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Jaquez-Durán G, Arellano-Ortiz AL. Western diet components that increase intestinal permeability with implications on health. INT J VITAM NUTR RES 2024; 94:405-421. [PMID: 38009780 DOI: 10.1024/0300-9831/a000801] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2023]
Abstract
Intestinal permeability is a physiological property that allows necessary molecules to enter the organism. This property is regulated by tight junction proteins located between intestinal epithelial cells. However, various factors can increase intestinal permeability (IIP), including diet. Specific components in the Western diet (WD), such as monosaccharides, fat, gluten, salt, alcohol, and additives, can affect the tight junctions between enterocytes, leading to increased permeability. This review explains how these components promote IIP and outlines their potential implications for health. In addition, we describe how a reduction in WD consumption may help improve dietary treatment of diseases associated with IIP. Research has shown that some of these components can cause changes in the gut microbiota, leading to dysbiosis, which can promote greater intestinal permeability and displacement of endotoxins into the bloodstream. These endotoxins include lipopolysaccharides derived from gram-negative bacteria, and their presence has been associated with various diseases, such as autoimmune, neurological, and metabolic diseases like diabetes and cardiovascular disease. Therefore, nutrition professionals should promote the reduction of WD consumption and consider the inclusion of healthy diet components as part of the nutritional treatment for diseases associated with increased intestinal permeability.
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Affiliation(s)
- Gilberto Jaquez-Durán
- Departamento de Ciencias de la Salud, División Multidisciplinaria de Ciudad Universitaria, Universidad Autónoma de Ciudad Juárez, México
| | - Ana Lidia Arellano-Ortiz
- Departamento de Ciencias de la Salud, División Multidisciplinaria de Ciudad Universitaria, Universidad Autónoma de Ciudad Juárez, México
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2
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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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Phuc BH, Tuan VP, Binh TT, Tung PH, Tri TD, Dung HDQ, Thuan NPM, Fauzia KA, Tshibangu-Kabamba E, Alfaray RI, Saruuljavkhlan B, Matsumoto T, Akada J, Yamaoka Y. Comparative genomics of two Vietnamese Helicobacter pylori strains, CHC155 from a non-cardia gastric cancer patient and VN1291 from a duodenal ulcer patient. Sci Rep 2023; 13:8869. [PMID: 37258611 DOI: 10.1038/s41598-023-35527-4] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2022] [Accepted: 05/19/2023] [Indexed: 06/02/2023] Open
Abstract
Helicobacter pylori is involved in the etiology and severity of several gastroduodenal diseases; however, plasticity of the H. pylori genome makes complete genome assembly difficult. We report here the full genomes of H. pylori strains CHC155 and VN1291 isolated from a non-cardia gastric cancer patient and a duodenal ulcer patient, respectively, and their virulence demonstrated by in vitro infection. Whole-genome sequences were obtained by combining long- and short-reads with a hybrid-assembly approach. Both CHC155 and VN1291 genome possessed four kinds of genomic island: a cag pathogenicity island (cagPAI), two type 4 secretion system islands within an integrative and conjugative element (tfs ICE), and prophage. CHC155 and VN1291 carried East Asian-type cagA and vacA s1m1, and outer membrane protein genes, including two copies of oipA. Corresponded to genetic determinants of antibiotic resistance, chromosomal mutations were identified in CHC155 (rdxA, gyrA, and 23S rRNA) and VN1291 (rdxA, 23S rRNA, and pbp1A). In vitro infection of AGS cells by both strains induced the cell scattering phenotype, tyrosine phosphorylation of CagA, and promoted high levels of IL8 secretion, indicating fully intact phenotypes of the cagPAI. Virulence genes in CHC155 and VN1291 genomes are crucial for H. pylori pathogenesis and are risk factors in the development of gastric cancer and duodenal ulcer. Our in vitro studies indicate that the strains CHC155 and VN1291 carry the pathogenic potential.
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Grants
- 21K08010 Ministry of Education, Culture, Sports, Science and Technology, Japan
- 21K07898 Ministry of Education, Culture, Sports, Science and Technology, Japan
- 221S0002 Ministry of Education, Culture, Sports, Science and Technology, Japan
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Affiliation(s)
- Bui Hoang Phuc
- Department of Environmental and Preventive Medicine, Oita University Faculty of Medicine, Yufu, Oita, Japan
- Faculty of Applied Technology, Van Lang University, Ho Chi Minh City, Vietnam
| | - Vo Phuoc Tuan
- Department of Endoscopy, Cho Ray Hospital, Ho Chi Minh City, Vietnam
| | - Tran Thanh Binh
- Department of Endoscopy, Cho Ray Hospital, Ho Chi Minh City, Vietnam
| | - Pham Huu Tung
- Department of Endoscopy, Cho Ray Hospital, Ho Chi Minh City, Vietnam
| | - Tran Dinh Tri
- Department of Endoscopy, Cho Ray Hospital, Ho Chi Minh City, Vietnam
| | - Ho Dang Quy Dung
- Department of Endoscopy, Cho Ray Hospital, Ho Chi Minh City, Vietnam
| | | | - Kartika Afrida Fauzia
- Department of Environmental and Preventive Medicine, Oita University Faculty of Medicine, Yufu, Oita, Japan
- Department of Public Health and Preventive Medicine, Faculty of Medicine, Universitas Airlangga, Surabaya, 60115, Indonesia
- Helicobacter pylori and Microbiota Study Group, Institute of Tropical Disease, Universitas Airlangga, Surabaya, 60115, Indonesia
| | - Evariste Tshibangu-Kabamba
- Department of Environmental and Preventive Medicine, Oita University Faculty of Medicine, Yufu, Oita, Japan
- Department of Parasitology, Graduate School of Medicine, Osaka Metropolitan University, Osaka, Japan
| | - Ricky Indra Alfaray
- Department of Environmental and Preventive Medicine, Oita University Faculty of Medicine, Yufu, Oita, Japan
- Helicobacter pylori and Microbiota Study Group, Institute of Tropical Disease, Universitas Airlangga, Surabaya, 60115, Indonesia
| | - Batsaikhan Saruuljavkhlan
- Department of Environmental and Preventive Medicine, Oita University Faculty of Medicine, Yufu, Oita, Japan
| | - Takashi Matsumoto
- Department of Environmental and Preventive Medicine, Oita University Faculty of Medicine, Yufu, Oita, Japan
| | - Junko Akada
- Department of Environmental and Preventive Medicine, Oita University Faculty of Medicine, Yufu, Oita, Japan
| | - Yoshio Yamaoka
- Department of Environmental and Preventive Medicine, Oita University Faculty of Medicine, Yufu, Oita, Japan.
- Research Center for GLOBAL and LOCAL Infectious Diseases, Oita University, Yufu, Oita, Japan.
- Department of Medicine, Gastroenterology and Hepatology Section, Baylor College of Medicine, Houston, TX, USA.
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Wroblewski LE, Peek RM. Clinical Pathogenesis, Molecular Mechanisms of Gastric Cancer Development. Curr Top Microbiol Immunol 2023; 444:25-52. [PMID: 38231214 PMCID: PMC10924282 DOI: 10.1007/978-3-031-47331-9_2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/18/2024]
Abstract
The human pathogen Helicobacter pylori is the strongest known risk factor for gastric disease and cancer, and gastric cancer remains a leading cause of cancer-related death across the globe. Carcinogenic mechanisms associated with H. pylori are multifactorial and are driven by bacterial virulence constituents, host immune responses, environmental factors such as iron and salt, and the microbiota. Infection with strains that harbor the cytotoxin-associated genes (cag) pathogenicity island, which encodes a type IV secretion system (T4SS) confer increased risk for developing more severe gastric diseases. Other important H. pylori virulence factors that augment disease progression include vacuolating cytotoxin A (VacA), specifically type s1m1 vacA alleles, serine protease HtrA, and the outer-membrane adhesins HopQ, BabA, SabA and OipA. Additional risk factors for gastric cancer include dietary factors such as diets that are high in salt or low in iron, H. pylori-induced perturbations of the gastric microbiome, host genetic polymorphisms, and infection with Epstein-Barr virus. This chapter discusses in detail host factors and how H. pylori virulence factors augment the risk of developing gastric cancer in human patients as well as how the Mongolian gerbil model has been used to define mechanisms of H. pylori-induced inflammation and cancer.
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Affiliation(s)
- Lydia E Wroblewski
- Division of Gastroenterology, Hepatology, and Nutrition, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA
| | - Richard M Peek
- Division of Gastroenterology, Hepatology, and Nutrition, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA.
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Carlosama-Rosero Y, Acosta-Astaiza C, Sierra-Torres CH, Bolaños-Bravo H, Quiroga-Quiroga A, Bonilla-Chaves J. Virulence Genes of Helicobacter pylori Increase the Risk of Premalignant Gastric Lesions in a Colombian Population. Can J Gastroenterol Hepatol 2022; 2022:7058945. [PMID: 36212919 PMCID: PMC9534724 DOI: 10.1155/2022/7058945] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/08/2022] [Accepted: 08/24/2022] [Indexed: 01/06/2023] Open
Abstract
BACKGROUND Genetic variability of Helicobacter pylori is associated with various gastrointestinal diseases; however, little is known about interaction with sociodemographic in the development of premalignant lesions in Colombian patients. METHODS An analytical study was conducted including cases (patients with gastric atrophy, intestinal metaplasia, and gastric dysplasia) and controls (patients with nonatrophic gastritis). Sociodemographic information was obtained using a questionnaire. Histopathological diagnosis was performed according to the Sydney System. The cagA and vacA genotypes were established using polymerase chain reaction in paraffin blocks. The effect of each variable on the study outcome (premalignant lesion) is presented as odds ratio (OR) and 95% CI. A p value of <0.05 was considered as statistically significant. RESULTS The vacA/s1m1 genotype increases the risk of developing premalignant lesions of the stomach (OR: 3.05, 95% IC: 1.57-5.91, p=0.001). Age and educational level showed a positive interaction with the s1m1 genotype (adjusted OR: 3.68, 95% CI: 1.73-7.82, p=0.001). The cagA genotype was not correlated to the development of premalignant lesions of the stomach (OR: 1.32, 95% CI: 0.90-1.94, p=0.151). CONCLUSIONS The vacA genotype, age, and educational level are indicators of the risk of developing premalignant lesions of the stomach in the study population. Significance Statement. Genetic variability of H. pylori and sociodemographic information could be used to predict the risk of premalignant lesions in stomach in Colombian population.
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Affiliation(s)
- Yeison Carlosama-Rosero
- Interdisciplinary Research Group on Health and Disease, Cooperative University of Colombia, Pasto, Colombia
| | | | | | - H. Bolaños-Bravo
- Human and Applied Genetics Research Group, University of Cauca, Popayán, Colombia
| | | | - Juan Bonilla-Chaves
- Human and Applied Genetics Research Group, University of Cauca, Popayán, Colombia
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Rinninella E, Cintoni M, Raoul P, Ianiro G, Laterza L, Ponziani FR, Pulcini G, Gasbarrini A, Mele MC. Diet-Induced Alterations in Gut Microbiota Composition and Function. COMPREHENSIVE GUT MICROBIOTA 2022:354-373. [DOI: 10.1016/b978-0-12-819265-8.00035-8] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/05/2025]
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Öztekin M, Yılmaz B, Ağagündüz D, Capasso R. Overview of Helicobacter pylori Infection: Clinical Features, Treatment, and Nutritional Aspects. Diseases 2021; 9:66. [PMID: 34698140 PMCID: PMC8544542 DOI: 10.3390/diseases9040066] [Citation(s) in RCA: 46] [Impact Index Per Article: 11.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2021] [Revised: 09/11/2021] [Accepted: 09/23/2021] [Indexed: 12/11/2022] Open
Abstract
Helicobacter pylori (H. pylori) is a 0.5-1 µm wide, 2-4 µm long, short helical, S-shaped Gram-negative microorganism. It is mostly found in the pyloric region of the stomach and causes chronic gastric infection. It is estimated that these bacteria infect more than half of the world's population. The mode of transmission and infection of H. pylori is still not known exactly, but the faecal-oral and oral-oral routes via water or food consumption are thought to be a very common cause. In the last three decades, research interest has increased regarding the pathogenicity, microbial activity, genetic predisposition, and clinical treatments to understand the severity of gastric atrophy and gastric cancer caused by H. pylori. Studies have suggested a relationship between H. pylori infection and malabsorption of essential micronutrients, and noted that H. pylori infection may affect the prevalence of malnutrition in some risk groups. On the other hand, dietary factors may play a considerably important role in H. pylori infection, and it has been reported that an adequate and balanced diet, especially high fruit and vegetable consumption and low processed salty food consumption, has a protective effect against the outcomes of H. pylori infection. The present review provides an overview of all aspects of H. pylori infection, such as clinical features, treatment, and nutrition.
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Affiliation(s)
- Merve Öztekin
- Department of Nutrition and Dietetics, Faculty of Health Sciences, Gazi University, Emek, Ankara 06490, Turkey; (M.Ö.); (B.Y.)
| | - Birsen Yılmaz
- Department of Nutrition and Dietetics, Faculty of Health Sciences, Gazi University, Emek, Ankara 06490, Turkey; (M.Ö.); (B.Y.)
- Department of Nutrition and Dietetics, Faculty of Health Sciences, Çukurova University, Sarıçam, Adana 01330, Turkey
| | - Duygu Ağagündüz
- Department of Nutrition and Dietetics, Faculty of Health Sciences, Gazi University, Emek, Ankara 06490, Turkey; (M.Ö.); (B.Y.)
| | - Raffaele Capasso
- Department of Agricultural Sciences, University of Naples Federico II, 80055 Portici, Italy
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8
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Abstract
Helicobacter pylori is present in approximately one-half of the world's population. There are significant differences in prevalence based on region, age, race/ethnicity, and socioeconomic status. H pylori is the most common cause of infection-related cancers. Studies have demonstrated the relationship between H pylori infection and gastric adenocarcinoma and mucosa-associated lymphoid tissue lymphoma. H pylori has features and enzymatic properties allowing it to survive in the acidic stomach environment, and has specific virulence factors that promote an increased risk of gastric pathology. Eradication of H pylori is first-line therapy for mucosa-associated lymphoid tissue lymphoma and decreases the risk of gastric adenocarcinoma.
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9
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Padda J, Khalid K, Cooper AC, Jean-Charles G. Association Between Helicobacter pylori and Gastric Carcinoma. Cureus 2021; 13:e15165. [PMID: 34168929 PMCID: PMC8216031 DOI: 10.7759/cureus.15165] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 05/21/2021] [Indexed: 12/24/2022] Open
Abstract
Gastric carcinoma is the third leading cause of cancer mortality worldwide. In 2018, the incidence of gastric carcinoma worldwide was over 1,000,000 new cases, with approximately 783,000 deaths. The rate of new cases is noticeably increased in Eastern Asia. Helicobacter pylori is responsible for the increased incidence of gastric cancer. In the year 2015, H. pylori had an approximate prevalence of 4.4 billion positive cases worldwide, with the most positive cases found within the region of Africa, Latin America and the Caribbean, and of Asia. H. pylori is known to have multiple strains which allow it to survive in the host cell epithelium chronically. Research has shown many factors which play a significant role in developing infection and thereafter its progression to gastric carcinoma. After H. pylori colonizes the gastric mucosa, its effects can be potentiated by virulence factors, host factors, and environmental factors. H. pylori contains virulence factors that aid in the adhesion, translocation, inflammation, and infectivity of the host gastric epithelium. It alters the functions of the host immune response and cytokines, utilizing these factors to invade and persist in the gastric epithelium for a long period of time. The human body will identify H. pylori to be foreign and will exacerbate an inflammatory response in an effort to eradicate the bacterium. Consequently, this will cause H. pylori to induce a serious infection which may progress to cancer. In this review, we will discuss the various factors involved in the infectious process of H. pylori and how they help the infection progress to gastric carcinoma. This will allow us to better understand and modulate treatments to effectively eradicate this bacterium before it triggers the body into developing cancer.
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Affiliation(s)
| | | | | | - Gutteridge Jean-Charles
- Internal Medicine, Advent Health and Orlando Health Hospital/JC Medical Center, Orlando, USA
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10
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Tan MC, Mallepally N, Ho Q, Liu Y, El-Serag HB, Thrift AP. Dietary Factors and Gastric Intestinal Metaplasia Risk Among US Veterans. Dig Dis Sci 2021; 66:1600-1610. [PMID: 32535778 PMCID: PMC8845052 DOI: 10.1007/s10620-020-06399-9] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/13/2019] [Accepted: 06/03/2020] [Indexed: 02/06/2023]
Abstract
BACKGROUND Studies on diet and gastric intestinal metaplasia (GIM) risk are lacking in US populations. AIM To determine the associations of dietary factors and risk of GIM among a US population with typical American diet. METHODS We analyzed data from a cross-sectional study of veterans attending primary care and endoscopy clinics at the Houston VA Medical Center. Patients completed a 110-item Block Food Frequency Questionnaire then underwent upper endoscopy with gastric mapping biopsies. We compared cases defined by GIM on ≥ 1 non-cardia gastric biopsy to controls without GIM. Associations of dietary factors and GIM were estimated using logistic regression models as odds ratios (OR) and 95% confidence intervals (CI). RESULTS Among 423 GIM cases and 1796 controls, cases were older (62.1 vs. 59.9 years) and more likely to be male (97.2% vs. 90.8%) and non-White (58.6% vs. 39.0%). GIM cases had lower fat intake (percent kcal from fat tertile 1: 43.6% vs. 33.4%) and higher carbohydrate intake (percent kcal from carbohydrate T3: 41.8% vs. 33.3%) than controls. Adjusting for age, gender, race, smoking, and Helicobacter pylori, percent kcal from carbohydrates (T3 vs. T1: OR 1.35, 95% CI 1.08-1.67), fruit intake (T3 vs. T1: OR 1.28, 95% CI 1.02-1.61), and fiber intake (T3 vs. T1: OR 1.37, 95% CI 1.04-1.80) were associated with GIM. In subgroup analyses, these associations were primarily seen in non-White patients. CONCLUSIONS Few dietary factors, including high carbohydrate intake, are associated with increased risk of GIM in US populations, independent of H. pylori or smoking.
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Affiliation(s)
- Mimi C Tan
- Section of Gastroenterology and Hepatology, Baylor College of Medicine, Baylor College of Medicine, One Baylor Plaza, MS: BCM 285, Houston, TX, 77030-3498, USA.
| | | | - Quynh Ho
- Section of Gastroenterology and Hepatology, Baylor College of Medicine, Baylor College of Medicine, One Baylor Plaza, MS: BCM 285, Houston, TX, 77030-3498, USA
- University of St. Thomas, Houston, TX, USA
| | - Yan Liu
- Section of Gastroenterology and Hepatology, Baylor College of Medicine, Baylor College of Medicine, One Baylor Plaza, MS: BCM 285, Houston, TX, 77030-3498, USA
- Houston VA HSR&D Center for Innovations in Quality, Effectiveness and Safety, Michael E. DeBakey Veterans Affairs Medical Center, Houston, TX, USA
| | - Hashem B El-Serag
- Department of Medicine, Baylor College of Medicine, Houston, TX, USA
- Houston VA HSR&D Center for Innovations in Quality, Effectiveness and Safety, Michael E. DeBakey Veterans Affairs Medical Center, Houston, TX, USA
| | - Aaron P Thrift
- Section of Epidemiology and Population Sciences, Department of Medicine, Baylor College of Medicine, Houston, TX, USA
- Dan L Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, TX, USA
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11
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Wen Y, Huang H, Tang T, Yang H, Wang X, Huang X, Gong Y, Zhang X, She F. AI-2 represses CagA expression and bacterial adhesion, attenuating the Helicobacter pylori-induced inflammatory response of gastric epithelial cells. Helicobacter 2021; 26:e12778. [PMID: 33400843 DOI: 10.1111/hel.12778] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/07/2020] [Revised: 11/27/2020] [Accepted: 11/28/2020] [Indexed: 01/05/2023]
Abstract
BACKGROUND Helicobacter pylori (H. pylori) infection of gastric epithelial cells induces inflammatory response. Outer membrane proteins (OMPs), Type 4 secretion system (T4SS) encoded by cagPAI, and the effector protein CagA are involved in the pathogenesis of H. pylori. H. pylori possesses a gene encoding LuxS which synthesizes AI-2, a quorum sensing signal molecule. The aim of this study was to investigate the role of AI-2 in the expression of virulence factors and the inflammatory response of gastric epithelial (AGS) cells induced by H. pylori. MATERIALS AND METHODS H. pylori ΔluxS mutant was constructed, and AI-2 activity was measured with Vibrio harveyi BB170. NF-κB activation, IL-8 production, expression of OMPs (outer membrane proteins), CagA, and T4SS encoded by cagPAI were investigated in H. pylori wild type, and ΔluxS with or without supplementation of AI-2. RESULTS H. pylori produced approximately 7 μM of AI-2 in the medium. AI-2 inhibited expression and translocation of CagA after infection of AGS cells. AI-2 upregulated the expression of CagM, CagE, and CagX, while had no effect to the interaction between T4SS and α5β1 integrin. AI-2 also reduced expression of adhesins and bacterial adhesion to AGS cells. Finally, AI-2 reduced the activation of NF-κB and expression of IL-8 in H. pylori-infected AGS. CONCLUSIONS AI-2 plays an important role in the pathogenesis of H. pylori. AI-2 inhibits the bacterial adhesion, expression, and translocation of CagA, and attenuates the inflammatory response of AGS cells induced by H. pylori.
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Affiliation(s)
- Yancheng Wen
- Key Laboratory of Ministry of Education for Gastrointestinal Cancer, School of Basic Medical Sciences, Fujian Medical University, Fuzhou, China.,Fujian Key Laboratory of Tumor Microbiology, Department of Medical Microbiology, Fujian Medical University, Fuzhou, China
| | - Hongming Huang
- Key Laboratory of Ministry of Education for Gastrointestinal Cancer, School of Basic Medical Sciences, Fujian Medical University, Fuzhou, China.,Fujian Key Laboratory of Tumor Microbiology, Department of Medical Microbiology, Fujian Medical University, Fuzhou, China
| | - Tiechen Tang
- The First Hospital of Nanping City, affiliated to Fujian Medical University, Nanping, Fujian, China
| | - Huang Yang
- Key Laboratory of Ministry of Education for Gastrointestinal Cancer, School of Basic Medical Sciences, Fujian Medical University, Fuzhou, China.,Fujian Key Laboratory of Tumor Microbiology, Department of Medical Microbiology, Fujian Medical University, Fuzhou, China
| | - Xi Wang
- Key Laboratory of Ministry of Education for Gastrointestinal Cancer, School of Basic Medical Sciences, Fujian Medical University, Fuzhou, China.,Fujian Key Laboratory of Tumor Microbiology, Department of Medical Microbiology, Fujian Medical University, Fuzhou, China
| | - Xi Huang
- Key Laboratory of Ministry of Education for Gastrointestinal Cancer, School of Basic Medical Sciences, Fujian Medical University, Fuzhou, China.,Fujian Key Laboratory of Tumor Microbiology, Department of Medical Microbiology, Fujian Medical University, Fuzhou, China
| | - Yingying Gong
- Key Laboratory of Ministry of Education for Gastrointestinal Cancer, School of Basic Medical Sciences, Fujian Medical University, Fuzhou, China.,Fujian Key Laboratory of Tumor Microbiology, Department of Medical Microbiology, Fujian Medical University, Fuzhou, China
| | - Xiaoyan Zhang
- Key Laboratory of Ministry of Education for Gastrointestinal Cancer, School of Basic Medical Sciences, Fujian Medical University, Fuzhou, China.,Fujian Key Laboratory of Tumor Microbiology, Department of Medical Microbiology, Fujian Medical University, Fuzhou, China
| | - Feifei She
- Key Laboratory of Ministry of Education for Gastrointestinal Cancer, School of Basic Medical Sciences, Fujian Medical University, Fuzhou, China.,Fujian Key Laboratory of Tumor Microbiology, Department of Medical Microbiology, Fujian Medical University, Fuzhou, China
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12
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Piscione M, Mazzone M, Di Marcantonio MC, Muraro R, Mincione G. Eradication of Helicobacter pylori and Gastric Cancer: A Controversial Relationship. Front Microbiol 2021; 12:630852. [PMID: 33613500 PMCID: PMC7889593 DOI: 10.3389/fmicb.2021.630852] [Citation(s) in RCA: 66] [Impact Index Per Article: 16.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2020] [Accepted: 01/14/2021] [Indexed: 12/15/2022] Open
Abstract
Worldwide, gastric cancer (GC) represents the fifth cancer for incidence, and the third as cause of death in developed countries. Indeed, it resulted in more than 780,000 deaths in 2018. Helicobacter pylori appears to be responsible for the majority of these cancers. On the basis of recent studies, and either alone or combined with additional etiological factors, H. pylori is considered a "type I carcinogen." Over recent decades, new insights have been obtained into the strategies that have been adopted by H. pylori to survive the acidic conditions of the gastric environment, and to result in persistent infection, and dysregulation of host functions. The multistep processes involved in the development of GC are initiated by transition of the mucosa into chronic non-atrophic gastritis, which is primarily triggered by infection with H. pylori. This gastritis then progresses into atrophic gastritis and intestinal metaplasia, and then to dysplasia, and following Correa's cascade, to adenocarcinoma. The use of antibiotics for eradication of H. pylori can reduce the incidence of precancerous lesions only in the early stages of gastric carcinogenesis. Here, we first survey the etiology and risk factors of GC, and then we analyze the mechanisms underlying tumorigenesis induced by H. pylori, focusing attention on virulence factor CagA, inflammation, oxidative stress, and ErbB2 receptor tyrosine kinase. Moreover, we investigate the relationships between H. pylori eradication therapy and other diseases, considering not only cardia (upper stomach) cancers and Barrett's esophagus, but also asthma and allergies, through discussion of the "hygiene hypothesis. " This hypothesis suggests that improved hygiene and antibiotic use in early life reduces microbial exposure, such that the immune response does not become primed, and individuals are not protected against atopic disorders, asthma, and autoimmune diseases. Finally, we overview recent advances to uncover the complex interplay between H. pylori and the gut microbiota during gastric carcinogenesis, as characterized by reduced bacterial diversity and increased microbial dysbiosis. Indeed, it is of particular importance to identify the bacterial taxa of the stomach that might predict the outcome of gastric disease through the stages of Correa's cascade, to improve prevention and therapy of gastric carcinoma.
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Affiliation(s)
| | | | | | | | - Gabriella Mincione
- Department of Innovative Technologies in Medicine and Dentistry, University “G. d’Annunzio” of Chieti–Pescara, Chieti, Italy
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Kim J, Oh A, Truong H, Laszkowska M, Camargo MC, Abrams J, Hur C. Low sodium diet for gastric cancer prevention in the United States: Results of a Markov model. Cancer Med 2020; 10:684-692. [PMID: 33259151 PMCID: PMC7877368 DOI: 10.1002/cam4.3615] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/04/2020] [Revised: 10/20/2020] [Accepted: 10/30/2020] [Indexed: 11/23/2022] Open
Abstract
Background and Aims High sodium consumption has been associated with an increased risk of gastric cancer. The mean daily sodium intake in the United States substantially exceeds the national recommended amount. The low sodium‐DASH diet has been shown to decrease the risk of cardiovascular disease in the United States, but its impact on gastric cancer has not been well studied. We therefore aimed to model the impact and cost‐effectiveness of the low sodium‐DASH diet for gastric cancer prevention in the U.S. population. Methods A Markov cohort state‐transition model was developed to simulate the impact of the low sodium‐DASH diet on gastric cancer outcomes for the average 40‐year‐old in the United States compared to no intervention. Primary outcomes of interest were gastric cancer incidence and incremental cost‐effectiveness ratios (ICER). Results Our model found that compared to the no intervention cohort, the risk of gastric cancer decreased by 24.8% for males and 21.2% for females on the low sodium‐DASH diet. 27 cases and 14 cases per 10,000 individuals were prevented for males and females, respectively, in the intervention group. The ICER for the low sodium‐DASH diet strategy was $287,726 for males and $423,878 for females compared to the no intervention strategy. Conclusions Using a Markov model of gastric cancer risk, we found that adherence to a low sodium‐DASH diet could decrease the risk of gastric cancer. This intervention was not cost‐effective due to the high cost of a low sodium‐DASH accordant diet, but significantly improved for high‐risk populations and when the cost of the diet became slightly more affordable.
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Affiliation(s)
- Judith Kim
- Division of Digestive and Liver Diseases, Department of Medicine, Columbia University Irving Medical Center, New York, NY, USA
| | - Aaron Oh
- Division of General Medicine, Department of Medicine, Columbia University Irving Medical Center, New York, NY, USA
| | - Han Truong
- Division of General Medicine, Department of Medicine, Columbia University Irving Medical Center, New York, NY, USA
| | - Monika Laszkowska
- Department of Medicine, Gastroenterology, Hepatology, and Nutrition Service, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - M Constanza Camargo
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, MD, USA
| | - Julian Abrams
- Division of Digestive and Liver Diseases, Department of Medicine, Columbia University Irving Medical Center, New York, NY, USA
| | - Chin Hur
- Division of Digestive and Liver Diseases, Department of Medicine, Columbia University Irving Medical Center, New York, NY, USA.,Division of General Medicine, Department of Medicine, Columbia University Irving Medical Center, New York, NY, USA
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14
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Rinninella E, Cintoni M, Raoul P, Lopetuso LR, Scaldaferri F, Pulcini G, Miggiano GAD, Gasbarrini A, Mele MC. Food Components and Dietary Habits: Keys for a Healthy Gut Microbiota Composition. Nutrients 2019; 11:E2393. [PMID: 31591348 PMCID: PMC6835969 DOI: 10.3390/nu11102393] [Citation(s) in RCA: 384] [Impact Index Per Article: 64.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2019] [Revised: 09/25/2019] [Accepted: 09/27/2019] [Indexed: 02/06/2023] Open
Abstract
The gut microbiota is a changing ecosystem, containing trillions of bacteria, continuously shaped by many factors, such as dietary habits, seasonality, lifestyle, stress, antibiotics use, or diseases. A healthy host-microorganisms balance must be respected in order to optimally maintain the intestinal barrier and immune system functions and, consequently, prevent disease development. In the past several decades, the adoption of modern dietary habits has become a growing health concern, as it is strongly associated with obesity and related metabolic diseases, promoting inflammation and both structural and behavioral changes in gut microbiota. In this context, novel dietary strategies are emerging to prevent diseases and maintain health. However, the consequences of these different diets on gut microbiota modulation are still largely unknown, and could potentially lead to alterations of gut microbiota, intestinal barrier, and the immune system. The present review aimed to focus on the impact of single food components (macronutrients and micronutrients), salt, food additives, and different dietary habits (i.e., vegan and vegetarian, gluten-free, ketogenic, high sugar, low FODMAP, Western-type, and Mediterranean diets) on gut microbiota composition in order to define the optimal diet for a healthy modulation of gut microbiota.
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Affiliation(s)
- Emanuele Rinninella
- UOC di Nutrizione Clinica, Dipartimento di Scienze Gastroenterologiche, Endocrino‑Metaboliche e Nefro‑Urologiche, Fondazione Policlinico Universitario A. Gemelli IRCCS, Largo A. Gemelli 8, 00168 Rome, Italy.
- Istituto di Patologia Speciale Medica, Università Cattolica del Sacro Cuore, Largo F. Vito 1, 00168 Rome, Italy.
| | - Marco Cintoni
- Scuola di Specializzazione in Scienza dell'Alimentazione, Università di Roma Tor Vergata, Via Montpellier 1, 00133 Rome, Italy.
| | - Pauline Raoul
- Istituto di Patologia Speciale Medica, Università Cattolica del Sacro Cuore, Largo F. Vito 1, 00168 Rome, Italy.
| | - Loris Riccardo Lopetuso
- Istituto di Patologia Speciale Medica, Università Cattolica del Sacro Cuore, Largo F. Vito 1, 00168 Rome, Italy.
- UOC di Medicina Interna e Gastroenterologia, Dipartimento di Scienze Gastroenterologiche, Endocrino‑Metaboliche e Nefro‑Urologiche, Fondazione Policlinico Universitario A. Gemelli IRCCS, Largo A. Gemelli 8, 00168 Rome, Italy.
| | - Franco Scaldaferri
- Istituto di Patologia Speciale Medica, Università Cattolica del Sacro Cuore, Largo F. Vito 1, 00168 Rome, Italy.
- UOC di Medicina Interna e Gastroenterologia, Dipartimento di Scienze Gastroenterologiche, Endocrino‑Metaboliche e Nefro‑Urologiche, Fondazione Policlinico Universitario A. Gemelli IRCCS, Largo A. Gemelli 8, 00168 Rome, Italy.
| | - Gabriele Pulcini
- Scuola di Specializzazione in Scienza dell'Alimentazione, Università di Roma Tor Vergata, Via Montpellier 1, 00133 Rome, Italy.
| | - Giacinto Abele Donato Miggiano
- UOC di Nutrizione Clinica, Dipartimento di Scienze Gastroenterologiche, Endocrino‑Metaboliche e Nefro‑Urologiche, Fondazione Policlinico Universitario A. Gemelli IRCCS, Largo A. Gemelli 8, 00168 Rome, Italy.
- Istituto di Patologia Speciale Medica, Università Cattolica del Sacro Cuore, Largo F. Vito 1, 00168 Rome, Italy.
| | - Antonio Gasbarrini
- Istituto di Patologia Speciale Medica, Università Cattolica del Sacro Cuore, Largo F. Vito 1, 00168 Rome, Italy.
- UOC di Medicina Interna e Gastroenterologia, Dipartimento di Scienze Gastroenterologiche, Endocrino‑Metaboliche e Nefro‑Urologiche, Fondazione Policlinico Universitario A. Gemelli IRCCS, Largo A. Gemelli 8, 00168 Rome, Italy.
| | - Maria Cristina Mele
- UOC di Nutrizione Clinica, Dipartimento di Scienze Gastroenterologiche, Endocrino‑Metaboliche e Nefro‑Urologiche, Fondazione Policlinico Universitario A. Gemelli IRCCS, Largo A. Gemelli 8, 00168 Rome, Italy.
- Istituto di Patologia Speciale Medica, Università Cattolica del Sacro Cuore, Largo F. Vito 1, 00168 Rome, Italy.
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15
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Caston RR, Loh JT, Voss BJ, McDonald WH, Scholz MB, McClain MS, Cover TL. Effect of environmental salt concentration on the Helicobacter pylori exoproteome. J Proteomics 2019; 202:103374. [PMID: 31063819 DOI: 10.1016/j.jprot.2019.05.002] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2019] [Revised: 04/20/2019] [Accepted: 05/02/2019] [Indexed: 02/07/2023]
Abstract
Helicobacter pylori infection and a high salt diet are each risk factors for gastric cancer. In this study, we tested the hypothesis that environmental salt concentration influences the composition of the H. pylori exoproteome. H. pylori was cultured in media containing varying concentrations of sodium chloride, and aliquots were fractionated and analyzed by liquid chromatography-tandem mass spectrometry (LC-MS/MS). We identified proteins that were selectively released into the extracellular space, and we identified selectively released proteins that were differentially abundant in culture supernatants, depending on the environmental salt concentration. We also used RNA-seq analysis to identify genes that were differentially expressed in response to environmental salt concentration. The salt-responsive proteins identified by proteomic analysis and salt-responsive genes identified by RNA-seq analysis were mostly non-concordant, but the secreted toxin VacA was salt-responsive in both analyses. Western blot analysis confirmed that VacA levels in the culture supernatant were increased in response to high salt conditions, and quantitative RT-qPCR experiments confirmed that vacA transcription was upregulated in response to high salt conditions. These results indicate that environmental salt concentration influences the composition of the H. pylori exoproteome, which could contribute to the increased risk of gastric cancer associated with a high salt diet. SIGNIFICANCE: Helicobacter pylori-induced alterations in the gastric mucosa have been attributed, at least in part, to the actions of secreted H. pylori proteins. In this study, we show that H. pylori growth in high salt concentrations leads to increased levels of a secreted VacA toxin. Salt-induced alterations in the composition of the H. pylori exoproteome is relevant to the increased risk of gastric cancer associated with consumption of a high salt diet.
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Affiliation(s)
- Rhonda R Caston
- Department of Pathology, Microbiology and Immunology, Vanderbilt University School of Medicine, Nashville, TN, USA
| | - John T Loh
- Department of Medicine, Vanderbilt University School of Medicine, Nashville, TN, USA
| | - Bradley J Voss
- Department of Pathology, Microbiology and Immunology, Vanderbilt University School of Medicine, Nashville, TN, USA
| | - W Hayes McDonald
- Proteomics Laboratory, Mass Spectrometry Research Center, Vanderbilt University School of Medicine, Nashville, TN, USA; Department of Biochemistry, Vanderbilt University School of Medicine, Nashville, TN, USA
| | - Matthew B Scholz
- Vanderbilt Technologies for Advanced Genetics (VANTAGE), Vanderbilt University Medical Center, Nashville, TN, USA
| | - Mark S McClain
- Department of Medicine, Vanderbilt University School of Medicine, Nashville, TN, USA
| | - Timothy L Cover
- Department of Pathology, Microbiology and Immunology, Vanderbilt University School of Medicine, Nashville, TN, USA; Department of Medicine, Vanderbilt University School of Medicine, Nashville, TN, USA; Veterans Affairs Tennessee Valley Healthcare System, Nashville, TN, USA.
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16
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Role of a Stem-Loop Structure in Helicobacter pylori cagA Transcript Stability. Infect Immun 2019; 87:IAI.00692-18. [PMID: 30510104 DOI: 10.1128/iai.00692-18] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2018] [Accepted: 11/26/2018] [Indexed: 12/21/2022] Open
Abstract
Helicobacter pylori CagA is a secreted effector protein that contributes to gastric carcinogenesis. Previous studies showed that there is variation among H. pylori strains in the steady-state levels of CagA and that a strain-specific motif downstream of the cagA transcriptional start site (the +59 motif) is associated with both high levels of CagA and premalignant gastric histology. The cagA 5' untranslated region contains a predicted stem-loop-forming structure adjacent to the +59 motif. In the current study, we investigated the effect of the +59 motif and the adjacent stem-loop on cagA transcript levels and cagA mRNA stability. Using site-directed mutagenesis, we found that mutations predicted to disrupt the stem-loop structure resulted in decreased steady-state levels of both the cagA transcript and the CagA protein. Additionally, these mutations resulted in a decreased cagA mRNA half-life. Mutagenesis of the +59 motif without altering the stem-loop structure resulted in reduced steady-state cagA transcript and CagA protein levels but did not affect cagA transcript stability. cagA transcript stability was not affected by increased sodium chloride concentrations, an environmental factor known to augment cagA transcript levels and CagA protein levels. These results indicate that both a predicted stem-loop structure and a strain-specific +59 motif in the cagA 5' untranslated region influence the levels of cagA expression.
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17
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Noto JM, Chopra A, Loh JT, Romero-Gallo J, Piazuelo MB, Watson M, Leary S, Beckett AC, Wilson KT, Cover TL, Mallal S, Israel DA, Peek RM. Pan-genomic analyses identify key Helicobacter pylori pathogenic loci modified by carcinogenic host microenvironments. Gut 2018; 67:1793-1804. [PMID: 28924022 PMCID: PMC5857411 DOI: 10.1136/gutjnl-2017-313863] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/27/2017] [Revised: 06/30/2017] [Accepted: 07/15/2017] [Indexed: 12/12/2022]
Abstract
OBJECTIVE Helicobacter pylori is the strongest risk factor for gastric cancer; however, the majority of infected individuals do not develop disease. Pathological outcomes are mediated by complex interactions among bacterial, host and environmental constituents, and two dietary factors linked with gastric cancer risk are iron deficiency and high salt. We hypothesised that prolonged adaptation of H. pylori to in vivo carcinogenic microenvironments results in genetic modification important for disease. DESIGN Whole genome sequencing of genetically related H. pylori strains that differ in virulence and targeted H. pylori sequencing following prolonged exposure of bacteria to in vitro carcinogenic conditions were performed. RESULTS A total of 180 unique single nucleotide polymorphisms (SNPs) were identified among the collective genomes when compared with a reference H. pylori genome. Importantly, common SNPs were identified in isolates harvested from iron-depleted and high salt carcinogenic microenvironments, including an SNP within fur (FurR88H). To investigate the direct role of low iron and/or high salt, H. pylori was continuously cultured in vitro under low iron or high salt conditions to assess fur genetic variation. Exposure to low iron or high salt selected for the FurR88H variant after only 5 days. To extend these results, fur was sequenced in 339 clinical H. pylori strains. Among the isolates examined, 17% (40/232) of strains isolated from patients with premalignant lesions harboured the FurR88H variant, compared with only 6% (6/107) of strains from patients with non-atrophic gastritis alone (p=0.0034). CONCLUSION These results indicate that specific genetic variation arises within H. pylori strains during in vivo adaptation to conditions conducive for gastric carcinogenesis.
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Affiliation(s)
- Jennifer M Noto
- Department of Medicine, Division of Gastroenterology, Vanderbilt University Medical Center, Nashville, Tennessee, USA
| | - Abha Chopra
- Institute for Immunology and Infectious Diseases, Murdoch University, Murdoch, Australia
| | - John T Loh
- Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, Tennessee, USA
| | - Judith Romero-Gallo
- Department of Medicine, Division of Gastroenterology, Vanderbilt University Medical Center, Nashville, Tennessee, USA
| | - M Blanca Piazuelo
- Department of Medicine, Division of Gastroenterology, Vanderbilt University Medical Center, Nashville, Tennessee, USA
| | - Mark Watson
- Institute for Immunology and Infectious Diseases, Murdoch University, Murdoch, Australia
| | - Shay Leary
- Institute for Immunology and Infectious Diseases, Murdoch University, Murdoch, Australia
| | - Amber C Beckett
- Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, Tennessee, USA
| | - Keith T Wilson
- Department of Medicine, Division of Gastroenterology, Vanderbilt University Medical Center, Nashville, Tennessee, USA,Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, Tennessee, USA,Department of Veterans Affairs, Tennessee Valley Healthcare System, Nashville, Tennessee, USA,Department of Cancer Biology, Vanderbilt University Medical Center, Nashville, Tennessee, USA
| | - Timothy L Cover
- Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, Tennessee, USA,Department of Veterans Affairs, Tennessee Valley Healthcare System, Nashville, Tennessee, USA,Department of Medicine, Division of Infectious Diseases, Vanderbilt University, Nashville, Tennessee, USA
| | - Simon Mallal
- Institute for Immunology and Infectious Diseases, Murdoch University, Murdoch, Australia,Department of Medicine, Division of Infectious Diseases, Vanderbilt University, Nashville, Tennessee, USA
| | - Dawn A Israel
- Department of Medicine, Division of Gastroenterology, Vanderbilt University Medical Center, Nashville, Tennessee, USA
| | - Richard M Peek
- Department of Medicine, Division of Gastroenterology, Vanderbilt University Medical Center, Nashville, Tennessee, USA,Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, Tennessee, USA,Department of Cancer Biology, Vanderbilt University Medical Center, Nashville, Tennessee, USA
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18
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High-Salt Conditions Alter Transcription of Helicobacter pylori Genes Encoding Outer Membrane Proteins. Infect Immun 2018; 86:IAI.00626-17. [PMID: 29229727 DOI: 10.1128/iai.00626-17] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2017] [Accepted: 11/30/2017] [Indexed: 12/14/2022] Open
Abstract
Helicobacter pylori infection and high dietary salt intake are risk factors for the development of gastric adenocarcinoma. One possible mechanism by which a high-salt diet could influence gastric cancer risk is by modulating H. pylori gene expression. In this study, we utilized transcriptome sequencing (RNA-seq) methodology to compare the transcriptional profiles of H. pylori grown in media containing different concentrations of sodium chloride. We identified 118 differentially expressed genes (65 upregulated and 53 downregulated in response to high-salt conditions), including multiple members of 14 operons. Twenty-nine of the differentially expressed genes encode proteins previously shown to undergo salt-responsive changes in abundance, based on proteomic analyses. Real-time reverse transcription (RT)-PCR analyses validated differential expression of multiple genes encoding outer membrane proteins, including adhesins (SabA and HopQ) and proteins involved in iron acquisition (FecA2 and FecA3). Transcript levels of sabA, hopA, and hopQ are increased under high-salt conditions, whereas transcript levels of fecA2 and fecA3 are decreased under high-salt conditions. Transcription of sabA, hopA, hopQ, and fecA3 is derepressed in an arsS mutant strain, but salt-responsive transcription of these genes is not mediated by the ArsRS two-component system, and the CrdRS and FlgRS two-component systems do not have any detectable effects on transcription of these genes. In summary, these data provide a comprehensive view of H. pylori transcriptional alterations that occur in response to high-salt environmental conditions.
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19
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Dynamic Expansion and Contraction of cagA Copy Number in Helicobacter pylori Impact Development of Gastric Disease. mBio 2017; 8:mBio.01779-16. [PMID: 28223454 PMCID: PMC5358911 DOI: 10.1128/mbio.01779-16] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Infection with Helicobacter pylori is a major risk factor for development of gastric disease, including gastric cancer. Patients infected with H. pylori strains that express CagA are at even greater risk of gastric carcinoma. Given the importance of CagA, this report describes a new molecular mechanism by which the cagA copy number dynamically expands and contracts in H. pylori. Analysis of strain PMSS1 revealed a heterogeneous population in terms of numbers of cagA copies; strains carried from zero to four copies of cagA that were arranged as direct repeats within the chromosome. Each of the multiple copies of cagA was expressed and encoded functional CagA; strains with more cagA repeats exhibited higher levels of CagA expression and increased levels of delivery and phosphorylation of CagA within host cells. This concomitantly resulted in more virulent phenotypes as measured by cell elongation and interleukin-8 (IL-8) induction. Sequence analysis of the repeat region revealed three cagA homologous areas (CHAs) within the cagA repeats. Of these, CHA-ud flanked each of the cagA copies and is likely important for the dynamic variation of cagA copy numbers. Analysis of a large panel of clinical isolates showed that 7.5% of H. pylori strains isolated in the United States harbored multiple cagA repeats, while none of the tested Korean isolates carried more than one copy of cagA. Finally, H. pylori strains carrying multiple cagA copies were differentially associated with gastric disease. Thus, the dynamic expansion and contraction of cagA copy numbers may serve as a novel mechanism by which H. pylori modulates gastric disease development. Severity of H. pylori-associated disease is directly associated with carriage of the CagA toxin. Though the sequences of the CagA protein can differ across strains, previous analyses showed that virtually all H. pylori strains carry one or no copies of cagA. This study showed that H. pylori can carry multiple tandem copies of cagA that can change dynamically. Isolates harboring more cagA copies produced more CagA, thus enhancing toxicity to host cells. Analysis of 314 H. pylori clinical strains isolated from patients in South Korea and the United States showed that 7.5% of clinical strains in the United States carried multiple cagA copies whereas none of the South Korean strains did. This study demonstrated a novel molecular mechanism by which H. pylori dynamically modulates cagA copy number, which affects CagA expression and activity and may impact downstream development of gastric disease.
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20
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Dietary Composition Influences Incidence of Helicobacter pylori-Induced Iron Deficiency Anemia and Gastric Ulceration. Infect Immun 2016; 84:3338-3349. [PMID: 27620719 DOI: 10.1128/iai.00479-16] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2016] [Accepted: 09/02/2016] [Indexed: 12/17/2022] Open
Abstract
Epidemiologic studies have provided conflicting data regarding an association between Helicobacter pylori infection and iron deficiency anemia (IDA) in humans. Here, a Mongolian gerbil model was used to investigate a potential role of H. pylori infection, as well as a possible role of diet, in H. pylori-associated IDA. Mongolian gerbils (either H. pylori infected or uninfected) received a normal diet or one of three diets associated with increased H. pylori virulence: high-salt, low-iron, or a combination of a high-salt and low-iron diet. In an analysis of all infected animals compared to uninfected animals (independent of diet), H. pylori-infected gerbils had significantly lower hemoglobin values than their uninfected counterparts at 16 weeks postinfection (P < 0.0001). The mean corpuscular volume (MCV) and serum ferritin values were significantly lower in H. pylori-infected gerbils than in uninfected gerbils, consistent with IDA. Leukocytosis and thrombocytosis were also detected in infected gerbils, indicating the presence of a systemic inflammatory response. In comparison to uninfected gerbils, H. pylori-infected gerbils had a higher gastric pH, a higher incidence of gastric ulcers, and a higher incidence of fecal occult blood loss. Anemia was associated with the presence of gastric ulceration but not gastric cancer. Infected gerbils consuming diets with a high salt content developed gastric ulcers significantly more frequently than gerbils consuming a normal-salt diet, and the lowest hemoglobin levels were in infected gerbils consuming a high-salt/low-iron diet. These data indicate that H. pylori infection can cause IDA and that the composition of the diet influences the incidence and severity of H. pylori-induced IDA.
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21
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Devi S, Ansari SA, Tenguria S, Kumar N, Ahmed N. Multipronged regulatory functions of a novel endonuclease (TieA) from Helicobacter pylori. Nucleic Acids Res 2016; 44:9393-9412. [PMID: 27550181 PMCID: PMC5100599 DOI: 10.1093/nar/gkw730] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/19/2016] [Accepted: 08/11/2016] [Indexed: 12/29/2022] Open
Abstract
Helicobacter pylori portrays a classical paradigm of persistent bacterial infections. A well balanced homeostasis of bacterial effector functions and host responses is purported to be the key in achieving long term colonization in specific hosts. H. pylori nucleases have been shown to assist in natural transformation, but their role in virulence and colonization remains elusive. Therefore, it is imperative to understand the involvement of these nucleases in the pathogenesis of H. pylori. Here, we report the multifaceted role of a TNFR-1 interacting endonuclease A (TieA) from H. pylori. tieA expression is differentially regulated in response to environmental stress and post adherence to gastric epithelial cells. Studies with isogenic knockouts of tieA revealed it to be a secretory protein which translocates into the host gastric epithelial cells independent of a type IV secretion system, gets phosphorylated by DNA-PK kinase and auto-phosphorylates as serine kinase. Furthermore, TieA binds to and cleaves DNA in a non-specific manner and promotes Fas mediated apoptosis in AGS cells. Additionally, TieA induced pro-inflammatory cytokine secretion via activation of transcription factor AP-1 and signaled through MAP kinase pathway. Collectively, TieA with its multipronged and moonlighting functions could facilitate H. pylori in maintaining a balance of bacterial adaptation, and elimination by the host responses.
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Affiliation(s)
- Savita Devi
- Pathogen Biology Laboratory, Department of Biotechnology and Bioinformatics, University of Hyderabad, Gachibowli, Hyderabad 500046, India
| | - Suhail A Ansari
- Pathogen Biology Laboratory, Department of Biotechnology and Bioinformatics, University of Hyderabad, Gachibowli, Hyderabad 500046, India
| | - Shivendra Tenguria
- Pathogen Biology Laboratory, Department of Biotechnology and Bioinformatics, University of Hyderabad, Gachibowli, Hyderabad 500046, India
| | - Naveen Kumar
- Pathogen Biology Laboratory, Department of Biotechnology and Bioinformatics, University of Hyderabad, Gachibowli, Hyderabad 500046, India
| | - Niyaz Ahmed
- Pathogen Biology Laboratory, Department of Biotechnology and Bioinformatics, University of Hyderabad, Gachibowli, Hyderabad 500046, India
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Yao Y, Jiang Q, Jiang L, Wu J, Zhang Q, Wang J, Feng H, Zang P. Lnc-SGK1 induced by Helicobacter pylori infection and highsalt diet promote Th2 and Th17 differentiation in human gastric cancer by SGK1/Jun B signaling. Oncotarget 2016; 7:20549-60. [PMID: 26942879 PMCID: PMC4991474 DOI: 10.18632/oncotarget.7823] [Citation(s) in RCA: 59] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2015] [Accepted: 02/14/2016] [Indexed: 01/05/2023] Open
Abstract
Serum and glucocorticoid-inducible kinase (SGK) 1can be triggered in several malignancies. Most research on SGK1has focused on its role in cancer cells, and we sought to investigate its potential upstream non-coding RNA nominated as Lnc-SGK1, and their expression and diagnostic value in T cells in human gastric cancer (GC). Excessive expression of Lnc-SGK1 and SGK1 were observed in T cell either within the tumor or peripheral T cells, and furthermore associated with Helicobacter pylori infection and high-salt diet (HSD). Within T cells, Helicobacter pylori (Hp) infection and high-salt dietcan up-regulated SGK1 expression and in turn enhance expression of Lnc-SGK1 through JunB activation. And expression of Lnc-SGK1 can further enhance transcription of SGK1 through cis regulatory mode. Lnc-SGK1 can induce Th2 and Th17 and reduce Th1 differentiation via SGK1/JunB signaling. Serum Lnc-SGK1 expression in combination with H. pylori infection and/or HSD in T cells was associated with poor prognosis of GC patients, and could be an ideal diagnostic index in human GC.
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Affiliation(s)
- Yongliang Yao
- Department of Clinical Laboratory, The First People's Hospital of Kunshan, Affiliated to Jiangsu University, Kunshan, Jiangsu, China
| | - Qingbo Jiang
- Department of Clinical Laboratory, The Third Affiliated Hospital of Suzhou University, Changzhou, Jiangsu, China
| | - Lixing Jiang
- Department of Clinical Laboratory, Wujin Hospital Affiliated to Jiangsu University, Changzhou, Jiangsu, China
| | - Jianhong Wu
- Department of Clinical Laboratory, The First People's Hospital of Kunshan, Affiliated to Jiangsu University, Kunshan, Jiangsu, China
| | - Qinghui Zhang
- Department of Clinical Laboratory, The First People's Hospital of Kunshan, Affiliated to Jiangsu University, Kunshan, Jiangsu, China
| | - Jianjun Wang
- Department of Clinical Laboratory, The First People's Hospital of Kunshan, Affiliated to Jiangsu University, Kunshan, Jiangsu, China
| | - Huang Feng
- Department of Clinical Laboratory, The First People's Hospital of Kunshan, Affiliated to Jiangsu University, Kunshan, Jiangsu, China
| | - Panpan Zang
- Department of Clinical Laboratory, The First People's Hospital of Kunshan, Affiliated to Jiangsu University, Kunshan, Jiangsu, China
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Raei N, Behrouz B, Zahri S, Latifi-Navid S. Helicobacter pylori Infection and Dietary Factors Act Synergistically to Promote Gastric Cancer. Asian Pac J Cancer Prev 2016; 17:917-21. [DOI: 10.7314/apjcp.2016.17.3.917] [Citation(s) in RCA: 29] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/10/2022] Open
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Zhang RG, Duan GC, Fan QT, Chen SY. Role of Helicobacter pylori infection in pathogenesis of gastric carcinoma. World J Gastrointest Pathophysiol 2016; 7:97-107. [PMID: 26909232 PMCID: PMC4753193 DOI: 10.4291/wjgp.v7.i1.97] [Citation(s) in RCA: 48] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/28/2015] [Revised: 09/18/2015] [Accepted: 11/04/2015] [Indexed: 02/06/2023] Open
Abstract
Gastric cancer (GC) is one of the most common carcinoma and the second leading cause of cancer-related deaths worldwide. Helicobacter pylori (H. pylori) infection causes a series of precancerous lesions like gastritis, atrophy, intestinal metaplasia and dysplasia, and is the strongest known risk factor for GC, as supported by epidemiological, preclinical and clinical studies. However, the mechanism of H. pylori developing gastric carcinoma has not been well defined. Among infected individuals, approximately 10% develop severe gastric lesions such as peptic ulcer disease, 1%-3% progresses to GC. The outcomes of H. pylori infection are determined by bacterial virulence, genetic polymorphism of hosts as well as environmental factors. It is important to gain further understanding of the pathogenesis of H. pylori infection for developing more effective treatments for this common but deadly malignancy. The recent findings on the bacterial virulence factors, effects of H. pylori on epithelial cells, genetic polymorphism of both the bacterium and its host, and the environmental factors for GC are discussed with focus on the role of H. pylori in gastric carcinogenesis in this review.
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Abstract
BACKGROUND Helicobacter pylori is a bacterial carcinogen that is supposed to have the highest known level of risk for the development of gastric cancer, a disease that claims hundreds of thousands of lives per year. Approximately 89% of the global gastric cancer burden and 5.5% of malignancies worldwide are attributed to H. pylori-induced inflammation and injury. However, only a fraction of colonized persons ever develop neoplasia, and disease risk involves well-choreographed interactions between pathogen and host, which are dependent upon strain-specific bacterial factors, host genotypic traits, and/or environmental conditions. KEY MESSAGES One H. pylori strain-specific virulence determinant that augments the risk for gastric cancer is the cag pathogenicity island, a secretion system that injects the bacterial oncoprotein CagA into host cells. Host polymorphisms within genes that regulate immunity and oncogenesis also heighten the risk for gastric cancer, in conjunction with H. pylori strain-specific constituents. Further, conditions such as iron deficiency and high salt intake can influence H. pylori phenotypes that lower the threshold for disease. CONCLUSIONS Delineation of bacterial, host, and environmental mediators that augment gastric cancer risk has profound ramifications for both physicians and biomedical researchers as such findings will not only focus prevention approaches that target H. pylori-infected human populations at increased risk for stomach cancer, but will also provide mechanistic insights into inflammatory carcinomas that develop beyond the gastric niche.
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Affiliation(s)
- Richard M. Peek
- Division of Gastroenterology, Department of Medicine, Vanderbilt University School of Medicine, 2215B Garland Ave Suite 1030C, 37232 Nashville, TN USA
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Amieva M, Peek RM. Pathobiology of Helicobacter pylori-Induced Gastric Cancer. Gastroenterology 2016; 150:64-78. [PMID: 26385073 PMCID: PMC4691563 DOI: 10.1053/j.gastro.2015.09.004] [Citation(s) in RCA: 628] [Impact Index Per Article: 69.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/07/2015] [Revised: 09/01/2015] [Accepted: 09/03/2015] [Indexed: 02/07/2023]
Abstract
Colonization of the human stomach by Helicobacter pylori and its role in causing gastric cancer is one of the richest examples of a complex relationship among human cells, microbes, and their environment. It is also a puzzle of enormous medical importance given the incidence and lethality of gastric cancer worldwide. We review recent findings that have changed how we view these relationships and affected the direction of gastric cancer research. For example, recent data have indicated that subtle mismatches between host and microbe genetic traits greatly affect the risk of gastric cancer. The ability of H pylori and its oncoprotein CagA to reprogram epithelial cells and activate properties of stemness show the sophisticated relationship between H pylori and progenitor cells in the gastric mucosa. The observation that cell-associated H pylori can colonize the gastric glands and directly affect precursor and stem cells supports these observations. The ability to mimic these interactions in human gastric organoid cultures as well as animal models will allow investigators to more fully unravel the extent of H pylori control on the renewing gastric epithelium. Finally, our realization that external environmental factors, such as dietary components and essential micronutrients, as well as the gastrointestinal microbiota, can change the balance between H pylori's activity as a commensal or a pathogen has provided direction to studies aimed at defining the full carcinogenic potential of this organism.
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Affiliation(s)
- Manuel Amieva
- Department of Microbiology and Immunology, Stanford University, Palo Alto, California; Department of Pediatrics, Stanford University, Palo Alto, California
| | - Richard M Peek
- Division of Gastroenterology, Hepatology, and Nutrition, Department of Medicine, Vanderbilt University, Nashville, Tennessee; Department of Cancer Biology, Vanderbilt University, Nashville, Tennessee.
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Sun Y, Huang XJ, Chen L. New progress in study of risk factors for gastric cancer. Shijie Huaren Xiaohua Zazhi 2015; 23:4831-4837. [DOI: 10.11569/wcjd.v23.i30.4831] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Gastric cancer is one of the most common malignant tumors, and its etiology is not clear yet. Numerous studies show that the development of gastric cancer is a complex process related with many factors, such as demographic, lifestyle and diet, infectious, hereditary, socioeconomic, and mental factors. Early prevention can effectively reduce the incidence of gastric cancer. Here we make a review of the new progress in research of risk factors for gastric cancer.
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Helicobacter pylori adaptation in vivo in response to a high-salt diet. Infect Immun 2015; 83:4871-83. [PMID: 26438795 DOI: 10.1128/iai.00918-15] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2015] [Accepted: 09/30/2015] [Indexed: 12/21/2022] Open
Abstract
Helicobacter pylori exhibits a high level of intraspecies genetic diversity. In this study, we investigated whether the diversification of H. pylori is influenced by the composition of the diet. Specifically, we investigated the effect of a high-salt diet (a known risk factor for gastric adenocarcinoma) on H. pylori diversification within a host. We analyzed H. pylori strains isolated from Mongolian gerbils fed either a high-salt diet or a regular diet for 4 months by proteomic and whole-genome sequencing methods. Compared to the input strain and output strains from animals fed a regular diet, the output strains from animals fed a high-salt diet produced higher levels of proteins involved in iron acquisition and oxidative-stress resistance. Several of these changes were attributable to a nonsynonymous mutation in fur (fur-R88H). Further experiments indicated that this mutation conferred increased resistance to high-salt conditions and oxidative stress. We propose a model in which a high-salt diet leads to high levels of gastric inflammation and associated oxidative stress in H. pylori-infected animals and that these conditions, along with the high intraluminal concentrations of sodium chloride, lead to selection of H. pylori strains that are most fit for growth in this environment.
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29
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Ferreira RM, Pinto-Ribeiro I, Wen X, Marcos-Pinto R, Dinis-Ribeiro M, Carneiro F, Figueiredo C. Helicobacter pylori cagA Promoter Region Sequences Influence CagA Expression and Interleukin 8 Secretion. J Infect Dis 2015; 213:669-73. [PMID: 26401027 DOI: 10.1093/infdis/jiv467] [Citation(s) in RCA: 39] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/24/2015] [Accepted: 09/15/2015] [Indexed: 12/12/2022] Open
Abstract
Heterogeneity at the Helicobacter pylori cagA gene promoter region has been linked to variation in CagA expression and gastric histopathology. Here, we characterized the cagA promoter and expression in 46 H. pylori strains from Portugal. Our results confirm the relationship between cagA promoter region variation and protein expression originally observed in strains from Colombia. We observed that individuals with intestinal metaplasia were all infected with H. pylori strains containing a specific cagA motif. Additionally, we provided novel functional evidence that strain-specific sequences in the cagA promoter region and CagA expression levels influence interleukin 8 secretion by the host gastric epithelial cells.
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Affiliation(s)
- Rui M Ferreira
- i3S - Instituto de Investigação e Inovação em Saúde Ipatimup - Institute of Molecular Pathology and Immunology
| | - Ines Pinto-Ribeiro
- i3S - Instituto de Investigação e Inovação em Saúde Ipatimup - Institute of Molecular Pathology and Immunology
| | - Xiaogang Wen
- Ipatimup - Institute of Molecular Pathology and Immunology Centro Hospitalar Vila Nova de Gaia/Espinho, Portugal
| | - Ricardo Marcos-Pinto
- Institute of Biomedical Sciences Abel Salazar CIDES/CINTESIS Department of Gastroenterology, Centro Hospitalar do Porto
| | | | - Fátima Carneiro
- i3S - Instituto de Investigação e Inovação em Saúde Ipatimup - Institute of Molecular Pathology and Immunology Faculty of Medicine, University of Porto Department of Pathology, Centro Hospitalar São João, Porto
| | - Ceu Figueiredo
- i3S - Instituto de Investigação e Inovação em Saúde Ipatimup - Institute of Molecular Pathology and Immunology Faculty of Medicine, University of Porto
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Voss BJ, Loh JT, Hill S, Rose KL, McDonald WH, Cover TL. Alteration of the Helicobacter pylori membrane proteome in response to changes in environmental salt concentration. Proteomics Clin Appl 2015; 9:1021-34. [PMID: 26109032 DOI: 10.1002/prca.201400176] [Citation(s) in RCA: 31] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2014] [Revised: 05/18/2015] [Accepted: 06/22/2015] [Indexed: 12/14/2022]
Abstract
PURPOSE Helicobacter pylori infection and a high dietary salt intake are each risk factors for the development of gastric cancer. We hypothesize that changes in environmental salt concentrations lead to alterations in the H. pylori membrane proteome. EXPERIMENTAL DESIGN Label-free and iTRAQ methods were used to identify H. pylori proteins that change in abundance in response to alterations in environmental salt concentrations. In addition, we biotinylated intact bacteria that were grown under high- or low-salt conditions, and thereby analyzed salt-induced changes in the abundance of surface-exposed proteins. RESULTS Proteins with increased abundance in response to high salt conditions included CagA, the outer membrane protein HopQ, and fibronectin domain-containing protein HP0746. Proteins with increased abundance in response to low salt conditions included VacA, two VacA-like proteins (ImaA and FaaA), outer-membrane iron transporter FecA3, and several proteins involved in flagellar activity. Consistent with the proteomic data, bacteria grown in high salt conditions exhibited decreased motility compared to bacteria grown in lower salt conditions. CONCLUSION AND CLINICAL RELEVANCE Alterations in the H. pylori membrane proteome in response to high salt conditions may contribute to the increased risk of gastric cancer associated with a high salt diet.
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Affiliation(s)
- Bradley J Voss
- Department of Pathology, Microbiology and Immunology, Vanderbilt University School of Medicine, Nashville, TN, USA
| | - John T Loh
- Department of Medicine, Vanderbilt University School of Medicine, Nashville, TN, USA
| | - Salisha Hill
- Proteomics Laboratory, Mass Spectrometry Research Center, Vanderbilt University School of Medicine, Nashville, TN, USA
| | - Kristie L Rose
- Proteomics Laboratory, Mass Spectrometry Research Center, Vanderbilt University School of Medicine, Nashville, TN, USA.,Department of Biochemistry, Vanderbilt University School of Medicine, Nashville, TN, USA
| | - W Hayes McDonald
- Proteomics Laboratory, Mass Spectrometry Research Center, Vanderbilt University School of Medicine, Nashville, TN, USA.,Department of Biochemistry, Vanderbilt University School of Medicine, Nashville, TN, USA
| | - Timothy L Cover
- Department of Pathology, Microbiology and Immunology, Vanderbilt University School of Medicine, Nashville, TN, USA.,Department of Medicine, Vanderbilt University School of Medicine, Nashville, TN, USA.,Veterans Affairs Tennessee Valley Healthcare System, Nashville, TN, USA
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31
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De Falco M, Lucariello A, Iaquinto S, Esposito V, Guerra G, De Luca A. Molecular Mechanisms of Helicobacter pylori Pathogenesis. J Cell Physiol 2015; 230:1702-7. [PMID: 25639461 DOI: 10.1002/jcp.24933] [Citation(s) in RCA: 48] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2014] [Accepted: 01/16/2015] [Indexed: 12/12/2022]
Abstract
Helicobacter pylori infects 50% of mankind. The vast majority of H. pylori infection occurs in the developing countries where up to 80% of the middle-aged adults may be infected. Bacterial infection causes an inflammatory response that proceeds through a series of intermediated stages of precancerous lesions (gastritis, atrophy, intestinal metaplasia, and dysplasia). Among infected individuals, approximately 10% develops severe gastric lesions such as peptic ulcer disease, 1-3% progresses to gastric cancer (GC) with a low 5-year survival rate, and 0.1% develops mucosa-associated lymphoid tissue (MALT). GC is one of the most common cancer and the third leading cause of cancer-related deaths worldwide. In this review, we have summarized the most recent papers about molecular mechanisms of H. pylori pathogenesis. The main important steps of H. pylori infection such as adhesion, entry in epithelial gastric cells, activation of intracellular pathways until epigenetic modifications have been described.
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Affiliation(s)
- Maria De Falco
- Department of Biology, University Federico II of Naples, Naples, Italy; National Institute of Biostructures and Biosystems (INBB), Rome, Italy
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The Human Antimicrobial Protein Calgranulin C Participates in Control of Helicobacter pylori Growth and Regulation of Virulence. Infect Immun 2015; 83:2944-56. [PMID: 25964473 DOI: 10.1128/iai.00544-15] [Citation(s) in RCA: 55] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2015] [Accepted: 04/30/2015] [Indexed: 12/18/2022] Open
Abstract
During infectious processes, antimicrobial proteins are produced by both epithelial cells and innate immune cells. Some of these antimicrobial molecules function by targeting transition metals and sequestering these metals in a process referred to as "nutritional immunity." This chelation strategy ultimately starves invading pathogens, limiting their growth within the vertebrate host. Recent evidence suggests that these metal-binding antimicrobial molecules have the capacity to affect bacterial virulence, including toxin secretion systems. Our previous work showed that the S100A8/S100A9 heterodimer (calprotectin, or calgranulin A/B) binds zinc and represses the elaboration of the H. pylori cag type IV secretion system (T4SS). However, there are several other S100 proteins that are produced in response to infection. We hypothesized that the zinc-binding protein S100A12 (calgranulin C) is induced in response to H. pylori infection and also plays a role in controlling H. pylori growth and virulence. To test this, we analyzed gastric biopsy specimens from H. pylori-positive and -negative patients for S100A12 expression. These assays showed that S100A12 is induced in response to H. pylori infection and inhibits bacterial growth and viability in vitro by binding nutrient zinc. Furthermore, the data establish that the zinc-binding activity of the S100A12 protein represses the activity of the cag T4SS, as evidenced by the gastric cell "hummingbird" phenotype, interleukin 8 (IL-8) secretion, and CagA translocation assays. In addition, high-resolution field emission gun scanning electron microscopy (FEG-SEM) was used to demonstrate that S100A12 represses biogenesis of the cag T4SS. Together with our previous work, these data reveal that multiple S100 proteins can repress the elaboration of an oncogenic bacterial surface organelle.
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Gaddy JA, Radin JN, Loh JT, Piazuelo MB, Kehl-Fie TE, Delgado AG, Ilca FT, Peek RM, Cover TL, Chazin WJ, Skaar EP, Scott Algood HM. The host protein calprotectin modulates the Helicobacter pylori cag type IV secretion system via zinc sequestration. PLoS Pathog 2014; 10:e1004450. [PMID: 25330071 PMCID: PMC4199781 DOI: 10.1371/journal.ppat.1004450] [Citation(s) in RCA: 70] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2014] [Accepted: 09/04/2014] [Indexed: 12/11/2022] Open
Abstract
Transition metals are necessary for all forms of life including microorganisms, evidenced by the fact that 30% of all proteins are predicted to interact with a metal cofactor. Through a process termed nutritional immunity, the host actively sequesters essential nutrient metals away from invading pathogenic bacteria. Neutrophils participate in this process by producing several metal chelating proteins, including lactoferrin and calprotectin (CP). As neutrophils are an important component of the inflammatory response directed against the bacterium Helicobacter pylori, a major risk factor for gastric cancer, it was hypothesized that CP plays a role in the host response to H. pylori. Utilizing a murine model of H. pylori infection and gastric epithelial cell co-cultures, the role CP plays in modifying H. pylori -host interactions and the function of the cag Type IV Secretion System (cag T4SS) was investigated. This study indicates elevated gastric levels of CP are associated with the infiltration of neutrophils to the H. pylori-infected tissue. When infected with an H. pylori strain harboring a functional cag T4SS, calprotectin-deficient mice exhibited decreased bacterial burdens and a trend toward increased cag T4SS -dependent inflammation compared to wild-type mice. In vitro data demonstrate that culturing H. pylori with sub-inhibitory doses of CP reduces the activity of the cag T4SS and the biogenesis of cag T4SS-associated pili in a zinc-dependent fashion. Taken together, these data indicate that zinc homeostasis plays a role in regulating the proinflammatory activity of the cag T4SS.
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Affiliation(s)
- Jennifer A. Gaddy
- Veterans Affairs Tennessee Valley Healthcare Services, Nashville, Tennessee, United States of America
- Department of Medicine, Vanderbilt University School of Medicine, Nashville, Tennessee, United States of America
| | - Jana N. Radin
- Department of Medicine, Vanderbilt University School of Medicine, Nashville, Tennessee, United States of America
| | - John T. Loh
- Department of Medicine, Vanderbilt University School of Medicine, Nashville, Tennessee, United States of America
| | - M. Blanca Piazuelo
- Department of Medicine, Vanderbilt University School of Medicine, Nashville, Tennessee, United States of America
| | - Thomas E. Kehl-Fie
- Department of Pathology, Microbiology and Immunology, Vanderbilt University School of Medicine, Nashville, Tennessee, United States of America
| | - Alberto G. Delgado
- Department of Medicine, Vanderbilt University School of Medicine, Nashville, Tennessee, United States of America
| | - Florin T. Ilca
- Department of Medicine, Vanderbilt University School of Medicine, Nashville, Tennessee, United States of America
| | - Richard M. Peek
- Department of Medicine, Vanderbilt University School of Medicine, Nashville, Tennessee, United States of America
| | - Timothy L. Cover
- Veterans Affairs Tennessee Valley Healthcare Services, Nashville, Tennessee, United States of America
- Department of Medicine, Vanderbilt University School of Medicine, Nashville, Tennessee, United States of America
- Department of Pathology, Microbiology and Immunology, Vanderbilt University School of Medicine, Nashville, Tennessee, United States of America
| | - Walter J. Chazin
- Department of Biochemistry, Vanderbilt University School of Medicine, Nashville, Tennessee, United States of America
- Center for Structural Biology, Vanderbilt University School of Medicine, Nashville, Tennessee, United States of America
| | - Eric P. Skaar
- Veterans Affairs Tennessee Valley Healthcare Services, Nashville, Tennessee, United States of America
- Department of Pathology, Microbiology and Immunology, Vanderbilt University School of Medicine, Nashville, Tennessee, United States of America
| | - Holly M. Scott Algood
- Veterans Affairs Tennessee Valley Healthcare Services, Nashville, Tennessee, United States of America
- Department of Medicine, Vanderbilt University School of Medicine, Nashville, Tennessee, United States of America
- Department of Pathology, Microbiology and Immunology, Vanderbilt University School of Medicine, Nashville, Tennessee, United States of America
- * E-mail:
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Abstract
Infection with Helicobacter pylori is established as the major risk factor for gastric cancer development. Damage of the mucosal barrier due to H. pylori-induced inflammation enhances the carcinogenic effect of other risk factors such as salt intake or tobacco smoking. The genetic disposition of both the bacterial strain and the host can increase the potential towards gastric cancer formation. Genetic variance of the bacterial proteins CagA and VacA is associated with a higher gastric cancer risk, as are polymorphisms and epigenetic changes in host gene coding for interleukins (IL1β, IL8), transcription factors (CDX2, RUNX3) and DNA repair enzymes. Application of high-throughput assays for genome-wide assessment of either genetic structural variance or gene expression patterns may lead to a better understanding of the pathobiological background of these processes, including the underlying signaling pathways. Understanding of the stepwise alterations that take place in the transition from chronic atrophic gastritis, via metaplastic changes, to invasive neoplasia is vital to define the 'point of no return' before which eradication of H. pylori has the potential to prevent gastric cancer. Currently, eradication as preventive strategy is only recommended for high-incidence regions in Asia; large population studies with an adequate follow-up are required to demonstrate the effectiveness of such an approach in Western populations.
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Affiliation(s)
- Jan Bornschein
- Department of Gastroenterology, Hepatology and Infectious Diseases, Otto von Guericke University of Magdeburg, Magdeburg, Germany
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35
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Wang F, Meng W, Wang B, Qiao L. Helicobacter pylori-induced gastric inflammation and gastric cancer. Cancer Lett 2014; 345:196-202. [PMID: 23981572 DOI: 10.1016/j.canlet.2013.08.016] [Citation(s) in RCA: 564] [Impact Index Per Article: 51.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/12/2013] [Revised: 08/07/2013] [Accepted: 08/13/2013] [Indexed: 02/06/2023]
Abstract
Helicobacter pylori (H. pylori) infect over half of the world's population. The prevalence of H. pylori infection and the predominant genotype of H. pylori virulence factors vary considerably across different geographical regions. H. pylori could uniquely persist for decades in the harsh stomach environment, where it damages the gastric mucosa and changes the pattern of gastric hormone release, thereby affects gastric physiology. By utilizing various virulence factors, H. pylori targets different cellular proteins to modulate the host inflammatory response and initiate multiple "hits" on the gastric mucosa, resulting in chronic gastritis and peptic ulceration. Among the long-term consequences of H. pylori infection is gastric malignancies, particularly gastric cancer (GC) and gastric mucosa-associated lymphoid tissue (MALT) lymphoma. As such, H. pylori has been recognized as a class I carcinogen by the International Agency for Research on Cancer. Despite a close causal link between H. pylori infection and the development of gastric malignancies, the precise mechanisms involved in this process are still obscure. Studies over the past two decades have revealed that H. pylori exert oncogenic effects on gastric mucosa through a complex interaction between bacterial factors, host factors, and environmental factors. Numerous signaling pathways can be activated by H. pylori. In this review, we aim to elaborate on the recent developments in the pathophysiological mechanisms of H. pylori-induced gastric inflammation and gastric cancer.
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Affiliation(s)
- Fei Wang
- Department of Gastroenterology, The First Affiliated Hospital of Guangxi Medical University, Nanning 530021, Guangxi Province, China
| | - Wenbo Meng
- The Second Department of General Surgery, The First Hospital of Lanzhou University, Hepatopancreatobiliary Surgery Institute of Gansu Province, Clinical Medical College Cancer, Center of Lanzhou University, Lanzhou 730000, Gansu Province, China
| | - Bingyuan Wang
- Department of Gastroenterology, The First Affiliated Hospital of China Medical University, Shenyang, Liaoning Province, China.
| | - Liang Qiao
- Storr Liver Unit at Westmead Millennium Institute, The University of Sydney at Westmead Hospital, Westmead, NSW 2145, Australia.
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Epplein M, Zheng W, Li H, Peek RM, Correa P, Gao J, Michel A, Pawlita M, Cai Q, Xiang YB, Shu XO. Diet, Helicobacter pylori strain-specific infection, and gastric cancer risk among Chinese men. Nutr Cancer 2014; 66:550-7. [PMID: 24666234 DOI: 10.1080/01635581.2014.894096] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Evidence for the association of diet and gastric cancer is equivocal, and the majority of previous studies have not evaluated the interaction of diet and infection with Helicobacter pylori, the leading risk factor for gastric cancer. We examined these associations among 226 cases and 451 controls nested within a prospective cohort. Dietary intakes were calculated from validated food frequency questionnaires. Blood levels of 15 antibodies to Helicobacter pylori proteins were assessed using multiplex serology. Odds ratios (ORs) were calculated using logistic regression. Among individuals infected with high-risk Helicobacter pylori (sero-positivity to 5-6 virulent H. pylori proteins), increasing intake of red meat, heme iron, and sodium increased risk (comparing highest tertile to lowest: ORs [95% confidence interval {CI}]: 1.85 [1.01-3.40]; 1.95 [1.06-3.57]; and 1.76 [0.91-3.43], respectively) while increasing intake of fruit decreased gastric cancer risk (comparing highest tertile of intake to lowest: OR [95% CI]: 0.52 [0.28-0.94]). No associations of diet with risk were found among individuals infected with low-risk H. pylori (P for interaction for red meat and sodium: 0.02 and 0.01, respectively). In this population with over 90% prevalence of CagA-positive H. pylori infection, categorizing individuals using H. pylori multiplex serology may identify individuals for whom a diet intervention may be effective.
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Affiliation(s)
- Meira Epplein
- a Division of Epidemiology, Department of Medicine, Vanderbilt Epidemiology Center and Vanderbilt-Ingram Cancer Center , Vanderbilt University School of Medicine , Nashville , Tennessee , USA
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Raghwan, Chowdhury R. Host cell contact induces fur-dependent expression of virulence factors CagA and VacA in Helicobacter pylori. Helicobacter 2014; 19:17-25. [PMID: 24020886 DOI: 10.1111/hel.12087] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
BACKGROUND Helicobacter pylori, a gram negative bacterium, colonizes the stomach in a majority of the world population. The two major virulence factors of H. pylori VacA and CagA, thought to be associated with chronic inflammation and disease, have been extensively studied, but the regulation of the expression of these virulence genes in H. pylori remains poorly understood. METHODS qRT-PCR was performed to quantify gene expression in unadhered and AGS-adhered H. pylori. Δfur mutant was constructed by splicing by overlap extension PCR and allelic exchange. RESULTS Adherence of H. pylori to the gastric epithelial cell line AGS strongly induces the expression of both cagA and vacA. Induction of cagA and vacA in the AGS cell-adhered H. pylori Δfur mutant strain was consistently lower than in the adhered parent strain. However, expression of the genes was similar between the wild-type and Δfur mutant strains in the unadhered state, suggesting that Fur has a role in the upregulation of cagA and vacA expression, especially in AGS-adhered H. pylori. Consistent with these results, microscopic observations revealed that infection of AGS cells with H. pylori Δfur mutant strain produced much less damage as compared to that produced by the wild-type H. pylori strain. CONCLUSIONS These results suggested that cagA and vacA gene expression is upregulated in H. pylori, especially by host cell contact, and Fur has a role in the upregulation.
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Affiliation(s)
- Raghwan
- Infectious Diseases and Immunology Division, Indian Institute of Chemical Biology, Council of Scientific and Industrial Research, Kolkata, India
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Abstract
Since its discovery in 1982, the global importance of Helicobacter pylori-induced disease, particularly in developing countries, remains high. The use of rodent models, particularly mice, and the unanticipated usefulness of the gerbil to study H. pylori pathogenesis have been used extensively to study the interactions of the host, the pathogen, and the environmental conditions influencing the outcome of persistent H. pylori infection. Dietary factors in humans are increasingly recognized as being important factors in modulating progression and severity of H. pylori-induced gastric cancer. Studies using rodent models to verify and help explain mechanisms whereby various dietary ingredients impact disease outcome should continue to be extremely productive.
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Affiliation(s)
- James G. Fox
- Division of Comparative Medicine, Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, Massachusetts
| | - Timothy C. Wang
- Division of Digestive and Liver Diseases, Department of Medicine, Columbia University Medical Center, New York, New York
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Abstract
Gastric adenocarcinoma is a leading cause of cancer-related death worldwide, and Helicobacter pylori infection is one of the strongest known risk factors for this malignancy. H. pylori strains exhibit a high level of genetic diversity, and the risk of gastric cancer is higher in persons carrying certain strain types (for example, those that contain a cag pathogenicity island or type s1 vacA alleles) than in persons carrying other strain types. Additional risk factors for gastric cancer include specific human genetic polymorphisms and specific dietary preferences (for example, a high-salt diet or a diet deficient in fruits and vegetables). Finally, iron-deficiency anemia is a risk factor for gastric cancer. Recent studies have provided evidence that several dietary risk factors for gastric cancer directly impact H. pylori virulence. In this review article, we discuss mechanisms by which diet can modulate H. pylori virulence and thereby influence gastric cancer risk.
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Affiliation(s)
- Timothy L Cover
- Division of Infectious Diseases; Vanderbilt University School of Medicine; Nashville, TN USA,Department of Pathology, Microbiology, and Immunology; Vanderbilt University School of Medicine; Nashville, TN USA,Veterans Affairs Tennessee Valley Healthcare System; Nashville, TN USA
| | - Richard M Peek, Jr
- Division of Gastroenterology, Department of Medicine; Vanderbilt University School of Medicine; Nashville, TN USA,Correspondence to: Richard M Peek, Jr,
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40
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Abstract
The discovery of Helicobacter pylori overturned the conventional dogma that the stomach was a sterile organ and that pH values<4 were capable of sterilizing the stomach. H. pylori are an etiological agent associated with gastritis, hypochlorhydria, duodenal ulcers, and gastric cancer. It is now appreciated that the human stomach supports a bacterial community with possibly 100s of bacterial species that influence stomach homeostasis. Other bacteria colonizing the stomach may also influence H. pylori-associated gastric pathogenesis by creating reactive oxygen and nitrogen species and modulating inflammatory responses. In this review, we summarize the available literature concerning the gastric microbiota in humans, mice, and Mongolian gerbils. We also discuss the gastric perturbations, many involving H. pylori, that facilitate the colonization by bacteria from other compartments of the gastrointestinal tract, and identify risk factors known to affect gastric homeostasis that contribute to changes in the microbiota.
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Cid TP, Fernández MC, Benito Martínez S, Jones NL. Pathogenesis of Helicobacter pylori infection. Helicobacter 2013; 18 Suppl 1:12-7. [PMID: 24011239 DOI: 10.1111/hel.12076] [Citation(s) in RCA: 50] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Helicobacter pylori infection and disease outcome are mediated by a complex interplay between bacterial, host, and environmental factors. Over the past year, our understanding of this complex interplay has been improved by a variety of studies focusing on both host and bacterial factors. These include studies assessing novel virulence factors as well as those most frequently associated with severity of disease outcome including cagA and the cag pathogenicity island, and the vacuolating cytotoxin. Several studies have focused on regulation of virulence factors by environmental factors. In addition, mechanisms by which bacterial virulence factors influence the host response and disease, by inducing epigenetic changes, autophagy and altered oxidative stress have also been elucidated. This review highlights key findings in the pathogenesis of H. pylori infection reported over the past year.
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Affiliation(s)
- Trinidad Parra Cid
- Unidad de Investigación, Hospital Universitario de Guadalajara, Guadalajara, Spain; CIBERehd (Centro de Investigación Biomédica en Red, Enfermedades Hepáticas y Digestivas), Madrid, Spain
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Role of energy sensor TlpD of Helicobacter pylori in gerbil colonization and genome analyses after adaptation in the gerbil. Infect Immun 2013; 81:3534-51. [PMID: 23836820 DOI: 10.1128/iai.00750-13] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022] Open
Abstract
Helicobacter pylori maintains colonization in its human host using a limited set of taxis sensors. TlpD is a proposed energy taxis sensor of H. pylori and dominant under environmental conditions of low bacterial energy yield. We studied the impact of H. pylori TlpD on colonization in vivo using a gerbil infection model which closely mimics the gastric physiology of humans. A gerbil-adapted H. pylori strain, HP87 P7, showed energy-dependent behavior, while its isogenic tlpD mutant lost it. A TlpD-complemented strain regained the wild-type phenotype. Infection of gerbils with the complemented strain demonstrated that TlpD is important for persistent infection in the antrum and corpus and suggested a role of TlpD in horizontal navigation and persistent corpus colonization. As a part of the full characterization of the model and to gain insight into the genetic basis of H. pylori adaptation to the gerbil, we determined the complete genome sequences of the gerbil-adapted strain HP87 P7, two HP87 P7 tlpD mutants before and after gerbil passage, and the original human isolate, HP87. The integrity of the genome, including that of a functional cag pathogenicity island, was maintained after gerbil adaptation. Genetic and phenotypic differences between the strains were observed. Major differences between the gerbil-adapted strain and the human isolate emerged, including evidence of recent recombination. Passage of the tlpD mutant through the gerbil selected for gain-of-function variation in a fucosyltransferase gene, futC (HP0093). In conclusion, a gerbil-adapted H. pylori strain with a stable genome has helped to establish that TlpD has important functions for persistent colonization in the stomach.
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Piazuelo MB, Correa P. Gastric cáncer: Overview. Colomb Med (Cali) 2013; 44:192-201. [PMID: 24892619 PMCID: PMC4002033] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2012] [Revised: 02/02/2013] [Accepted: 07/02/2013] [Indexed: 12/03/2022] Open
Abstract
Gastric cancer ranks fourth in incidence and second in mortality among all cancers worldwide. Despite the decrease in incidence in some regions of the world, gastric cancer continues to present a major clinical challenge due to most cases being diagnosed in advanced stages with poor prognosis and limited treatment options. The development of gastric cancer is a complex and multifactorial process involving a number of etiological factors and multiple genetic and epigenetic alterations. Among the predisposing factors are: Helicobacter pylori infection, high salt intake, smoking, and in a small percentage of patients, a familial genetic component. More than 95% of stomach cancer cases are adenocarcinomas, which are classified into two major histologic types: intestinal and diffuse. Intestinal type adenocarcinoma is preceded by a sequence of gastric lesions known as Correa´s cascade and is the histologic type associated with the global decrease in gastric cancer rates. Diffuse type adenocarcinomas have a more aggressive behavior and worse prognosis than those of the intestinal type. According to the anatomical location, adenocarcinomas are classified as proximal (originating in the cardia) and distal (originating in the body and antrum). This classification seems to recognize two different clinical entities. Surgical resection of the tumor at an early stage is the only effective treatment method. Therefore, the identification and surveillance of patients at risk may play a significant role in survival rates. Anti-Helicobacter pylori therapy has been shown to be an effective measure in the prevention of gastric cancer.
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Affiliation(s)
- M. Blanca Piazuelo
- Division of Gastroenterology, Department of Medicine,Vanderbilt University School of Medicine, Nashville, TN, USA
| | - Pelayo Correa
- Division of Gastroenterology, Department of Medicine,Vanderbilt University School of Medicine, Nashville, TN, USA
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Wroblewski LE, Peek RM. Helicobacter pylori in gastric carcinogenesis: mechanisms. Gastroenterol Clin North Am 2013; 42:285-98. [PMID: 23639641 PMCID: PMC3648881 DOI: 10.1016/j.gtc.2013.01.006] [Citation(s) in RCA: 81] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
Helicobacter pylori infection induces chronic inflammation and is the strongest known risk factor for gastric cancer. The genomes of H pylori are highly diverse and therefore bacterial virulence factors play an important role in determining the outcome of H pylori infection, in combination with host responses that are augmented by environmental and dietary risk factors. It is important to gain further understanding of the pathogenesis of H pylori infection to develop more effective treatments for this common but deadly malignancy. This review focuses on the specific mechanisms used by H pylori to drive gastric carcinogenesis.
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Affiliation(s)
| | - Richard M. Peek
- Department of Medicine, Vanderbilt University, Nashville, TN.
,Department of Cancer Biology, Vanderbilt University, Nashville, TN
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High dietary salt intake exacerbates Helicobacter pylori-induced gastric carcinogenesis. Infect Immun 2013; 81:2258-67. [PMID: 23569116 DOI: 10.1128/iai.01271-12] [Citation(s) in RCA: 152] [Impact Index Per Article: 12.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
Persistent colonization of the human stomach with Helicobacter pylori is a risk factor for gastric adenocarcinoma, and H. pylori-induced carcinogenesis is dependent on the actions of a bacterial oncoprotein known as CagA. Epidemiological studies have shown that high dietary salt intake is also a risk factor for gastric cancer. To investigate the effects of a high-salt diet, we infected Mongolian gerbils with a wild-type (WT) cagA(+) H. pylori strain or an isogenic cagA mutant strain and maintained the animals on a regular diet or a high-salt diet. At 4 months postinfection, gastric adenocarcinoma was detected in 100% of the WT-infected/high-salt-diet animals, 58% of WT-infected/regular-diet animals, and none of the animals infected with the cagA mutant strain (P < 0.0001). Among animals infected with the WT strain, those fed a high-salt diet had more severe gastric inflammation, higher gastric pH, increased parietal cell loss, increased gastric expression of interleukin 1β (IL-1β), and decreased gastric expression of hepcidin and hydrogen potassium ATPase (H,K-ATPase) compared to those on a regular diet. Previous studies have detected upregulation of CagA synthesis in response to increased salt concentrations in the bacterial culture medium, and, concordant with the in vitro results, we detected increased cagA transcription in vivo in animals fed a high-salt diet compared to those on a regular diet. Animals infected with the cagA mutant strain had low levels of gastric inflammation and did not develop hypochlorhydria. These results indicate that a high-salt diet potentiates the carcinogenic effects of cagA(+) H. pylori strains.
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