SE90187 Umeå, Sweden
- The Biochemical Imaging Center Umeå (BICU), Umeå University, SE90187 Umeå, Sweden
- Present address: Pfizer Worldwide R&D, BioMedicine Design, 10 555 Science Center Drive, San Diego CA, 92121 USA
| | - Yevgen A. Chernov
- Department of Medical Biochemistry and Biophysics, Umeå University, SE90187 Umeå, Sweden
| | - Kaisa Thorel
- Department of Infectious Diseases, Institute of Biomedicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
| | - Iryna Tkachenko
- Department of Medical Biochemistry and Biophysics, Umeå University, SE90187 Umeå, Sweden
- Department of Public Health, Medical Institute, Sumy State University, 40007 Sumy, Ukraine
| | - Oleksandra Sharova
- Department of Medical Biochemistry and Biophysics, Umeå University, SE90187 Umeå, Sweden
- Department of Pediatrics, Medical Institute, Sumy State University, 40018 Sumy, Ukraine
| | - Iryna Vikhrova
- Department of Medical Biochemistry and Biophysics, Umeå University, SE90187 Umeå, Sweden
- Department of Pediatrics, Medical Institute, Sumy State University, 40018 Sumy, Ukraine
| | - Anna Butsyk
- Department of Medical Biochemistry and Biophysics, Umeå University, SE90187 Umeå, Sweden
- Department of Public Health, Medical Institute, Sumy State University, 40007 Sumy, Ukraine
| | - Pavlo Shubin
- Department of Medical Biochemistry and Biophysics, Umeå University, SE90187 Umeå, Sweden
- Department of Public Health, Medical Institute, Sumy State University, 40007 Sumy, Ukraine
| | - Ruslana Chyzhma
- Department of Medical Biochemistry and Biophysics, Umeå University, SE90187 Umeå, Sweden
- SUMEYA, The Ukrainian-Swedish Research Center, Sumy State University, 40022 Sumy, Ukraine
- Department of Pathology, Medical Institute, Sumy State University, 40007 Sumy, Ukraine
| | - Daniel X. Johansson
- Department of Clinical Neuroscience, Karolinska Institutet at Center for Molecular Medicine, Karolinska University Hospital, Solna, SE17176 Stockholm, Sweden
| | - Harold Marcotte
- Department of Medical Biochemistry and Biophysics, Umeå University, SE90187 Umeå, Sweden
- Division of Clinical Immunology and Transfusion Medicine, Karolinska Institutet at Karolinska University Hospital, SE14186 Huddinge, Sweden
- Department of Biosciences and Nutrition, Karolinska Institutet, SE14183, Huddinge, Sweden
| | - Rolf Sjöström
- Department of Medical Biochemistry and Biophysics, Umeå University, SE90187 Umeå, Sweden
| | - Anna Shevtsova
- Department of Medical Biochemistry and Biophysics, Umeå University, SE90187 Umeå, Sweden
| | - Göran Bylund
- Department of Medical Biochemistry and Biophysics, Umeå University, SE90187 Umeå, Sweden
| | - Lena Rakhimova
- Department of Medical Biochemistry and Biophysics, Umeå University, SE90187 Umeå, Sweden
- Present address: Department of Odontology, Umeå University, SE90187 Umeå, Sweden
| | - Anders Lundquist
- Department of Statistics, USBE, Umeå University, SE90187 Umeå, Sweden
- Umeå Center for Functional Brain Imaging, Umeå University, SE90187 Umeå, Sweden
| | - Oleksandra Berhilevych
- Department of Public Health, Medical Institute, Sumy State University, 40007 Sumy, Ukraine
| | - Victoria Kasianchuk
- Department of Public Health, Medical Institute, Sumy State University, 40007 Sumy, Ukraine
| | - Andrii Loboda
- Department of Pediatrics, Medical Institute, Sumy State University, 40018 Sumy, Ukraine
| | - Volodymyr Ivanytsia
- Department of Microbiology, Virology and Biotechnology, Odesa Mechnikov National University, 65082 Odesa, Ukraine
| | - Kjell Hultenby
- Departments of Laboratory Medicine, Division of Biomolecular and Cellular Medicine, Karolinska Institutet at Karolinska University Hospital, SE14186 Huddinge, Sweden
| | - Mats A. A. Persson
- Department of Clinical Neuroscience, Karolinska Institutet at Center for Molecular Medicine, Karolinska University Hospital, Solna, SE17176 Stockholm, Sweden
| | - Joana Gomes
- i3S – Instituto de Investigação e Inovação em Saúde, Universidade do Porto, 4200-135 Porto, Portugal
- IPATIMUP – Institute of Molecular Pathology and Immunology of the University of Porto, 4200-135 Porto, Portugal
| | - Rita Matos
- i3S – Instituto de Investigação e Inovação em Saúde, Universidade do Porto, 4200-135 Porto, Portugal
- IPATIMUP – Institute of Molecular Pathology and Immunology of the University of Porto, 4200-135 Porto, Portugal
| | - Fátima Gartner
- i3S – Instituto de Investigação e Inovação em Saúde, Universidade do Porto, 4200-135 Porto, Portugal
- IPATIMUP – Institute of Molecular Pathology and Immunology of the University of Porto, 4200-135 Porto, Portugal
- Instituto de Ciências Biomédicas Abel Salazar, University of Porto, 4050-313 Porto, Portugal
| | - Celso A. Reis
- i3S – Instituto de Investigação e Inovação em Saúde, Universidade do Porto, 4200-135 Porto, Portugal
- IPATIMUP – Institute of Molecular Pathology and Immunology of the University of Porto, 4200-135 Porto, Portugal
- Instituto de Ciências Biomédicas Abel Salazar, University of Porto, 4050-313 Porto, Portugal
- Faculty of Medicine, University of Porto, 4200-319 Porto, Portugal
| | | | - D. Scott Merrell
- Department of Microbiology and Immunology, USUHS, Bethesda, MD 20814, USA
| | - Qiang Pan-Hammarström
- Department of Biosciences and Nutrition, Karolinska Institutet, SE14183, Huddinge, Sweden
| | - Maréne Landström
- Present address: Department of Medical Biosciences, Umeå University, SE90185 Umeå, Sweden
| | - Stefan Oscarson
- Centre for Synthesis and Chemical Biology, School of Chemistry, University College Dublin, Belfield, Dublin 4, Ireland
| | - Mario M. D’Elios
- Department of Experimental and Clinical Medicine, Largo Brambilla 3, 50134 Firenze, Italy
| | - Lars Agreus
- Division of Family Medicine and Primary Care, Karolinska Institutet, SE14183 Huddinge, Sweden
| | - Jukka Ronkainen
- University of Oulu, Center for Life Course Health Research and Primary Health Care Center, Tornio Finland
| | - Pertti Aro
- University of Oulu, Center for Life Course Health Research and Primary Health Care Center, Tornio Finland
| | - Lars Engstrand
- Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, SE17177 Stockholm, Sweden
- Present address: Science for Life Laboratory, SE17165, Solna, Sweden
| | - David Y. Graham
- Department of Medicine, Molecular Virology and Microbiology, Baylor College of Medicine, Michael E. DeBakey VAMC, 2002 Holcombe Blvd. Houston, TX, 77030 USA
| | - Vladyslava Kachkovska
- Department of Internal Medicine, Medical Institute, Sumy State University, 40007 Sumy, Ukraine
| | - Asish Mukhopadhyay
- Division of Bacteriology, ICMR-National Institute of Cholera and Enteric Diseases P 33, CIT Road, Scheme XM, Kolkata 700010, India
| | - Sujit Chaudhuri
- Department of Gastroenterology, AMRI Hospital, Salt Lake City. Kolkata, West Bengal 700098, India
| | - Bipul Chandra Karmakar
- Division of Bacteriology, ICMR-National Institute of Cholera and Enteric Diseases P 33, CIT Road, Scheme XM, Kolkata 700010, India
| | - Sangita Paul
- Division of Bacteriology, ICMR-National Institute of Cholera and Enteric Diseases P 33, CIT Road, Scheme XM, Kolkata 700010, India
| | - Oleksandr Kravets
- Department of Surgery, Traumatology, Orthopedics and Physiology, Medical Institute, Sumy State University, 40007 Sumy, Ukraine
| | - Margarita Camorlinga
- Unidad de Investigacion en Enfermedades Infecciosas, UMAE Pediatria, CMN SXXI, Instituto Mexicano del Seguro Social, Mexico City, Mexico
| | - Javier Torres
- Unidad de Investigacion en Enfermedades Infecciosas, UMAE Pediatria, CMN SXXI, Instituto Mexicano del Seguro Social, Mexico City, Mexico
| | - Douglas E. Berg
- Department of Medicine, University of California San Diego, La Jolla, CA 92093, USA
| | - Roman Moskalenko
- SUMEYA, The Ukrainian-Swedish Research Center, Sumy State University, 40022 Sumy, Ukraine
- Department of Pathology, Medical Institute, Sumy State University, 40007 Sumy, Ukraine
| | - Rainer Haas
- German Center for Infection Research (DZIF), Munich Site, 80336 Munich, Germany
- Chair of Medical Microbiology and Hospital Epidemiology, Max von Pettenkofer-Institute, Faculty of Medicine, LMU Munich, Germany
| | - Han Remaut
- Structural and Molecular Microbiology, VIB Department of Structural Biology, VIB, 1050 Brussels, Belgium
- Structural Biology Brussels, Vrije Universiteit Brussel, 1050 Brussels, Belgium
| | - Lennart Hammarström
- Department of Biosciences and Nutrition, Karolinska Institutet, SE14183, Huddinge, Sweden
| | - Thomas Borén
- Department of Medical Biochemistry and Biophysics, Umeå University, SE90187 Umeå, Sweden
- SUMEYA, The Ukrainian-Swedish Research Center, Sumy State University, 40022 Sumy, Ukraine
- Lead contact
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45
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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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Malfertheiner P, Camargo MC, El-Omar E, Liou JM, Peek R, Schulz C, Smith SI, Suerbaum S. Helicobacter pylori infection. Nat Rev Dis Primers 2023; 9:19. [PMID: 37081005 PMCID: PMC11558793 DOI: 10.1038/s41572-023-00431-8] [Citation(s) in RCA: 328] [Impact Index Per Article: 164.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 03/17/2023] [Indexed: 04/22/2023]
Abstract
Helicobacter pylori infection causes chronic gastritis, which can progress to severe gastroduodenal pathologies, including peptic ulcer, gastric cancer and gastric mucosa-associated lymphoid tissue lymphoma. H. pylori is usually transmitted in childhood and persists for life if untreated. The infection affects around half of the population in the world but prevalence varies according to location and sanitation standards. H. pylori has unique properties to colonize gastric epithelium in an acidic environment. The pathophysiology of H. pylori infection is dependent on complex bacterial virulence mechanisms and their interaction with the host immune system and environmental factors, resulting in distinct gastritis phenotypes that determine possible progression to different gastroduodenal pathologies. The causative role of H. pylori infection in gastric cancer development presents the opportunity for preventive screen-and-treat strategies. Invasive, endoscopy-based and non-invasive methods, including breath, stool and serological tests, are used in the diagnosis of H. pylori infection. Their use depends on the specific individual patient history and local availability. H. pylori treatment consists of a strong acid suppressant in various combinations with antibiotics and/or bismuth. The dramatic increase in resistance to key antibiotics used in H. pylori eradication demands antibiotic susceptibility testing, surveillance of resistance and antibiotic stewardship.
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Affiliation(s)
- Peter Malfertheiner
- Medical Department II, University Hospital, Ludwig-Maximilians-Universität, Munich, Germany.
- Medical Department Klinik of Gastroenterology, Hepatology and Infectiology, Otto-von-Guericke Universität, Magdeburg, Germany.
| | - M Constanza Camargo
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, MD, USA
| | - Emad El-Omar
- Microbiome Research Centre, St George & Sutherland Clinical Campuses, School of Clinical Medicine, Faculty of Medicine and Health, UNSW Sydney, Sydney, New South Wales, Australia
| | - Jyh-Ming Liou
- Department of Internal Medicine, National Taiwan University Cancer Center, National Taiwan University Hospital, National Taiwan University College of Medicine, Taipei, Taiwan
| | - Richard Peek
- Division of Gastroenterology, Hepatology, and Nutrition, Vanderbilt University Medical Center, Nashville, TN, USA
| | - Christian Schulz
- Medical Department II, University Hospital, Ludwig-Maximilians-Universität, Munich, Germany
- DZIF Deutsches Zentrum für Infektionsforschung, Partner Site Munich, Munich, Germany
| | - Stella I Smith
- Department of Molecular Biology and Biotechnology, Nigerian Institute of Medical Research, Yaba, Lagos, Nigeria
| | - Sebastian Suerbaum
- DZIF Deutsches Zentrum für Infektionsforschung, Partner Site Munich, Munich, Germany
- Max von Pettenkofer Institute, Faculty of Medicine, Ludwig-Maximilians-Universität, Munich, Germany
- National Reference Center for Helicobacter pylori, Munich, Germany
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47
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Yang H, Wang L, Zhang M, Hu B. The Role of Adhesion in Helicobacter pylori Persistent Colonization. Curr Microbiol 2023; 80:185. [PMID: 37071212 DOI: 10.1007/s00284-023-03264-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2022] [Accepted: 03/10/2023] [Indexed: 04/19/2023]
Abstract
Helicobacter pylori (H. pylori) has coevolved with its human host for more than 100 000 years. It can safely colonize around the epithelium of gastric glands via their specific microstructures and proteins. Unless patients receive eradication treatment, H. pylori infection is always lifelong. However, few studies have discussed the reasons. This review will focus on the adhesion of H. pylori from the oral cavity to gastric mucosa and summarize the possible binding and translocation characteristics. Adhesion is the first step for persistent colonization after the directional motility, and factors related to adhesion are necessary. Outer membrane proteins, such as the blood group antigen binding adhesin (BabA) and the sialic acid binding adhesin (SabA), play pivotal roles in binding to human mucins and cellular surfaces. And this may offer different perspectives on eradication.
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Affiliation(s)
- Hang Yang
- Department of Gastroenterology, West China Hospital, Sichuan University, No.37, Guo Xue Alley, Wu Hou District, Chengdu City, 610041, Sichuan Province, China
| | - Lixia Wang
- The Second Department of Gastroenterology, The First Affiliated Hospital of Dalian Medical University, Dalian, Liaoning, China
| | - Miao Zhang
- Department of Gastroenterology, West China Hospital, Sichuan University, No.37, Guo Xue Alley, Wu Hou District, Chengdu City, 610041, Sichuan Province, China
| | - Bing Hu
- Department of Gastroenterology, West China Hospital, Sichuan University, No.37, Guo Xue Alley, Wu Hou District, Chengdu City, 610041, Sichuan Province, China.
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48
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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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49
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Okoye JC, Holland A, Pitoulias M, Paschalis V, Piddubnyi A, Dufailu OA, Borén T, Oldfield NJ, Mahdavi J, Soultanas P. Ferric quinate (QPLEX) inhibits the interaction of major outer membrane protein (MOMP) with the Lewis b (Leb) antigen and limits Campylobacter colonization in broilers. Front Microbiol 2023; 14:1146418. [PMID: 36970690 PMCID: PMC10036597 DOI: 10.3389/fmicb.2023.1146418] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2023] [Accepted: 02/27/2023] [Indexed: 03/12/2023] Open
Abstract
Campylobacter jejuni colonizes hosts by interacting with Blood Group Antigens (BgAgs) on the surface of gastrointestinal epithelia. Genetic variations in BgAg expression affects host susceptibility to C. jejuni. Here, we show that the essential major outer membrane protein (MOMP) of C. jejuni NCTC11168 binds to the Lewis b (Leb) antigen on the gastrointestinal epithelia of host tissues and this interaction can be competitively inhibited by ferric quinate (QPLEX), a ferric chelate structurally similar to bacterial siderophores. We provide evidence that QPLEX competitively inhibits the MOMP-Leb interaction. Furthermore, we demonstrate that QPLEX can be used as a feed additive in broiler farming to significantly reduce C. jejuni colonization. Our results indicate that QPLEX can be a viable alternative to the preventative use of antibiotics in broiler farming to combat C. jejuni infections.
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Affiliation(s)
- Jennifer C. Okoye
- Biodiscovery Institute, School of Chemistry, University of Nottingham, Nottingham, United Kingdom
| | - Alexandria Holland
- Biodiscovery Institute, School of Chemistry, University of Nottingham, Nottingham, United Kingdom
| | - Matthaios Pitoulias
- Biodiscovery Institute, School of Chemistry, University of Nottingham, Nottingham, United Kingdom
| | - Vasileios Paschalis
- Biodiscovery Institute, School of Chemistry, University of Nottingham, Nottingham, United Kingdom
| | - Artem Piddubnyi
- Department Medical Biochemistry and Biophysics, Umeå University, Umeå, Sweden
- SUMEYA, The Ukrainian-Swedish Research Center, Sumy State University, Sumy, Ukraine
| | - Osman A. Dufailu
- Faculty of Engineering and Science, School of Science, University of Greenwich, London, United Kingdom
| | - Thomas Borén
- Department Medical Biochemistry and Biophysics, Umeå University, Umeå, Sweden
| | - Neil J. Oldfield
- School of Life Sciences, University of Nottingham, Nottingham, United Kingdom
| | - Jafar Mahdavi
- Biodiscovery Institute, School of Chemistry, University of Nottingham, Nottingham, United Kingdom
- Jafar Mahdavi,
| | - Panos Soultanas
- Biodiscovery Institute, School of Chemistry, University of Nottingham, Nottingham, United Kingdom
- *Correspondence: Panos Soultanas,
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50
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O’Brien VP, Jackson LK, Frick JP, Rodriguez Martinez AE, Jones DS, Johnston CD, Salama NR. Helicobacter pylori Chronic Infection Selects for Effective Colonizers of Metaplastic Glands. mBio 2023; 14:e0311622. [PMID: 36598261 PMCID: PMC9973278 DOI: 10.1128/mbio.03116-22] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2022] [Accepted: 12/05/2022] [Indexed: 01/05/2023] Open
Abstract
Chronic gastric infection with Helicobacter pylori can lead to progressive tissue changes that culminate in cancer, but how H. pylori adapts to the changing tissue environment during disease development is not fully understood. In a transgenic mouse gastric metaplasia model, we found that strains from unrelated individuals differed in their ability to infect the stomach, to colonize metaplastic glands, and to alter the expression of the metaplasia-associated protein TFF3. H. pylori isolates from different stages of disease from a single individual had differential ability to colonize healthy and metaplastic gastric glands. Exposure to the metaplastic environment selected for high gastric colonization by one of these strains. Complete genome sequencing revealed a unique alteration in the frequency of a variant allele of the putative adhesin sabB, arising from a recombination event with the related sialic acid binding adhesin (SabA) gene. Mutation of sabB in multiple H. pylori strain backgrounds strongly reduced adherence to both normal and metaplastic gastric tissue, and highly attenuated stomach colonization in mice. Thus, the changing gastric environment during disease development promotes bacterial adhesin gene variation associated with enhanced gastric colonization. IMPORTANCE Chronic infection with Helicobacter pylori is the primary risk factor for developing stomach cancer. As disease progresses H. pylori must adapt to a changing host tissue environment that includes induction of new cell fates in the cells that line the stomach. We tested representative H. pylori isolates collected from the same patient during early and later stages of disease in a mouse model where we can rapidly induce disease-associated tissue changes. Only the later-stage H. pylori strains could robustly colonize the diseased stomach environment. We also found that the ability to colonize the diseased stomach was associated with genetic variation in a putative cell surface adhesin gene called sabB. Additional experiments revealed that SabB promotes binding to stomach tissue and is critical for stomach colonization by the late-stage strains. Thus, H. pylori diversifies its genome during disease progression and these genomic changes highlight critical factors for bacterial persistence.
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Affiliation(s)
- V. P. O’Brien
- Human Biology Division, Fred Hutchinson Cancer Center, Seattle, Washington, USA
| | - L. K. Jackson
- Human Biology Division, Fred Hutchinson Cancer Center, Seattle, Washington, USA
- Molecular and Cellular Biology Graduate Program, University of Washington, Seattle, Washington, USA
| | - J. P. Frick
- Human Biology Division, Fred Hutchinson Cancer Center, Seattle, Washington, USA
- Department of Microbiology, University of Washington, Seattle, Washington, USA
| | | | - D. S. Jones
- Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Center, Seattle, Washington, USA
| | - C. D. Johnston
- Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Center, Seattle, Washington, USA
| | - N. R. Salama
- Human Biology Division, Fred Hutchinson Cancer Center, Seattle, Washington, USA
- Molecular and Cellular Biology Graduate Program, University of Washington, Seattle, Washington, USA
- Department of Microbiology, University of Washington, Seattle, Washington, USA
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