|
1
|
Clyne M, Ó Cróinín T. Pathogenicity and virulence of Helicobacter pylori: A paradigm of chronic infection. Virulence 2025; 16:2438735. [PMID: 39725863 DOI: 10.1080/21505594.2024.2438735] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2024] [Revised: 11/18/2024] [Accepted: 12/02/2024] [Indexed: 12/28/2024] Open
Abstract
Infection with Helicobacter pylori is one of the most common infections of mankind. Infection typically occurs in childhood and persists for the lifetime of the host unless eradicated with antimicrobials. The organism colonizes the stomach and causes gastritis. Most infected individuals are asymptomatic, but infection also causes gastric and duodenal ulceration, and gastric cancer. H. pylori possesses an arsenal of virulence factors, including a potent urease enzyme for protection from acid, flagella that mediate motility, an abundance of outer membrane proteins that can mediate attachment, several immunomodulatory proteins, and an ability to adapt to specific conditions in individual human stomachs. The presence of a type 4 secretion system that injects effector molecules into gastric cells and subverts host cell signalling is associated with virulence. In this review we discuss the interplay of H. pylori colonization and virulence factors with host and environmental factors to determine disease outcome in infected individuals.
Collapse
Affiliation(s)
- Marguerite Clyne
- School of Medicine, University College Dublin, Dublin, Ireland
- The Conway Institute of Biomolecular and Biomedical Science, University College Dublin, Dublin, Ireland
| | - Tadhg Ó Cróinín
- The Conway Institute of Biomolecular and Biomedical Science, University College Dublin, Dublin, Ireland
- School of Biomolecular and Biomedical Science, University College Dublin, Dublin, Ireland
| |
Collapse
|
|
2
|
Guan X, Ning J, Fu W, Wang Y, Zhang J, Ding S. Helicobacter pylori with trx1 high expression promotes gastric diseases via upregulating the IL23A/NF-κB/IL8 pathway. Helicobacter 2024; 29:e13072. [PMID: 38686467 DOI: 10.1111/hel.13072] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/01/2023] [Revised: 03/19/2024] [Accepted: 03/28/2024] [Indexed: 05/02/2024]
Abstract
BACKGROUND Helicobacter pylori infection is one of the main causes of gastric cancer. thioredoxin-1 (Trx1) and arginase (RocF) expressed by H. pylori were found to be closely related to its pathogenicity. However, whether Trx1 and RocF can be used in clinical screening of highly pathogenic H. pylori and the pathogenesis of trx1 high expressing H. pylori remain still unknown. MATERIALS AND METHODS We investigated the expression level of H. pylori trx1 and H. pylori rocF in human gastric antrum tissues using reverse transcription and quantitative real-time PCR (RT-qPCR) and clarified the clinical application value of trx1 and rocF for screening highly pathogenic H. pylori. The pathogenic mechanism of Trx1 were further explored by RNA-seq of GES-1 cells co-cultured with trx1 high or low expressing H. pylori. Differentially expressed genes and signaling pathways were validated by RT-qPCR, Enzyme-linked immunosorbent assay (ELISA), western blot, immunohistochemistry and immunofluorescence. We also assessed the adherence of trx1 high and low expressing H. pylori to GES-1 cells. RESULTS We found that H. pylori trx1 and H. pylori rocF were more significantly expressed in the gastric cancer and peptic ulcer group than that in the gastritis group and the parallel diagnosis of H. pylori trx1 and H. pylori rocF had high sensitivity. The trx1 high expressing H. pylori had stronger adhesion ability to GES-1 cells and upregulated the interleukin (IL) 23A/nuclear factor κappaB (NF-κB)/IL17A, IL6, IL8 pathway. CONCLUSIONS H. pylori trx1 and H. pylori rocF can be used in clinical screening of highly pathogenic H. pylori and predicting the outcome of H. pylori infection. The trx1 high expressing H. pylori has stronger adhesion capacity and promotes the development of gastric diseases by upregulating the activation of NF-κB signaling pathway.
Collapse
Affiliation(s)
- Xin Guan
- Beijing Key Laboratory for Helicobacter pylori Infection and Upper Gastrointestinal Diseases, Department of Gastroenterology, Peking University Third Hospital, Beijing, China
| | - Jing Ning
- Beijing Key Laboratory for Helicobacter pylori Infection and Upper Gastrointestinal Diseases, Department of Gastroenterology, Peking University Third Hospital, Beijing, China
| | - Weiwei Fu
- Beijing Key Laboratory for Helicobacter pylori Infection and Upper Gastrointestinal Diseases, Department of Gastroenterology, Peking University Third Hospital, Beijing, China
| | - Ye Wang
- Beijing Key Laboratory for Helicobacter pylori Infection and Upper Gastrointestinal Diseases, Department of Gastroenterology, Peking University Third Hospital, Beijing, China
| | - Jing Zhang
- Beijing Key Laboratory for Helicobacter pylori Infection and Upper Gastrointestinal Diseases, Department of Gastroenterology, Peking University Third Hospital, Beijing, China
| | - Shigang Ding
- Beijing Key Laboratory for Helicobacter pylori Infection and Upper Gastrointestinal Diseases, Department of Gastroenterology, Peking University Third Hospital, Beijing, China
| |
Collapse
|
|
3
|
Peng J, Xie J, Liu D, Yang K, Wu S, Liu D, Huang D, Xie Y. Impact of Helicobacter pylori colonization density and depth on gastritis severity. Ann Clin Microbiol Antimicrob 2024; 23:4. [PMID: 38217000 PMCID: PMC10785438 DOI: 10.1186/s12941-024-00666-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2023] [Accepted: 01/04/2024] [Indexed: 01/14/2024] Open
Abstract
BACKGROUND AND OBJECTIVES Helicobacter pylori (H. pylori) infection is the most common etiology of chronic gastric. H. pylori gastritis would gradually evolve into gastric atrophy, intestinal metaplasia, dysplasia and malignant lesions. Herein, this study aimed to investigate the potential impact of H. pylori colonization density and depth on the severity of histological parameters of gastritis. METHODS A prospective monocentric study was conducted from December 2019 to July 2022, enrolling patients with confirmed chronic H. pylori infection via histopathological evaluation. H. pylori colonization status was detected by immunohistochemical staining, pathological changes of gastric specimens were detected by hematoxylin eosin staining. Epidemiological, endoscopic and histopathological data were collected. RESULTS A total of 1120 patients with a mean age of 45.8 years were included. Regardless of the previous history of H. pylori eradication treatment, significant correlations were observed between the density and depth of H. pylori colonization and the intensity of gastritis activity (all P < 0.05). Patients with the lowest level of H. pylori colonization density and depth exhibited the highest level of mild activity. In whole participants and anti-H. pylori treatment-naive participants, H. pylori colonization density and depth were markedly correlated with the severity of chronic gastritis and gastric atrophy (all P < 0.05). H. pylori colonization density (P = 0.001) and depth (P = 0.047) were significantly associated with ulcer formation in patients naive to any anti-H. pylori treatment. No significant associations were observed between the density and depth of H. pylori colonization and other histopathological findings including lymphadenia, lymphoid follicle formation and dysplasia. CONCLUSIONS As the density and depth of H. pylori colonization increased, so did the activity and severity of gastritis, along with an elevated risk of ulcer formation.
Collapse
Affiliation(s)
- Jianxiang Peng
- Department of Gastroenterology, Digestive Disease Hospital, The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, 17 Yongwaizheng Street, Donghu District, Nanchang, 330006, Jiangxi Province, China
- Jiangxi Clinical Research Center for Gastroenterology, Nanchang, Jiangxi Province, China
| | - Jinliang Xie
- Department of Gastroenterology, Digestive Disease Hospital, The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, 17 Yongwaizheng Street, Donghu District, Nanchang, 330006, Jiangxi Province, China
- Jiangxi Clinical Research Center for Gastroenterology, Nanchang, Jiangxi Province, China
| | - Dingwei Liu
- Department of Gastroenterology, Digestive Disease Hospital, The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, 17 Yongwaizheng Street, Donghu District, Nanchang, 330006, Jiangxi Province, China
- Jiangxi Clinical Research Center for Gastroenterology, Nanchang, Jiangxi Province, China
| | - Kaijie Yang
- Department of Gastroenterology, Digestive Disease Hospital, The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, 17 Yongwaizheng Street, Donghu District, Nanchang, 330006, Jiangxi Province, China
- Jiangxi Clinical Research Center for Gastroenterology, Nanchang, Jiangxi Province, China
- Ganzhou People's Hospital, Ganzhou, Jiangxi Province, China
| | - Shuang Wu
- Department of Gastroenterology, Digestive Disease Hospital, The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, 17 Yongwaizheng Street, Donghu District, Nanchang, 330006, Jiangxi Province, China
- Jiangxi Clinical Research Center for Gastroenterology, Nanchang, Jiangxi Province, China
- The Second People's Hospital of Jingdezhen, Jingdezhen, Jiangxi Province, China
| | - Dongsheng Liu
- Department of Gastroenterology, Digestive Disease Hospital, The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, 17 Yongwaizheng Street, Donghu District, Nanchang, 330006, Jiangxi Province, China
- Jiangxi Clinical Research Center for Gastroenterology, Nanchang, Jiangxi Province, China
| | - Deqiang Huang
- Department of Gastroenterology, Digestive Disease Hospital, The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, 17 Yongwaizheng Street, Donghu District, Nanchang, 330006, Jiangxi Province, China.
- Jiangxi Clinical Research Center for Gastroenterology, Nanchang, Jiangxi Province, China.
| | - Yong Xie
- Department of Gastroenterology, Digestive Disease Hospital, The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, 17 Yongwaizheng Street, Donghu District, Nanchang, 330006, Jiangxi Province, China.
- Jiangxi Clinical Research Center for Gastroenterology, Nanchang, Jiangxi Province, China.
| |
Collapse
|
|
4
|
Sit WY, Cheng ML, Chen TJ, Chen CJ, Chen BN, Huang DJ, Chen PL, Chen YC, Lo CJ, Wu DC, Hsieh WC, Chang CT, Chen RH, Wang WC. Helicobacter pylori PldA modulates TNFR1-mediated p38 signaling pathways to regulate macrophage responses for its survival. Gut Microbes 2024; 16:2409924. [PMID: 39369445 PMCID: PMC11457642 DOI: 10.1080/19490976.2024.2409924] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/21/2024] [Revised: 08/16/2024] [Accepted: 09/11/2024] [Indexed: 10/08/2024] Open
Abstract
Helicobacter pylori, a dominant member of the gastric microbiota was associated with various gastrointestinal diseases and presents a significant challenge due to increasing antibiotic resistance. This study identifies H. pylori's phospholipase A (PldA) as a critical factor in modulating host macrophage responses, facilitating H. pylori 's evasion of the immune system and persistence. PldA alters membrane lipids through reversible acylation and deacylation, affecting their structure and function. We found that PldA incorporates lysophosphatidylethanolamine into macrophage membranes, disrupting their bilayer structure and impairing TNFR1-mediated p38-MK2 signaling. This disruption results in reduced macrophage autophagy and elevated RIP1-dependent apoptosis, thereby enhancing H. pylori survival, a mechanism also observed in multidrug-resistant strains. Pharmacological inhibition of PldA significantly decreases H. pylori viability and increases macrophage survival. In vivo studies corroborate PldA's essential role in H. pylori persistence and immune cell recruitment. Our findings position PldA as a pivotal element in H. pylori pathogenesis through TNFR1-mediated membrane modulation, offering a promising therapeutic target to counteract bacterial resistance.
Collapse
Affiliation(s)
- Wei Yang Sit
- Institute of Molecular and Cellular Biology & Department of Life Science, National Tsing Hua University, Hsinchu, Taiwan, ROC
| | - Mei-Ling Cheng
- Department of Biomedical Sciences, Chang Gung University, Taoyuan, Taiwan, ROC
| | - Tsan-Jan Chen
- Institute of Molecular and Cellular Biology & Department of Life Science, National Tsing Hua University, Hsinchu, Taiwan, ROC
| | - Chia-Jo Chen
- Institute of Molecular and Cellular Biology & Department of Life Science, National Tsing Hua University, Hsinchu, Taiwan, ROC
| | - Bo-Nian Chen
- Institute of Molecular and Cellular Biology & Department of Life Science, National Tsing Hua University, Hsinchu, Taiwan, ROC
| | - Ding-Jun Huang
- Institute of Molecular and Cellular Biology & Department of Life Science, National Tsing Hua University, Hsinchu, Taiwan, ROC
| | - Pei-Lien Chen
- Institute of Molecular and Cellular Biology & Department of Life Science, National Tsing Hua University, Hsinchu, Taiwan, ROC
| | - Yun-Ching Chen
- Institute of Biomedical Engineering, National Tsing-Hua University, Hsinchu, Taiwan, ROC
| | - Chi-Jen Lo
- Department of Biomedical Sciences, Chang Gung University, Taoyuan, Taiwan, ROC
| | - Deng-Chyang Wu
- Division of Gastroenterology, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan, ROC
| | - Wan-Chen Hsieh
- Institute of Molecular and Cellular Biology & Department of Life Science, National Tsing Hua University, Hsinchu, Taiwan, ROC
| | - Chung-Ting Chang
- Institute of Molecular and Cellular Biology & Department of Life Science, National Tsing Hua University, Hsinchu, Taiwan, ROC
| | - Ruey-Hwa Chen
- Institute of Biological Chemistry, Academia Sinica, Taipei, Taiwan, ROC
| | - Wen-Ching Wang
- Institute of Molecular and Cellular Biology & Department of Life Science, National Tsing Hua University, Hsinchu, Taiwan, ROC
| |
Collapse
|
|
5
|
Elshenawi Y, Hu S, Hathroubi S. Biofilm of Helicobacter pylori: Life Cycle, Features, and Treatment Options. Antibiotics (Basel) 2023; 12:1260. [PMID: 37627679 PMCID: PMC10451559 DOI: 10.3390/antibiotics12081260] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2023] [Revised: 07/27/2023] [Accepted: 07/28/2023] [Indexed: 08/27/2023] Open
Abstract
Helicobacter pylori is a gastric pathogen that infects nearly half of the global population and is recognized as a group 1 carcinogen by the Word Health Organization. The global rise in antibiotic resistance has increased clinical challenges in treating H. pylori infections. Biofilm growth has been proposed to contribute to H. pylori's chronic colonization of the host stomach, treatment failures, and the eventual development of gastric diseases. Several components of H. pylori have been identified to promote biofilm growth, and several of these may also facilitate antibiotic tolerance, including the extracellular matrix, outer membrane proteins, shifted morphology, modulated metabolism, efflux pumps, and virulence factors. Recent developments in therapeutic approaches targeting H. pylori biofilm have shown that synthetic compounds, such as small molecule drugs and plant-derived compounds, are effective at eradicating H. pylori biofilms. These combined topics highlight the necessity for biofilm-based research in H. pylori, to improve current H. pylori-targeted therapeutic approaches and alleviate relative public health burden. In this review we discuss recent discoveries that have decoded the life cycle of H. pylori biofilms and current biofilm-targeted treatment strategies.
Collapse
Affiliation(s)
- Yasmine Elshenawi
- Department of Microbiology and Environmental Toxicology, University of California, Santa Cruz, CA 95064, USA;
| | - Shuai Hu
- Department of Microbiology and Environmental Toxicology, University of California, Santa Cruz, CA 95064, USA;
| | - Skander Hathroubi
- Spartha Medical, CRBS 1 Rue Eugène Boeckel, 67000 Strasbourg, France
| |
Collapse
|
|
6
|
Peng X, Yao S, Huang J, Zhao Y, Chen H, Chen L, Yu Z. Alterations in bacterial community dynamics from noncancerous to Gastric cancer. Front Microbiol 2023; 14:1138928. [PMID: 36970687 PMCID: PMC10034189 DOI: 10.3389/fmicb.2023.1138928] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/06/2023] [Accepted: 02/20/2023] [Indexed: 03/12/2023] Open
Abstract
Gastric microbiome has been shown to contribute to gastric carcinogenesis, understanding how alterations in gastric microbiome is helpful to the prevention and treatment of gastric cancer (GC). However, few studies have focused on the change of microbiome during the gastric carcinogenesis. In this study, the microbiome of gastric juice samples from healthy control (HC), gastric precancerous lesions (GPL) and gastric cancer (GC) was investigated by 16S rRNA gene sequencing. Our results showed that the alpha diversity of patients with GC was significantly lower than other groups. Compared to other groups, some genera in GC group were shown to be up-regulated (e.g., Lautropia and Lactobacillus) and down-regulated (e.g., Peptostreptococcus and Parvimonas). More importantly, the emergence of Lactobacillus was closely related to the occurrence and development of GC. Moreover, the microbial interactions and networks in GPL exhibited higher connectivity, complexity and lower clustering property, while GC showed the opposite trend. Taken together, we suggest that changes in the gastric microbiome are associated with GC and perform a key function in maintaining the tumor microenvironment. Therefore, our findings will provide new ideas and references for the treatment of GC.
Collapse
Affiliation(s)
- Xuan Peng
- Department of Microbiology, School of Basic Medical Science, Central South University, Changsha, China
| | - Siqi Yao
- Department of Microbiology, School of Basic Medical Science, Central South University, Changsha, China
| | - Jing Huang
- Department of Medical Parasitology, School of Basic Medical Science, Central South University, Changsha, China
| | - Yiming Zhao
- Department of Microbiology, School of Basic Medical Science, Central South University, Changsha, China
| | - Hao Chen
- Department of Medical Parasitology, School of Basic Medical Science, Central South University, Changsha, China
| | - Liyu Chen
- Department of Microbiology, School of Basic Medical Science, Central South University, Changsha, China
- Liyu Chen,
| | - Zheng Yu
- Department of Microbiology, School of Basic Medical Science, Central South University, Changsha, China
- *Correspondence: Zheng Yu,
| |
Collapse
|
|
7
|
A Complex Connection Between the Diversity of Human Gastric Mucin O-Glycans, Helicobacter pylori Binding, Helicobacter Infection and Fucosylation. Mol Cell Proteomics 2022; 21:100421. [PMID: 36182101 PMCID: PMC9661725 DOI: 10.1016/j.mcpro.2022.100421] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2020] [Revised: 09/25/2022] [Accepted: 09/26/2022] [Indexed: 01/18/2023] Open
Abstract
Helicobacter pylori colonizes the stomach of half of the human population. Most H. pylori are located in the mucus layer, which is mainly comprised by glycosylated mucins. Using mass spectrometry, we identified 631 glycans (whereof 145 were fully characterized and the remainder assigned as compositions) on mucins isolated from 14 Helicobacter spp.-infected and 14 Helicobacter spp.-noninfected stomachs. Only six identified glycans were common to all individuals, from a total of 60 to 189 glycans in each individual. An increased number of unique glycan structures together with an increased intraindividual diversity and larger interindividual variation were identified among O-glycans from Helicobacter spp.-infected stomachs compared with noninfected stomachs. H. pylori strain J99, which carries the blood group antigen-binding adhesin (BabA), the sialic acid-binding adhesin (SabA), and the LacdiNAc-binding adhesin, bound both to Lewis b (Leb)-positive and Leb-negative mucins. Among Leb-positive mucins, H. pylori J99 binding was higher to mucins from Helicobacter spp.-infected individuals than noninfected individuals. Statistical correlation analysis, binding experiments with J99 wt, and J99ΔbabAΔsabA and inhibition experiments using synthetic glycoconjugates demonstrated that the differences in H. pylori-binding ability among these four groups were governed by BabA-dependent binding to fucosylated structures. LacdiNAc levels were lower in mucins that bound to J99 lacking BabA and SabA than in mucins that did not, suggesting that LacdiNAc did not significantly contribute to the binding. We identified 24 O-glycans from Leb-negative mucins that correlated well with H. pylori binding whereof 23 contained α1,2-linked fucosylation. The large and diverse gastric glycan library identified, including structures that correlated with H. pylori binding, could be used to select glycodeterminants to experimentally investigate further for their importance in host-pathogen interactions and as candidates to develop glycan-based therapies.
Collapse
|
|
8
|
Xia X. Multiple regulatory mechanisms for pH homeostasis in the gastric pathogen, Helicobacter pylori. ADVANCES IN GENETICS 2022; 109:39-69. [PMID: 36334916 DOI: 10.1016/bs.adgen.2022.07.001] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/27/2023]
Abstract
Acid-resistance in gastric pathogen Helicobacter pylori requires the coordination of four essential processes to regulate urease activity. Firstly, urease expression above a base level needs to be finely tuned at different ambient pH. Secondly, as nickel is needed to activate urease, nickel homeostasis needs to be maintained by proteins that import and export nickel ions, and sequester, store and release nickel when needed. Thirdly, urease accessary proteins that activate urease activity by nickel insertion need to be expressed. Finally, a reliable source of urea needs to be maintained by both intrinsic and extrinsic sources of urea. Two-component systems (arsRS and flgRS), as well as a nickel response regulator (NikR), sense the change in pH and act on a variety of genes to accomplish the function of acid resistance without causing cellular overalkalization and nickel toxicity. Nickel storage proteins also feature built-in switches to store nickel at neutral pH and release nickel at low pH. This review summarizes the current status of H. pylori research and highlights a number of hypotheses that need to be tested.
Collapse
Affiliation(s)
- Xuhua Xia
- Department of Biology, University of Ottawa, Ottawa, Canada; Ottawa Institute of Systems Biology, Ottawa, Canada.
| |
Collapse
|
|
9
|
Potapova MV, Broyaka NA, Skvortsov KY, Konobeeva EV. Helicobacter pylori roles in haematology disease pathogenesis. СИБИРСКИЙ НАУЧНЫЙ МЕДИЦИНСКИЙ ЖУРНАЛ 2022; 42:18-35. [DOI: 10.18699/ssmj20220302] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/06/2025]
Affiliation(s)
- M. V. Potapova
- Saratov State Medical University n.a. V.I. Razumovsky of Minzdrav of Russia
| | - N. A. Broyaka
- Saratov State Medical University n.a. V.I. Razumovsky of Minzdrav of Russia
| | | | - E. V. Konobeeva
- Saratov State Medical University n.a. V.I. Razumovsky of Minzdrav of Russia
| |
Collapse
|
|
10
|
Qiang L, Hu J, Tian M, Li Y, Ren C, Deng Y, Jiang Y. Extracellular vesicles from helicobacter pylori-infected cells and helicobacter pylori outer membrane vesicles in atherosclerosis. Helicobacter 2022; 27:e12877. [PMID: 35099837 DOI: 10.1111/hel.12877] [Citation(s) in RCA: 19] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/11/2021] [Revised: 12/26/2021] [Accepted: 01/11/2022] [Indexed: 12/15/2022]
Abstract
BACKGROUND The role of H. pylori infection has been reported in various extragastric diseases, particularly, the correlation between H. pylori and atherosclerosis (AS) have received lots of attention. Some scholars demonstrated that the presence of H. pylori-specific DNA in the sclerotic plaques of atheromatous patients provides biological evidences, with indicating that H. pylori infection is a potential factor of AS. However, the underlying mechanism of H. pylori or their products cross the epithelial barriers to enter the blood circulation remains unclear. Recent studies have shown that the extracellular vesicles (EVs) derived from H. pylori-infected gastric epithelial cells encapsulated H. pylori virulence factor cytotoxin-associated gene A (CagA) and existed in the blood samples of patients or mice, which indicating that they can carry CagA into the blood circulation. Based on these findings, some researchers proposed a hypothesis that H. pylori is involved in the pathogenesis of AS via EVs-based mechanisms. In addition, outer membrane vesicles (OMVs) serve as transport vehicles to deliver H. pylori virulence factors to epithelial cells. It is necessary to discuss the role of H. pylori OMVs in the development of AS. OBJECTIVES This review will focus on the correlation between H. pylori infection and AS and tried to unveil the possible role of EVs from H. pylori-infected cells and H. pylori OMVs in the pathogenesis of AS, with a view to providing help in refining our knowledge in this aspect. METHODS All of information included in this review was retrieved from published studies on H. pylori infection in AS. RESULTS H. pylori infection may be an atherosclerotic risk factor and drives researchers to reevaluate the role of H. pylori in the pathogenesis of AS. Some findings proposed a new hypothesis that H. pylori may be involved in the pathogenesis of AS through EVs-based mechanisms. Besides EVs from H. pylori-infected cells, whether H. pylori OMVs may play some role in the pathogenesis of AS is still remain unclear. CONCLUSION Existing epidemiological and clinical evidence had shown that there is a possible association between H. pylori and AS. However, except for the larger randomized controlled trials, more basic research about EVs from H. pylori-infected cells and H. pylori OMVs is the need of the hour to unveil the possible role of H. pylori infection in the pathogenesis of AS.
Collapse
Affiliation(s)
- Liming Qiang
- Department of Gastroenterology, West China-Guang'an Hospital, Sichuan University, Guang'an, China
| | - Jianguo Hu
- Department of Obstetrics and Gynecology, The Second Affiliated Hospital, Chongqing Medical University, Chongqing, China
| | - Mingyuan Tian
- Department of Endocrinology, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Yu Li
- Clinical Medical College, The First Affiliated Hospital of Chengdu Medical College, Chengdu, China
| | - Chao Ren
- Clinical Medical College, The First Affiliated Hospital of Chengdu Medical College, Chengdu, China
| | - Yi Deng
- Clinical Medical College, The First Affiliated Hospital of Chengdu Medical College, Chengdu, China
| | - Yuan Jiang
- Clinical Medical College, The First Affiliated Hospital of Chengdu Medical College, Chengdu, China
| |
Collapse
|
|
11
|
Do AD, Su CH, Hsu YM. Antagonistic Activities of Lactobacillus rhamnosus JB3 Against Helicobacter pylori Infection Through Lipid Raft Formation. Front Immunol 2022; 12:796177. [PMID: 35095872 PMCID: PMC8794797 DOI: 10.3389/fimmu.2021.796177] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2021] [Accepted: 12/24/2021] [Indexed: 11/13/2022] Open
Abstract
Helicobacter pylori is a Gram-negative pathogen that can increase the risk of stomach cancer in infected patients. H. pylori exploits lipid rafts to infect host cells. Infection triggers clustering of Lewis x antigen (Lex) and integrins in lipid rafts to facilitate H. pylori adherence to the gastric epithelium. H. pylori infection can be treated with probiotics containing lactic acid bacteria that offer numerous benefits to the host while lacking the side effects associated with antibiotic therapy. Previously, we showed that the cell-free supernatant (CFS) derived from Lactobacillus rhamnosus JB3 (LR-JB3) at a multiplicity of infection (MOI) of 25 attenuated the pathogenicity of H. pylori. In this study, we established a mucin model to simulate the gastric environment and to further understand the influence of mucin on the pathogenesis of H. pylori. Porcine stomach mucin dramatically upregulated H. pylori virulence gene expression, including that of babA, sabA, fucT, vacA, hp0499, cagA, and cagL, as well as the adhesion and invasion ability of H. pylori and induced increased levels of IL-8 in infected-AGS cells. The CFS derived from LR-JB3 at a MOI of 25 reduced the expression of H. pylori sabA, fucT, and hp0499 in mucin, as well as that of the Lex antigen and the α5β1 integrin in AGS cells during co-cultivation. These inhibitory effects of LR-JB3 also suppressed lipid raft clustering and attenuated Lewis antigen-dependent adherence, type IV secretion system-mediated cell contact, and lipid raft-mediated entry of VacA to host cells. In conclusion, LR-JB3 could affect H. pylori infection through mediating lipid raft formation of the host cells. The currently unknown cues secreted from LR-JB3 are valuable not only for treating H. pylori infection, but also for treating diseases that are also mediated by lipid raft signaling, such as cancer and aging-associated and neurodegenerative conditions.
Collapse
Affiliation(s)
- Anh Duy Do
- Department of Biological Science and Technology, China Medical University, Taichung, Taiwan
| | - Chiu-Hsian Su
- Department of Biological Science and Technology, China Medical University, Taichung, Taiwan.,Department of Animal Science and Technology, Tunghai University, Taichung, Taiwan
| | - Yuan-Man Hsu
- Department of Biological Science and Technology, China Medical University, Taichung, Taiwan.,Department of Animal Science and Technology, Tunghai University, Taichung, Taiwan
| |
Collapse
|
|
12
|
Lopes-de-Campos D, Leal Seabra C, Pinto RM, Adam Słowiński M, Sarmento B, Nunes C, Cristina L Martins M, Reis S. Targeting and Killing the Ever-Challenging Ulcer Bug. Int J Pharm 2022; 617:121582. [PMID: 35176334 DOI: 10.1016/j.ijpharm.2022.121582] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2021] [Revised: 02/08/2022] [Accepted: 02/10/2022] [Indexed: 11/26/2022]
Abstract
TreatingHelicobacter pylori(H. pylori) infections has been a never-ending challenge, which has contributed to the high incidence of gastric cancer. The antibiotics commonly used are not reaching the infection site in its active state and in a concentration high enough to effectively kill the bacteria. In this context, amoxicillin-loaded lipid nanoparticles with carefully chosen materials were developed, namely dioleoylphosphatidylethanolamine (DOPE) as a targeting agent and Tween®80 and linolenic acid as antimicrobial agents. This work shows the ability of these nanoparticles in (i) targeting the bacteria (imaging flow cytometry) and inhibiting their adhesion to MKN-74 cells (bacteria-gastric cells adhesion model); (ii) killing the bacteria even as an antibiotic-free strategy (time-kill kineticstudies, scanning electron microscopy, and bacterial membrane permeability studies); (iii)overcoming gastrointestinal features using a newly developedin vitroinfection model that includes both physical (epithelial cells and mucus) and the chemical (acid medium) barriers; and in (iv) being incorporated in a floating system that can increase the retention time at the stomach. Overall, this work presents an effective nanosystem to deal with the ulcer-bug. Besides, it also provides two innovative tools transferable to other fields-anin vitroinfection model and a floating system to incorporate nanoparticles.
Collapse
Affiliation(s)
- Daniela Lopes-de-Campos
- LAQV, REQUIMTE, Departamento de Ciencias Químicas, Faculdade de Farmacia, Universidade do Porto, Portugal
| | - Catarina Leal Seabra
- LAQV, REQUIMTE, Departamento de Ciencias Químicas, Faculdade de Farmacia, Universidade do Porto, Portugal; i3S - Instituto de Investigacao e Inovacao em Saúde, Universidade do Porto, Rua Alfredo Allen 208, 4200-393 Porto, Portugal; INEB - Instituto de Engenharia Biomedica, Universidade do Porto, Rua Alfredo Allen 208, 4200-393 Porto, Portugal
| | - Rita M Pinto
- LAQV, REQUIMTE, Departamento de Ciencias Químicas, Faculdade de Farmacia, Universidade do Porto, Portugal
| | - Mateusz Adam Słowiński
- LAQV, REQUIMTE, Departamento de Ciencias Químicas, Faculdade de Farmacia, Universidade do Porto, Portugal
| | - Bruno Sarmento
- i3S - Instituto de Investigacao e Inovacao em Saúde, Universidade do Porto, Rua Alfredo Allen 208, 4200-393 Porto, Portugal; INEB - Instituto de Engenharia Biomedica, Universidade do Porto, Rua Alfredo Allen 208, 4200-393 Porto, Portugal; IINFACTS, Instituto de Investigacao e Formacao Avancada em Ciencias e Tecnologias da Saude, Instituto Universitario de Ciencias da Saude, Gandra, Portugal
| | - Cláudia Nunes
- LAQV, REQUIMTE, Departamento de Ciencias Químicas, Faculdade de Farmacia, Universidade do Porto, Portugal
| | - M Cristina L Martins
- i3S - Instituto de Investigacao e Inovacao em Saúde, Universidade do Porto, Rua Alfredo Allen 208, 4200-393 Porto, Portugal; INEB - Instituto de Engenharia Biomedica, Universidade do Porto, Rua Alfredo Allen 208, 4200-393 Porto, Portugal; ICBAS - Instituto de Ciencias Biomedicas Abel Salazar, Universidade do Porto, Portugal
| | - Salette Reis
- LAQV, REQUIMTE, Departamento de Ciencias Químicas, Faculdade de Farmacia, Universidade do Porto, Portugal.
| |
Collapse
|
|
13
|
Ihtesham A, Maqbool S, Nadeem M, Bilawal Abbas Janjua M, Sundus O, Bakht Naqqash A, Inayat Mohamed W, Turab Haider S, Ahmad M, Ahmad Talha Mustafa M, Osama Mehboob H. Helicobacter pylori induced Immune Thrombocytopenic Purpura and perspective role of Helicobacter pylori eradication therapy for treating Immune Thrombocytopenic Purpura. AIMS Microbiol 2021; 7:284-303. [PMID: 34708173 PMCID: PMC8500795 DOI: 10.3934/microbiol.2021018] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2021] [Accepted: 08/30/2021] [Indexed: 12/12/2022] Open
Abstract
Immune thrombocytopenic purpura (ITP) is an autoimmune disease characterised by production of autoantibodies against platelet surface antigens. Recent studies have demonstrated a paramount association of ITP and Helicobacter pylori (H-pylori) infection with significant rise in platelet count following H-pylori eradication therapy. The H-pylori infection induced ITP is validated by many proposed mechanisms such as molecular mimicry due to production of autoantibodies against H-pylori surface virulent factors (CagA) and cross reactivity of these antibodies with platelet surface antigens (GP IIb/IIIa, GP Ib/IX, and GP Ia/IIa), phagocytic perturbation due to enhanced phagocytic activity of monocytes, enhanced dendritic cell numbers and response, platelets aggregation due to presence of anti- H-pylori IgG and von Willebrand factor (vWf) and finally host immune response against H-pylori virulent factors CagA and VacA leading to ITP. The effectiveness of H-pylori eradication therapy has also been demonstrated with platelet count being used as a predictive factor for assessment of treatment efficacy. Out of 201 patients 118 were responding to the triple therapy and remaining 83 patients were non-responders, showing the response rate of 58.7%. Out of 118 responders 69 patients were showing complete response (CR) and 49 were showing partial response (PR) to the H-pylori eradication therapy. However, more studies are required to elucidate this association and treatment efficacy.
Collapse
Affiliation(s)
| | | | | | | | - Omaima Sundus
- House officers Rawalpindi Medical University, Pakistan
| | | | | | | | - Muhmmad Ahmad
- House officers Services Institute of Medical Sciences, Pakistan
| | | | | |
Collapse
|
|
14
|
Helicobacter pylori BabA-SabA Key Roles in the Adherence Phase: The Synergic Mechanism for Successful Colonization and Disease Development. Toxins (Basel) 2021; 13:toxins13070485. [PMID: 34357957 PMCID: PMC8310295 DOI: 10.3390/toxins13070485] [Citation(s) in RCA: 50] [Impact Index Per Article: 12.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2021] [Revised: 07/03/2021] [Accepted: 07/07/2021] [Indexed: 01/21/2023] Open
Abstract
Helicobacter pylori is a pathogenic microorganism that successfully inhabits the human stomach, colonizing it by producing several virulence factors responsible for preventing host self-defense mechanisms. The adherence mechanism to gastric mucosal tissue is one of the most important processes for effective colonization in the stomach. The blood group antigen-binding adhesion (BabA) and sialic acid-binding adherence (SabA) are two H. pylori outer membrane proteins able to interact with antigens in the gastroduodenal tract. H. pylori possesses several mechanisms to control the regulation of both BabA and SabA in either the transcriptional or translational level. BabA is believed to be the most important protein in the early infection phase due to its ability to interact with various Lewis antigens, whereas SabA interaction with sialylated Lewis antigens may prove important for the adherence process in the inflamed gastric mucosal tissue in the ongoing-infection phase. The adherence mechanisms of BabA and SabA allow H. pylori to anchor in the gastric mucosa and begin the colonization process.
Collapse
|
|
15
|
Coelho LGV, Coelho MCF. Helicobacter pylori and colorectal neoplasms: a concise review. ARQUIVOS DE GASTROENTEROLOGIA 2021; 58:114-119. [PMID: 33909789 DOI: 10.1590/s0004-2803.202100000-19] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/29/2020] [Accepted: 09/17/2020] [Indexed: 12/16/2022]
Abstract
Helicobacter pylori is the main etiological agent of all malignant tumors caused by an infectious disease. It is a major, at times dominant, factor in the pathogenesis of a large spectrum of diseases such as acute and chronic gastritis, gastric and duodenal ulcers, gastric carcinoma, and lymphoma. Epidemiological and experimental studies suggest that H. pylori chronic infection may be related to different extragastric diseases, including colorectal neoplasms. This concise review aims to explore the association of H. pylori infection with colorectal cancer and adenoma, including the recent epidemiological findings, the diagnostic methods employed to detect H. pylori and virulent factors, and the potentially involved mechanisms. Furthermore, is attempted to establish the current data integration for causal inference using the Bradford-Hill causality criteria. The weak, although global, strength of the epidemiological positive association between H. pylori infection and colonic neoplasms associated to new mechanisms postulated to explain this interaction, including intestinal dysbiosis, should stimulate future studies. Prospective confirmatory studies to establish the role of H. pylori eradication in the process of carcinogenic transformation of the colonic epithelium may define its eventual role in the treatment and prevention of colonic neoplasms.
Collapse
Affiliation(s)
- Luiz Gonzaga Vaz Coelho
- Universidade Federal de Minas Gerais, Instituto Alfa de Gastroenterologia, Belo Horizonte, MG, Brasil
| | | |
Collapse
|
|
16
|
Galeev A, Suwandi A, Cepic A, Basu M, Baines JF, Grassl GA. The role of the blood group-related glycosyltransferases FUT2 and B4GALNT2 in susceptibility to infectious disease. Int J Med Microbiol 2021; 311:151487. [PMID: 33662872 DOI: 10.1016/j.ijmm.2021.151487] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2020] [Revised: 02/01/2021] [Accepted: 02/23/2021] [Indexed: 12/12/2022] Open
Abstract
The glycosylation profile of the gastrointestinal tract is an important factor mediating host-microbe interactions. Variation in these glycan structures is often mediated by blood group-related glycosyltransferases, and can lead to wide-ranging differences in susceptibility to both infectious- as well as chronic disease. In this review, we focus on the interplay between host glycosylation, the intestinal microbiota and susceptibility to gastrointestinal pathogens based on studies of two exemplary blood group-related glycosyltransferases that are conserved between mice and humans, namely FUT2 and B4GALNT2. We highlight that differences in susceptibility can arise due to both changes in direct interactions, such as bacterial adhesion, as well as indirect effects mediated by the intestinal microbiota. Although a large body of experimental work exists for direct interactions between host and pathogen, determining the more complex and variable mechanisms underlying three-way interactions involving the intestinal microbiota will be the subject of much-needed future research.
Collapse
Affiliation(s)
- Alibek Galeev
- Max Planck Institute for Evolutionary Biology, Plön, Germany and Institute for Experimental Medicine, Kiel University, Kiel, Germany
| | - Abdulhadi Suwandi
- Institute of Medical Microbiology and Hospital Epidemiology, Hannover Medical School and German Center for Infection Research (DZIF), Hannover, Germany
| | - Aleksa Cepic
- Max Planck Institute for Evolutionary Biology, Plön, Germany and Institute for Experimental Medicine, Kiel University, Kiel, Germany
| | - Meghna Basu
- Max Planck Institute for Evolutionary Biology, Plön, Germany and Institute for Experimental Medicine, Kiel University, Kiel, Germany
| | - John F Baines
- Max Planck Institute for Evolutionary Biology, Plön, Germany and Institute for Experimental Medicine, Kiel University, Kiel, Germany.
| | - Guntram A Grassl
- Institute of Medical Microbiology and Hospital Epidemiology, Hannover Medical School and German Center for Infection Research (DZIF), Hannover, Germany.
| |
Collapse
|
|
17
|
Abstract
INTRODUCTION Various types of cancers threaten human life. The role of bacteria in causing cancer is controversial, but it has been determined that the Helicobacter pylori infection is one of the identified risk factors for gastric cancer. Helicobacter pylori infection is highly prevalent, and about half of the world,s population is infected with it. OBJECTIVE The aim of this study was the role of Helicobacter pylori in the development of gastric cancer. METHOD We obtained information from previously published articles. RESULTS AND CONCLUSION The bacterium has various virulence factors, including cytotoxin- associated gene A, vacuolating cytotoxin A, and the different outer membrane proteins that cause cancer by different mechanisms. These virulence factors activate cell signaling pathways such as PI3-kinase/Akt, JAK/STAT and Ras, Raf, and ERK signaling that control cell proliferation. Uncontrolled proliferation can lead to cancer.
Collapse
Affiliation(s)
- Majid Alipour
- Department of Cell and Molecular Biology, Islamic Azad University, Babol Branch, Babol, Iran.
| |
Collapse
|
|
18
|
Chao G, Chen X, Zhang S. Study on the correlation between Helicobacter Pylori and biological characteristics of early Gastric Cancer. J Cancer 2021; 12:1838-1845. [PMID: 33613772 PMCID: PMC7890311 DOI: 10.7150/jca.46392] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2020] [Accepted: 12/29/2020] [Indexed: 01/08/2023] Open
Abstract
Objective: Retrospective analysis was used to determine the population diagnosed with EGC, and HP infection was used as the cut-off point to further evaluate the correlation between helicobacter pylori (HP) infection and tumor biological characteristics of early gastric cancer (EGC). Methods: All cases were collected from patients diagnosed with EGC through endoscopic surgery or surgical procedures from January 2009 to October 2018. General information, tumor site, tumor pathology, HER2 immunohistochemical results, and degree of HP infection were collected for retrospective analysis. Results: A total of 111 cases were collected in this study. Among the HP negative group, there were statistically significant differences in tumor sites between the uninfected group and the previously infected group (P<0.05).There were significant differences in monocyte infiltration and neutrophil infiltration between the positive and negative groups (P<0.05).The differentiated adenocarcinoma in the positive group was significantly lower than that in the negative group. The incidence rate of Mixed type cancer was significantly higher than that in the positive group (P<0.01). In the positive group of HP, there was a statistically significant difference in HER2 between the unsterilized group and the previously sterilized group (P<0.05).There was a statistically significant difference in HER2 between the HP positive group and the HP negative group (P<0.01). HP infection was significantly correlated with HER2 index and presented a positive correlation (P=0.014). Conclusion: HP infection is related to the tumor site and mucosal inflammatory infiltration of EGC. The malignant degree of EGC complicated with HP infection is higher, and most of them are mixed type. The degree of HP infection was positively correlated with the degree of invasion and malignancy of ECG. Furthermore, the tumor indicator HER2 is closely related to HP infection, and the detection of HP combined with HER2 is of great significance in the discovery of EGC and the evaluation of its malignancy.
Collapse
Affiliation(s)
- Guanqun Chao
- Department of Family Medicine, Sir Run Run Shaw Hospital, Zhejiang University, China
| | - Xinli Chen
- Department of Gastroenterology, The First Affiliated Hospital, Zhejiang Chinese Medical University, China
| | - Shuo Zhang
- Department of Gastroenterology, The First Affiliated Hospital, Zhejiang Chinese Medical University, China
| |
Collapse
|
|
19
|
Resuscitation of the Helicobacter pylori Coccoid Forms by Resuscitation Promoter Factor Obtained from Micrococcus Luteus. Curr Microbiol 2020; 77:2093-2103. [PMID: 32504323 DOI: 10.1007/s00284-020-02043-x] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2019] [Accepted: 05/20/2020] [Indexed: 02/07/2023]
|
|
20
|
Alpízar-Alpízar W, Skindersoe ME, Rasmussen L, Kriegbaum MC, Christensen IJ, Lund IK, Illemann M, Laerum OD, Krogfelt KA, Andersen LP, Ploug M. Helicobacter pylori Colonization Drives Urokinase Receptor (uPAR) Expression in Murine Gastric Epithelium During Early Pathogenesis. Microorganisms 2020; 8:microorganisms8071019. [PMID: 32660136 PMCID: PMC7409347 DOI: 10.3390/microorganisms8071019] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/10/2020] [Revised: 07/04/2020] [Accepted: 07/07/2020] [Indexed: 12/16/2022] Open
Abstract
(1) Background: Persistent Helicobacter pylori infection is the most important risk factor for gastric cancer. The urokinase receptor (uPAR) is upregulated in lesions harboring cancer invasion and inflammation. Circumstantial evidence tends to correlate H. pylori colonization with increased uPAR expression in the human gastric epithelium, but a direct causative link has not yet been established in vivo; (2) Methods: In a mouse model of H. pylori-induced gastritis, we investigated the temporal emergence of uPAR protein expression in the gastric mucosa in response to H. pylori (SS1 strain) infection; (3) Results: We observed intense uPAR immunoreactivity in foveolar epithelial cells of the gastric corpus due to de novo synthesis, compared to non-infected animals. This uPAR induction represents a very early response, but it increases progressively over time as do infiltrating immune cells. Eradication of H. pylori infection by antimicrobial therapy causes a regression of uPAR expression to its physiological baseline levels. Suppression of the inflammatory response by prostaglandin E2 treatment attenuates uPAR expression. Notwithstanding this relationship, H. pylori does induce uPAR expression in vitro in co-cultures with gastric cancer cell lines; (4) Conclusions: We showed that persistent H. pylori colonization is a necessary event for the emergence of a relatively high uPAR protein expression in murine gastric epithelial cells.
Collapse
Affiliation(s)
- Warner Alpízar-Alpízar
- The Finsen Laboratory, Rigshospitalet, 2100 Copenhagen, Denmark; (M.C.K.); (I.J.C); (I.K.L.); (M.I.); (O.D.L.)
- Biotech Research and Innovation Centre (BRIC), University of Copenhagen, 2100 Copenhagen, Denmark
- Centre for Research on Microscopic Structures (CIEMic) and Department of Biochemistry, University of Costa Rica, 2060 San José, Costa Rica
- Correspondence: (W.A.-A.); (M.P.)
| | - Mette E. Skindersoe
- Department of Bacteria, Parasites and Fungi, Statens Serum Institute, 2300 Copenhagen, Denmark; (M.E.S.); (K.A.K.)
- Bacthera, Kogle Allé 6, 2970 Hoersholm, Denmark
| | - Lone Rasmussen
- Department of Clinical Microbiology, Rigshospitalet, 2100 Copenhagen, Denmark; (L.P.A.); (L.R.)
| | - Mette C. Kriegbaum
- The Finsen Laboratory, Rigshospitalet, 2100 Copenhagen, Denmark; (M.C.K.); (I.J.C); (I.K.L.); (M.I.); (O.D.L.)
- Biotech Research and Innovation Centre (BRIC), University of Copenhagen, 2100 Copenhagen, Denmark
| | - Ib J. Christensen
- The Finsen Laboratory, Rigshospitalet, 2100 Copenhagen, Denmark; (M.C.K.); (I.J.C); (I.K.L.); (M.I.); (O.D.L.)
- Biotech Research and Innovation Centre (BRIC), University of Copenhagen, 2100 Copenhagen, Denmark
- Hvidovre Hospital, University of Copenhagen, 2650 Copenhagen, Denmark
| | - Ida K. Lund
- The Finsen Laboratory, Rigshospitalet, 2100 Copenhagen, Denmark; (M.C.K.); (I.J.C); (I.K.L.); (M.I.); (O.D.L.)
- Biotech Research and Innovation Centre (BRIC), University of Copenhagen, 2100 Copenhagen, Denmark
| | - Martin Illemann
- The Finsen Laboratory, Rigshospitalet, 2100 Copenhagen, Denmark; (M.C.K.); (I.J.C); (I.K.L.); (M.I.); (O.D.L.)
- Biotech Research and Innovation Centre (BRIC), University of Copenhagen, 2100 Copenhagen, Denmark
| | - Ole D. Laerum
- The Finsen Laboratory, Rigshospitalet, 2100 Copenhagen, Denmark; (M.C.K.); (I.J.C); (I.K.L.); (M.I.); (O.D.L.)
- Biotech Research and Innovation Centre (BRIC), University of Copenhagen, 2100 Copenhagen, Denmark
| | - Karen A. Krogfelt
- Department of Bacteria, Parasites and Fungi, Statens Serum Institute, 2300 Copenhagen, Denmark; (M.E.S.); (K.A.K.)
- Department of Science and Environment, Roskilde University, 4000 Roskilde, Denmark
- Department of Virus and microbiological Diagnostics, Statens Serum Institute, 2300 Copenhagen, Denmark
| | - Leif P. Andersen
- Department of Clinical Microbiology, Rigshospitalet, 2100 Copenhagen, Denmark; (L.P.A.); (L.R.)
| | - Michael Ploug
- The Finsen Laboratory, Rigshospitalet, 2100 Copenhagen, Denmark; (M.C.K.); (I.J.C); (I.K.L.); (M.I.); (O.D.L.)
- Biotech Research and Innovation Centre (BRIC), University of Copenhagen, 2100 Copenhagen, Denmark
- Correspondence: (W.A.-A.); (M.P.)
| |
Collapse
|
|
21
|
Wang YC, Chen YP, Ho CY, Liu TW, Chu CH, Wang HY, Liou TC. The Impact of Gastric Juice pH on the Intraluminal Therapy for Helicobacter pylori Infection. J Clin Med 2020; 9:jcm9061852. [PMID: 32545856 PMCID: PMC7356802 DOI: 10.3390/jcm9061852] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2020] [Revised: 06/02/2020] [Accepted: 06/11/2020] [Indexed: 02/07/2023] Open
Abstract
Background: Helicobacter pylori (H. pylori) can be topically eradicated in stomach lumen on endoscopic examination. The procedures of intraluminal therapy for H. pylori infection (ILTHPI) include the control of intragastric pH, mucolytic irrigation of the gastric mucosal surface, and a single-dose medicament containing antimicrobial agents. Aims: To detect gastric juice pH and evaluate its impact on the success rate of ILTHPI. Methods: We enrolled 324 patients with upper abdominal discomfort for endoscopic examinations. Among them, 13C-urea breath test was positive in 218 patients, where 100 underwent ILTHPI, and negative in 106. All patients had their gastric juice pH detected and set into three ranges, including normal acidity (pH < 4.0), low-level hypoacidity (pH 4.0–5.5), and high-level hypoacidity (pH ≥ 6.0). The impact of gastric juice pH on the success rate of ILTHPI was evaluated. Results: Distribution of pH level showed no significant difference between two groups of H. pylori-infected patients (p = 0.942). The eradication rate of ILTHPI is significantly lower in patients with gastric juice pH below 4 (p < 0.001). Conclusions: Detection of gastric juice pH in ILTHPI is extremely important. Rapid control of stomach pH at or above 4 for patients prior to ILTHPI is strongly recommended. (NCT03124420).
Collapse
Affiliation(s)
- Yu-Chio Wang
- Department of General Medicine, MacKay Memorial Hospital, Taipei 10449, Taiwan; (Y.-C.W.); (T.-W.L.); (C.-H.C.)
- Department of Medicine, MacKay Medical College, New Taipei City 25245, Taiwan; (Y.-P.C.); (C.-Y.H.); (H.-Y.W.)
| | - Yen-Po Chen
- Department of Medicine, MacKay Medical College, New Taipei City 25245, Taiwan; (Y.-P.C.); (C.-Y.H.); (H.-Y.W.)
- Division of Gastroenterology, Department of Internal Medicine, MacKay Memorial Hospital, New Taipei City 25173, Taiwan
| | - Cheng-Yu Ho
- Department of Medicine, MacKay Medical College, New Taipei City 25245, Taiwan; (Y.-P.C.); (C.-Y.H.); (H.-Y.W.)
- Division of Gastroenterology, Department of Internal Medicine, MacKay Memorial Hospital, New Taipei City 25173, Taiwan
| | - Ting-Wen Liu
- Department of General Medicine, MacKay Memorial Hospital, Taipei 10449, Taiwan; (Y.-C.W.); (T.-W.L.); (C.-H.C.)
- Department of Medicine, MacKay Medical College, New Taipei City 25245, Taiwan; (Y.-P.C.); (C.-Y.H.); (H.-Y.W.)
| | - Cheng-Hsin Chu
- Department of General Medicine, MacKay Memorial Hospital, Taipei 10449, Taiwan; (Y.-C.W.); (T.-W.L.); (C.-H.C.)
- Department of Medicine, MacKay Medical College, New Taipei City 25245, Taiwan; (Y.-P.C.); (C.-Y.H.); (H.-Y.W.)
- Division of Gastroenterology, Department of Internal Medicine, MacKay Memorial Hospital, Taipei 10449, Taiwan
| | - Horng-Yuan Wang
- Department of Medicine, MacKay Medical College, New Taipei City 25245, Taiwan; (Y.-P.C.); (C.-Y.H.); (H.-Y.W.)
- Division of Gastroenterology, Department of Internal Medicine, MacKay Memorial Hospital, Taipei 10449, Taiwan
| | - Tai-Cherng Liou
- Department of Medicine, MacKay Medical College, New Taipei City 25245, Taiwan; (Y.-P.C.); (C.-Y.H.); (H.-Y.W.)
- Division of Gastroenterology, Department of Internal Medicine, MacKay Memorial Hospital, New Taipei City 25173, Taiwan
- Division of Gastroenterology, Department of Internal Medicine, MacKay Memorial Hospital, Taipei 10449, Taiwan
- Correspondence: ; Tel.: +88-62-2543-3535 (ext. 3993)
| |
Collapse
|
|
22
|
Holland RL, Bosi KD, Harpring GH, Luo J, Wallig M, Phillips H, Blanke SR. Chronic in vivo exposure to Helicobacter pylori VacA: Assessing the efficacy of automated and long-term intragastric toxin infusion. Sci Rep 2020; 10:9307. [PMID: 32518315 PMCID: PMC7283276 DOI: 10.1038/s41598-020-65787-3] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2019] [Accepted: 05/04/2020] [Indexed: 12/24/2022] Open
Abstract
Helicobacter pylori (Hp) secrete VacA, a diffusible pore-forming exotoxin that is epidemiologically linked to gastric disease in humans. In vitro studies indicate that VacA modulates gastric epithelial and immune cells, but the in vivo contributions of VacA as an important determinant of Hp colonization and chronic infection remain poorly understood. To identify perturbations in the stomachs of C57BL/6 or BALB/C mice that result specifically from extended VacA exposure, we evaluated the efficacy of administering purified toxin using automated infusion via surgically-implanted, intragastric catheters. At 3 and 30 days of interrupted infusion, VacA was detected in association with gastric glands. In contrast to previously-reported tissue damage resulting from short term exposure to Hp extracts administered by oral gavage, extended infusion of VacA did not damage stomach, esophageal, intestinal, or liver tissue. However, several alterations previously reported during Hp infection were detected in animals infused with VacA, including reduction of the gastric mucus layer, and increased vacuolation of parietal cells. VacA infusion invoked an immune response, as indicated by the detection of circulating VacA antibodies. These foundational studies support the use of VacA infusion for identifying gastric alterations that are unambiguously attributable to long-term exposure to toxin.
Collapse
Affiliation(s)
- Robin L Holland
- Department of Pathobiology, College of Veterinary Medicine, University of Illinois at Urbana-Champaign, Urbana, Illinois, 61801, USA
| | - Kristopher D Bosi
- Department of Microbiology, School of Molecular and Cellular Biology, University of Illinois at Urbana-Champaign, Urbana, Illinois, 61801, USA
| | - Gregory H Harpring
- Department of Microbiology, School of Molecular and Cellular Biology, University of Illinois at Urbana-Champaign, Urbana, Illinois, 61801, USA
| | - Jiayi Luo
- Department of Microbiology, School of Molecular and Cellular Biology, University of Illinois at Urbana-Champaign, Urbana, Illinois, 61801, USA
| | - Matthew Wallig
- Department of Pathobiology, College of Veterinary Medicine, University of Illinois at Urbana-Champaign, Urbana, Illinois, 61801, USA
| | - Heidi Phillips
- Department of Veterinary Clinical Medicine, College of Veterinary Medicine, University of Illinois at Urbana-Champaign, Urbana, Illinois, 61801, USA
| | - Steven R Blanke
- Department of Pathobiology, College of Veterinary Medicine, University of Illinois at Urbana-Champaign, Urbana, Illinois, 61801, USA. .,Department of Microbiology, School of Molecular and Cellular Biology, University of Illinois at Urbana-Champaign, Urbana, Illinois, 61801, USA. .,Carle Illinois College of Medicine, University of Illinois at Urbana-Champaign, Urbana, Illinois, 61801, USA.
| |
Collapse
|
|
23
|
Jan HM, Chen YC, Yang TC, Ong LL, Chang CC, Muthusamy S, Abera AB, Wu MS, Gervay-Hague J, Mong KKT, Lin CH. Cholesteryl α-D-glucoside 6-acyltransferase enhances the adhesion of Helicobacter pylori to gastric epithelium. Commun Biol 2020; 3:120. [PMID: 32170208 PMCID: PMC7069968 DOI: 10.1038/s42003-020-0855-y] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2019] [Accepted: 02/20/2020] [Indexed: 12/18/2022] Open
Abstract
Helicobacter pylori, the most common etiologic agent of gastric diseases including gastric cancer, is auxotrophic for cholesterol and has to hijack it from gastric epithelia. Upon uptake, the bacteria convert cholesterol to cholesteryl 6′-O-acyl-α-D-glucopyranoside (CAG) to promote lipid raft clustering in the host cell membranes. However, how CAG appears in the host to exert the pathogenesis still remains ambiguous. Herein we identified hp0499 to be the gene of cholesteryl α-D-glucopyranoside acyltransferase (CGAT). Together with cholesteryl glucosyltransferase (catalyzing the prior step), CGAT is secreted via outer membrane vesicles to the host cells for direct synthesis of CAG. This significantly enhances lipid rafts clustering, gathers adhesion molecules (including Lewis antigens and integrins α5, β1), and promotes more bacterial adhesion. Furthermore, the clinically used drug amiodarone was shown as a potent inhibitor of CGAT to effectively reduce the bacterial adhesion, indicating that CGAT is a potential target of therapeutic intervention. Jan et al. identify cholesteryl α-D- glucopyranoside acyltransferase as a key enzyme in Helicobacter pylori’s synthesis of cholesteryl 6’-O-acyl-α-D-glucopyranoside, which promotes bacterial adhesion. This study provides insights into the H. pylori-induced pathogenesis and therapeutic strategies against it.
Collapse
Affiliation(s)
- Hau-Ming Jan
- Institute of Biological Chemistry, Academia Sinica, No. 128 Academic Road Section 2, Nan-Kang, Taipei, 11529, Taiwan
| | - Yi-Chi Chen
- Institute of Biological Chemistry, Academia Sinica, No. 128 Academic Road Section 2, Nan-Kang, Taipei, 11529, Taiwan.,Department of Chemistry and Institute of Biochemical Sciences, National Taiwan University, Taipei, 10617, Taiwan
| | - Tsai-Chen Yang
- Institute of Biological Chemistry, Academia Sinica, No. 128 Academic Road Section 2, Nan-Kang, Taipei, 11529, Taiwan
| | - Lih-Lih Ong
- Institute of Biological Chemistry, Academia Sinica, No. 128 Academic Road Section 2, Nan-Kang, Taipei, 11529, Taiwan.,Department of Applied Chemistry, National Chiao Tung University, Hsin-Chu, 30010, Taiwan.,Sustainable Chemical Science and Technology, Taiwan International Graduate Program, Academia Sinica and National Chiao Tung University, Taipei, 11529, Taiwan
| | - Chia-Chen Chang
- Department of Applied Chemistry, National Chiao Tung University, Hsin-Chu, 30010, Taiwan
| | - Sasikala Muthusamy
- Institute of Biological Chemistry, Academia Sinica, No. 128 Academic Road Section 2, Nan-Kang, Taipei, 11529, Taiwan.,Molecular and Biological Agricultural Sciences, Taiwan International Graduate Program, Academia Sinica and National Chung-Hsing University, Taipei, 11529, Taiwan.,Graduate Institute of Biotechnology, National Chung-Hsing University, Taichung, 40227, Taiwan
| | - Andualem Bahiru Abera
- Institute of Biological Chemistry, Academia Sinica, No. 128 Academic Road Section 2, Nan-Kang, Taipei, 11529, Taiwan.,Molecular and Biological Agricultural Sciences, Taiwan International Graduate Program, Academia Sinica and National Chung-Hsing University, Taipei, 11529, Taiwan.,Graduate Institute of Biotechnology, National Chung-Hsing University, Taichung, 40227, Taiwan
| | - Ming-Shiang Wu
- Division of Gastroenterology, Department of Internal Medicine, National Taiwan University Hospital, Taipei, 10002, Taiwan
| | | | - Kwok-Kong Tony Mong
- Department of Applied Chemistry, National Chiao Tung University, Hsin-Chu, 30010, Taiwan.
| | - Chun-Hung Lin
- Institute of Biological Chemistry, Academia Sinica, No. 128 Academic Road Section 2, Nan-Kang, Taipei, 11529, Taiwan. .,Department of Chemistry and Institute of Biochemical Sciences, National Taiwan University, Taipei, 10617, Taiwan.
| |
Collapse
|
|
24
|
The Interaction of Helicobacter pylori with TFF1 and Its Role in Mediating the Tropism of the Bacteria Within the Stomach. Int J Mol Sci 2019; 20:ijms20184400. [PMID: 31500233 PMCID: PMC6769565 DOI: 10.3390/ijms20184400] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2019] [Revised: 08/27/2019] [Accepted: 09/06/2019] [Indexed: 02/07/2023] Open
Abstract
Helicobacter pylori colonises the human stomach and has tropism for the gastric mucin, MUC5AC. The majority of organisms live in the adherent mucus layer within their preferred location, close to the epithelial surface where the pH is near neutral. Trefoil factor 1 (TFF1) is a small trefoil protein co-expressed with the gastric mucin MUC5AC in surface foveolar cells and co-secreted with MUC5AC into gastric mucus. Helicobacter pylori binds with greater avidity to TFF1 dimer, which is present in gastric mucus, than to TFF1 monomer. Binding of H. pylori to TFF1 is mediated by the core oligosaccharide subunit of H. pylori lipopolysaccharide at pH 5.0–6.0. Treatment of H. pylori lipopolysaccharide with mannosidase or glucosidase inhibits its interaction with TFF1. Both TFF1 and H. pylori have a propensity for binding to mucins with terminal non-reducing α- or β-linked N-acetyl-d-glucosamine or α-(2,3) linked sialic acid or Gal-3-SO42−. These findings are strong evidence that TFF1 has carbohydrate-binding properties that may involve a conserved patch of aromatic hydrophobic residues on the surface of its trefoil domain. The pH-dependent lectin properties of TFF1 may serve to locate H. pylori deep in the gastric mucus layer close to the epithelium rather than at the epithelial surface. This restricted localisation could limit the interaction of H. pylori with epithelial cells and the subsequent host signalling events that promote inflammation.
Collapse
|
|
25
|
Zain MA, Zafar F, Ashfaq A, Jamil AR, Ahmad A. Helicobacter pylori: An Underrated Cause of Immune Thrombocytopenic Purpura. A Comprehensive Review. Cureus 2019; 11:e5551. [PMID: 31695974 PMCID: PMC6820323 DOI: 10.7759/cureus.5551] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
Abstract
Idiopathic thrombocytopenic purpura (ITP) is the autoimmune-mediated destruction of platelets. ITP is a diagnosis of exclusion after other identifiable etiologies have been ruled out. After the first report by Gasbarrini et al. (1998) showing rising platelet counts in ITP patients following Helicobacter pylori (HP) eradication therapy, there is growing evidence that highlights the role of HP in triggering ITP. However, the exact pathophysiology of HP-associated ITP is still unclear, but many theories have been implicated in this regard. According to various reports, the postulated mechanisms for the role of HP in cITP include molecular mimicry, increased plasmacytoid dendritic cell numbers, phagocytic perturbation, and variable host immune response to HP virulence factors. One famous theory suggested molecular mimicry between platelet surface antigen and bacterial virulence factor, i.e. cytotoxin-associated gene A (CagA). It is thought that a chronic inflammatory response following an HP infection induces the host autoantibodies' response against CagA, which cross-reacts with platelet surface glycoproteins; therefore, it may accelerate platelet destruction in the host reticuloendothelial system. However, further studies are mandated to better understand the causal link between ITP and HP and study the role of biogeography. Nowadays, it is recommended that every patient with ITP should undergo HP diagnostic testing and triple therapy should be administered in all those candidates who test positive for HP infection. In our review, there were a few pregnant female ITP patients who took HP eradication therapy mainly after 20 weeks of gestation without maternal or fetal worst outcomes. However, large-scale studies are advisable to study the adverse fetal outcomes following triple therapy use.
Collapse
Affiliation(s)
- Muhammad A Zain
- Internal Medicine, Sheikh Zayed Medical College and Hospital, Rahim Yar Khan, PAK
| | - Fahad Zafar
- Internal Medicine, Maimonides Medical Center, Brooklyn, USA
| | - Ammar Ashfaq
- Internal Medicine, Abington Hospital - Jefferson Health, Abington, USA
| | - Abdur R Jamil
- Internal Medicine, Central Michigan University, Saginaw, USA
| | - Asrar Ahmad
- Internal Medicine, Abington Hospital - Jefferson Health, Abington, USA
| |
Collapse
|
|
26
|
Fung C, Tan S, Nakajima M, Skoog EC, Camarillo-Guerrero LF, Klein JA, Lawley TD, Solnick JV, Fukami T, Amieva MR. High-resolution mapping reveals that microniches in the gastric glands control Helicobacter pylori colonization of the stomach. PLoS Biol 2019; 17:e3000231. [PMID: 31048876 PMCID: PMC6497225 DOI: 10.1371/journal.pbio.3000231] [Citation(s) in RCA: 71] [Impact Index Per Article: 11.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/07/2019] [Accepted: 03/29/2019] [Indexed: 12/22/2022] Open
Abstract
Lifelong infection of the gastric mucosa by Helicobacter pylori can lead to peptic ulcers and gastric cancer. However, how the bacteria maintain chronic colonization in the face of constant mucus and epithelial cell turnover in the stomach is unclear. Here, we present a new model of how H. pylori establish and persist in stomach, which involves the colonization of a specialized microenvironment, or microniche, deep in the gastric glands. Using quantitative three-dimensional (3D) confocal microscopy and passive CLARITY technique (PACT), which renders tissues optically transparent, we analyzed intact stomachs from mice infected with a mixture of isogenic, fluorescent H. pylori strains with unprecedented spatial resolution. We discovered that a small number of bacterial founders initially establish colonies deep in the gastric glands and then expand to colonize adjacent glands, forming clonal population islands that persist over time. Gland-associated populations do not intermix with free-swimming bacteria in the surface mucus, and they compete for space and prevent newcomers from establishing in the stomach. Furthermore, bacterial mutants deficient in gland colonization are outcompeted by wild-type (WT) bacteria. Finally, we found that host factors such as the age at infection and T-cell responses control bacterial density within the glands. Collectively, our results demonstrate that microniches in the gastric glands house a persistent H. pylori reservoir, which we propose replenishes the more transient bacterial populations in the superficial mucosa.
Collapse
Affiliation(s)
- Connie Fung
- Department of Microbiology and Immunology, Stanford University School of Medicine, Stanford, California, United States of America
| | - Shumin Tan
- Department of Molecular Biology and Microbiology, Tufts University School of Medicine, Boston, Massachusetts, United States of America
| | - Mifuyu Nakajima
- Department of Biology, Stanford University, Stanford, California, United States of America
| | - Emma C Skoog
- Center for Comparative Medicine, University of California, Davis School of Medicine, Davis, California, United States of America
| | | | - Jessica A Klein
- Department of Pediatrics, Stanford University School of Medicine, Stanford, California, United States of America
| | - Trevor D Lawley
- Host-Microbiota Interactions Laboratory, Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, United Kingdom
| | - Jay V Solnick
- Center for Comparative Medicine, University of California, Davis School of Medicine, Davis, California, United States of America
- Department of Medicine, University of California, Davis School of Medicine, Davis, California, United States of America
- Department of Microbiology and Immunology, University of California, Davis School of Medicine, Davis, California, United States of America
| | - Tadashi Fukami
- Department of Biology, Stanford University, Stanford, California, United States of America
| | - Manuel R Amieva
- Department of Microbiology and Immunology, Stanford University School of Medicine, Stanford, California, United States of America
- Department of Pediatrics, Stanford University School of Medicine, Stanford, California, United States of America
| |
Collapse
|
|
27
|
Lopes-de-Campos D, Pinto RM, Lima SAC, Santos T, Sarmento B, Nunes C, Reis S. Delivering amoxicillin at the infection site - a rational design through lipid nanoparticles. Int J Nanomedicine 2019; 14:2781-2795. [PMID: 31114195 PMCID: PMC6488159 DOI: 10.2147/ijn.s193992] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
Purpose Amoxicillin is a commonly used antibiotic, although degraded by the acidic pH of the stomach. This is an important limitation for the treatment of Helicobacter pylori infections. The purpose of this work was to encapsulate amoxicillin in lipid nanoparticles, increasing the retention time at the site of infection (gastric mucosa), while protecting the drug from the harsh conditions of the stomach lumen. Materials and methods The nanoparticles were produced by the double emulsion technique and optimized by a three-level Box-Behnken design. Tween 80 and linolenic acid were used as potential therapeutic adjuvants and dioleoylphosphatidylethanolamine as a targeting agent to Helicobacter pylori. Nanoparticles were characterized regarding their physico-chemical features, their storage stability, and their usability for oral administration (assessment of in vitro release, in vitro cell viability, permeability, and interaction with mucins). Results The nanoparticles were stable for at least 6 months at 4°C. In vitro release studies revealed a high resistance to harsh conditions, including acidic pH and physiologic temperature. The nanoparticles have a low cytotoxicity effect in both fibroblasts and gastric cell lines, and they have the potential to be retained at the gastric mucosa. Conclusion Overall, the designed formulations present suitable physico-chemical features for being henceforward used by oral administration to treat Helicobacter pylori infections.
Collapse
Affiliation(s)
- Daniela Lopes-de-Campos
- LAQV, REQUIMTE, Departamento de Ciências Químicas, Faculdade de Farmácia, Universidade do Porto, Porto, Portugal,
| | - Rita M Pinto
- LAQV, REQUIMTE, Departamento de Ciências Químicas, Faculdade de Farmácia, Universidade do Porto, Porto, Portugal,
| | - Sofia A Costa Lima
- LAQV, REQUIMTE, Departamento de Ciências Químicas, Faculdade de Farmácia, Universidade do Porto, Porto, Portugal,
| | - Tiago Santos
- INEB - Instituto de Engenharia Biomédica, Universidade do Porto, Porto, Portugal.,i3S - Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Porto, Portugal
| | - Bruno Sarmento
- INEB - Instituto de Engenharia Biomédica, Universidade do Porto, Porto, Portugal.,i3S - Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Porto, Portugal.,IINFACTS, Instituto de Investigação e Formação Avançada em Ciências e Tecnologias da Saúde, Instituto Universitário de Ciências da Saúde, Gandra, Portugal
| | - Cláudia Nunes
- LAQV, REQUIMTE, Departamento de Ciências Químicas, Faculdade de Farmácia, Universidade do Porto, Porto, Portugal,
| | - Salette Reis
- LAQV, REQUIMTE, Departamento de Ciências Químicas, Faculdade de Farmácia, Universidade do Porto, Porto, Portugal,
| |
Collapse
|
|
28
|
The Relationship between Toll-like Receptors and Helicobacter pylori-Related Gastropathies: Still a Controversial Topic. J Immunol Res 2019; 2019:8197048. [PMID: 30863783 PMCID: PMC6378784 DOI: 10.1155/2019/8197048] [Citation(s) in RCA: 46] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2018] [Accepted: 01/02/2019] [Indexed: 12/13/2022] Open
Abstract
Innate immunity represents the first barrier against bacterial invasion. Toll-like receptors (TLRs) belong to the large family of pattern recognition receptors (PRRs), and their activation leads to the induction of inflammatory cytokines, chemokines, antigen-presenting molecules, and costimulatory molecules. Recent studies have focused on identifying the association between TLRs and Helicobacter pylori- (H. pylori-) related diseases. Therefore, this minireview focuses on assessing the role of these TLRs in the development of H. pylori-related gastropathies. Both TLR2 and TLR were found to be involved in H. pylori LPS recognition, with contradictory results most likely due to both the inability to obtain pure LPS in experimental studies and the heterogeneity of the bacterial LPS. In addition, TLR2 was found to be the most extensively expressed gene among all the TLRs in gastric tumors. High levels of TLR4 were also associated with a higher risk of gastric cancer. TLR5 was initially associated with the recognition of H. pylori flagellin, but it seems that this bacterium has developed mechanisms to escape this recognition representing an important factor involved in the persistence of this infection and subsequent carcinogenesis. TLR9, the only TLR with both anti- and proinflammatory roles, was involved in the recognition of H. pylori DNA. The dichotomous role of TLR9, promoting or suppressing the infection, depends on the gastric environment. Recently, TLR7 and TLR8 were shown to recognize purified H. pylori RNA, thereby inducing proinflammatory cytokines. TLR1 and TLR10 gene polymorphisms were associated with a higher risk for gastric cancer in H. pylori-infected individuals. Different gene polymorphisms of these TLRs were found to be associated with gastric cancer depending mostly on ethnicity. Further studies are required in order to develop preventive and therapeutic strategies against H. pylori infections based on the functions of TLRs.
Collapse
|
|
29
|
Qureshi N, Li P, Gu Q. Probiotic therapy in Helicobacter pylori infection: a potential strategy against a serious pathogen? Appl Microbiol Biotechnol 2019; 103:1573-1588. [PMID: 30610283 DOI: 10.1007/s00253-018-09580-3] [Citation(s) in RCA: 46] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2018] [Revised: 12/11/2018] [Accepted: 12/12/2018] [Indexed: 12/18/2022]
Abstract
Helicobacter pylori is a highly prevalent human pathogen responsible for chronic inflammation of the gastric tissues, gastroduodenal ulcers, and cancer. The treatment includes a pair of antibiotics with a proton pump inhibitor PPI. Despite the presence of different treatments, the infection rate is still increasing both in developed and developing states. The challenge of treatment failure is greatly due to the resistance of H. pylori to antibiotics and its side effects. Probiotics potential to cure H. pylori infection is well-documented. Probiotics combined with conventional treatment regime appear to have great potential in eradicating H. pylori infection, therefore, provide an excellent alternative approach to manage H. pylori load and its threatening disease outcome. Notably, anti-H. pylori activity of probiotics is strain specific,therefore establishing standard guidelines regarding the dose and formulation of individual strain is inevitable. This review is focused on probiotic's antagonism against H. pylori summarizing their three main potential aspects: their efficiency (i) as an alternative to H. pylori eradication treatment, (ii) as an adjunct to H. pylori eradication treatment and (iii) as a vaccine delivery vehicle.
Collapse
Affiliation(s)
- Nuzhat Qureshi
- Key Laboratory for Food Microbial Technology of Zhejiang Province, Department of Biotechnology, Zhejiang Gongshang University, Hangzhou, Zhejiang, 310018, People's Republic of China
| | - Ping Li
- Key Laboratory for Food Microbial Technology of Zhejiang Province, Department of Biotechnology, Zhejiang Gongshang University, Hangzhou, Zhejiang, 310018, People's Republic of China
| | - Qing Gu
- Key Laboratory for Food Microbial Technology of Zhejiang Province, Department of Biotechnology, Zhejiang Gongshang University, Hangzhou, Zhejiang, 310018, People's Republic of China.
| |
Collapse
|
|
30
|
Induction of TNF, CXCL8 and IL-1β in macrophages by Helicobacter pylori secreted protein HP1173 occurs via MAP-kinases, NF-κB and AP-1 signaling pathways. Microb Pathog 2018; 125:295-305. [DOI: 10.1016/j.micpath.2018.09.037] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2018] [Revised: 09/06/2018] [Accepted: 09/24/2018] [Indexed: 02/07/2023]
|
|
31
|
Chen ME, Su CH, Yang JS, Lu CC, Hou YC, Wu JB, Hsu YM. Baicalin, Baicalein, and Lactobacillus Rhamnosus JB3 Alleviated Helicobacter pylori Infections in Vitro and in Vivo. J Food Sci 2018; 83:3118-3125. [PMID: 30468256 DOI: 10.1111/1750-3841.14372] [Citation(s) in RCA: 31] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/03/2018] [Revised: 09/09/2018] [Accepted: 09/15/2018] [Indexed: 12/13/2022]
Abstract
Helicobacter pylori infection is associated with chronic gastritis, peptic ulcers, and gastric cancer. The flavonoid compounds baicalin and baicalein found in many medicinal plants exhibit an anti-inflammatory effect. The administration of Lactobacillus strains reducing the risk of H. pylori infection is well accepted. In this study, the therapeutic effects against H. pylori infection of baicalin, baicalein, and L. rhamnosus JB3 (LR-JB3), isolated from a dairy product, were investigated. Compared to baicalin, baicalein exhibited stronger anti-H. pylori activity and cytotoxicity on human gastric cancer epithelial AGS cells. Baicalin and baicalein both suppressed the vacA gene expression of H. pylori and interfered with the adhesion and invasion ability of H. pylori to AGS cells, as well as decreased H. pylori-induced interleukin (IL)-8 expression. In the mice infection model, high dosages of baicalin and baicalein inhibited H. pylori growth in the mice stomachs. Serum IL-1β levels and H. pylori-specific serum IgM and IgA levels in mice treated with baicalin and baicalein were decreased. Moreover, a synergistic therapeutic effect of baicalein and LR-JB3 on eradicating H. pylori infections was observed. Thus, administrating baicalin, baicalein, or LR-JB3 for an H. pylori infection could offer similar therapeutic effects to administering antibiotics while not disturbing the balance of gut microbiota. This study revealed the effects of baicalin, baicalein, and LR-JB3 on attenuating the virulence of H. pylori. The synergistic effect with baicalein and LR-JB3 provides the experimental rationale for testing the reliability, safety, and efficacy of this approach in higher animals and perhaps ultimately in humans to eradicate H. pylori infections. PRACTICAL APPLICATION: Baicalin and baicalein exert health promotion and avoidance of H. pylori infections by interfering with H. pylori growth and virulence. Lactobacillus rhamnosus JB3 was used to reduce the gastric inflammation caused by H. pylori infection.
Collapse
Affiliation(s)
- Mu-En Chen
- Dept. of Biological Science and Technology, China Medical Univ., Taichung, 40402, Taiwan
| | - Chiu-Hsian Su
- Dept. of Biological Science and Technology, China Medical Univ., Taichung, 40402, Taiwan
| | - Jai-Sing Yang
- Dept. of Medical Research, China Medical Univ. Hospital, China Medical Univ., Taichung, 40447, Taiwan
| | - Chi-Cheng Lu
- Dept. of Sport Performance, Natl. Taiwan Univ. of Sport, Taichung, 40404, Taiwan
| | - Yu-Chi Hou
- School of Pharmacy, China Medical Univ., Taichung, 40402, Taiwan
| | - Jin-Bin Wu
- School of Pharmacy, China Medical Univ., Taichung, 40402, Taiwan
| | - Yuan-Man Hsu
- Dept. of Biological Science and Technology, China Medical Univ., Taichung, 40402, Taiwan
| |
Collapse
|
|
32
|
Pozdeev ОК, Pozdeeva АО, Valeeva YV, Gulyaev PE. MECHANISMS OF INTERRACTION OF HELICOBACTER PYLORI WITH EPITHELIUM OF GASTRIC MUCOSA. I. PATHOGENIC FACTORS PROMOTING SUCCESSFUL COLONIZATION. RUSSIAN JOURNAL OF INFECTION AND IMMUNITY 2018; 8:273-283. [DOI: 10.15789/2220-7619-2018-3-273-283] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/02/2025]
Abstract
H. pylori is a Gram-negative, crimp and motile bacterium that colonizes the hostile microniche of the human stomach roughly one half of the human population. Then persists for the host’s entire life, but only causes overt gastric disease in a subset of infected hosts. To the reasons contributing to the development of diseases, usually include: concomitant infections of the gastrointestinal tract, improper sterilization of medical instruments, usually endoscopes, nonobservance of personal hygiene rules, prolonged contact with infected or carriers, including family members and a number of other factors. Clinically, H. pylori plays a causative role in the development of a wide spectrum of diseases including chronic active gastritis, peptic and duodenal ulceration, gastric adenocarcinoma, and gastric mucosa-associated lymphoid tissue lymphoma. Due to the global distribution of H. pylori, we are able to conclude that smart strategies are contributing to adaptation of the bacterium in an aggressive environment of a stomach and lifelong permanent circulation in its host. Thirty-four years after the discovery of this bacterium, there are still many unanswered questions. For example, which strategies help the bacterium to survive in this inhospitable conditions? Understanding the mechanisms governing H. pylori persistence will improve identification of the increased risk of different gastric diseases in persons infected with this bacterium. A well-defined and long-term equilibrium between the human host and H. pylori allows bacterial persistence in the gastric microniche; although this coexistence leads to a high risk of severe diseases the diseases which are listed above. In this review, we discuss the pathogenesis of this bacterium and the mechanisms it uses to promote persistent colonization of the gastric mucosa, with a focus on recent insights into the role of some virulence factors like urease, LPS, outer membrane proteins, cytotoxins, factors, promoting invasion. Information on the mechanisms related to H. pylori persistence can also provide the direction for future research concerning effective therapy and management of gastroduodenal disorders. The topics presented in the current review are important for elucidating the strategies used by H. pylori to help the bacterium persist in relation to the many unfavorable features of living in the gastric microniche.
Collapse
|
|
33
|
Álvarez A, Uribe F, Canales J, Romero C, Soza A, Peña MA, Antonelli M, Almarza O, Cerda O, Toledo H. KCTD5 and Ubiquitin Proteasome Signaling Are Required for Helicobacter pylori Adherence. Front Cell Infect Microbiol 2017; 7:450. [PMID: 29114497 PMCID: PMC5660694 DOI: 10.3389/fcimb.2017.00450] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2017] [Accepted: 10/04/2017] [Indexed: 12/19/2022] Open
Abstract
In order to establish infection, bacterial pathogens modulate host cellular processes by using virulence factors, which are delivered from the bacteria to the host cell leading to cellular reprogramming. In this context, several pathogens regulate the ubiquitin proteasome system in order to regulate the cellular effectors required for their successful colonization and persistance. In this study, we investigated how Helicobacter pylori affect the ubiquitination of the host proteins to achieve the adherence to the cells, using AGS gastric epithelial cells cultured with H. pylori strains, H. pylori 26695 and two isogenic mutants H. pylori cag::cat and vacA::apha3, to characterize the ability of H. pylori to reprogram the ubiquitin proteasome systems. The infection assays suggest that the ubiquitination of the total proteins does not change when cells were co-culture with H. pylori. We also found that the proteasome activity is necessary for H. pylori adhesion to AGS cells and the adherence increases when the level of KCTD5, an adaptor of Cullin-3, decrease. Moreover, we found that KCTD5 is ubiquitinated and degraded by the proteasome system and that CagA and VacA played no role on reducing KCTD5 levels. Furthermore, H. pylori impaired KCTD5 ubiquitination and did not increase global proteasome function. These results suggest that H. pylori affect the ubiquitin-proteasome system (UPS) to facilitate the adhesion of this microorganism to establish stable colonization in the gastric epithelium and improve our understanding of how H. pylori hijack host systems to establish the adherence.
Collapse
Affiliation(s)
- Alhejandra Álvarez
- Molecular and Cellular Biology Program, Faculty of Medicine, Instituto de Ciencias Biomédicas (ICBM), Universidad de Chile, Santiago, Chile
| | - Felipe Uribe
- Molecular and Cellular Biology Program, Faculty of Medicine, Instituto de Ciencias Biomédicas (ICBM), Universidad de Chile, Santiago, Chile
| | - Jimena Canales
- Molecular and Cellular Biology Program, Faculty of Medicine, Instituto de Ciencias Biomédicas (ICBM), Universidad de Chile, Santiago, Chile
| | - Cristóbal Romero
- Molecular and Cellular Biology Program, Faculty of Medicine, Instituto de Ciencias Biomédicas (ICBM), Universidad de Chile, Santiago, Chile
| | - Andrea Soza
- Department of Biological and Chemical Sciences, Faculty of Science, Universidad San Sebastián, Santiago, Chile
| | - María A Peña
- Molecular and Cellular Biology Program, Faculty of Medicine, Instituto de Ciencias Biomédicas (ICBM), Universidad de Chile, Santiago, Chile
| | - Marcelo Antonelli
- Molecular and Cellular Biology Program, Faculty of Medicine, Instituto de Ciencias Biomédicas (ICBM), Universidad de Chile, Santiago, Chile
| | - Oscar Almarza
- Molecular and Cellular Biology Program, Faculty of Medicine, Instituto de Ciencias Biomédicas (ICBM), Universidad de Chile, Santiago, Chile
| | - Oscar Cerda
- Molecular and Cellular Biology Program, Faculty of Medicine, Instituto de Ciencias Biomédicas (ICBM), Universidad de Chile, Santiago, Chile.,Millennium Nucleus of Ion Channels-Associated Diseases (MiNICAD), Santiago, Chile
| | - Héctor Toledo
- Molecular and Cellular Biology Program, Faculty of Medicine, Instituto de Ciencias Biomédicas (ICBM), Universidad de Chile, Santiago, Chile
| |
Collapse
|
|
34
|
Pompaiah M, Bartfeld S. Gastric Organoids: An Emerging Model System to Study Helicobacter pylori Pathogenesis. Curr Top Microbiol Immunol 2017; 400:149-168. [PMID: 28124153 DOI: 10.1007/978-3-319-50520-6_7] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
Helicobacter research classically uses fixed human tissue, animal models or cancer cell lines. Each of these study objects has its advantages and has brought central insights into the infection process. Nevertheless, in model systems for basic and medical research, there is a gap between two-dimensional and most often transformed cell cultures and three-dimensional, highly organized tissues. In recent years, stem cell research has provided the means to fill this gap. The identification of the niche factors that support growth, expansion and differentiation of stem cells in vitro has allowed the development of three-dimensional culture systems called organoids. Gastric organoids are grown from gastric stem cells and are organized epithelial structures that comprise all the differentiated cell types of the stomach. They can be expanded without apparent limitation and are amenable to a wide range of standard laboratory techniques. Here, we review different stem cell-derived organoid model systems useful for Helicobacter pylori research and outline their advantages for infection studies.
Collapse
Affiliation(s)
- Malvika Pompaiah
- Research Centre for Infectious Diseases, Institute for Molecular Infection Biology, University of Würzburg, Würzburg, Germany
| | - Sina Bartfeld
- Research Centre for Infectious Diseases, Institute for Molecular Infection Biology, University of Würzburg, Würzburg, Germany.
| |
Collapse
|
|
35
|
Ruch TR, Engel JN. Targeting the Mucosal Barrier: How Pathogens Modulate the Cellular Polarity Network. Cold Spring Harb Perspect Biol 2017; 9:cshperspect.a027953. [PMID: 28193722 DOI: 10.1101/cshperspect.a027953] [Citation(s) in RCA: 25] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/28/2022]
Abstract
The mucosal barrier is composed of polarized epithelial cells with distinct apical and basolateral surfaces separated by tight junctions and serves as both a physical and immunological barrier to incoming pathogens. Specialized polarity proteins are critical for establishment and maintenance of polarity. Many human pathogens have evolved virulence mechanisms that target the polarity network to enhance binding, create replication niches, move through the barrier by transcytosis, or bypass the barrier by disrupting cell-cell junctions. This review summarizes recent advances and compares and contrasts how three important human pathogens that colonize mucosal surfaces, Pseudomonas aeruginosa, Helicobacter pylori, and Neisseria meningitidis, subvert the host cell polarization machinery during infection.
Collapse
Affiliation(s)
- Travis R Ruch
- Department of Medicine, University of California, San Francisco, San Francisco, California 94143
| | - Joanne N Engel
- Department of Medicine, University of California, San Francisco, San Francisco, California 94143.,Department of Microbiology and Immunology, University of California, San Francisco, San Francisco, California 94143
| |
Collapse
|
|
36
|
Diversification of the AlpB Outer Membrane Protein of Helicobacter pylori Affects Biofilm Formation and Cellular Adhesion. J Bacteriol 2017; 199:JB.00729-16. [PMID: 28031283 PMCID: PMC5331671 DOI: 10.1128/jb.00729-16] [Citation(s) in RCA: 29] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2016] [Accepted: 12/19/2016] [Indexed: 02/07/2023] Open
Abstract
Helicobacter pylori is one of the most common causes of bacterial infection in humans, and it forms biofilms on human gastric mucosal epithelium as well as on in vitro abiotic surfaces. Bacterial biofilm is critical not only for environmental survival but also for successful infection. We previously demonstrated that strain TK1402, which was isolated from a Japanese patient with duodenal and gastric ulcers, has high biofilm-forming ability in vitro relative to other strains. In addition, we showed that outer membrane vesicles (OMV) play an important role in biofilm formation. The aim of this study was to analyze which protein(s) in the OMV contributes to biofilm formation in TK1402. We obtained a spontaneous mutant strain derived from TK1402 lacking biofilm-forming ability. The protein profiles of the OMV were compared between this mutant strain and the wild type, and it was found that AlpB, an outer membrane protein in the OMV of the mutant strain, was markedly decreased compared to that of the wild type. Restoration of TK1402 alpB to the mutant strain fully recovered the ability to form biofilm. However, restoration with alpB from other strains demonstrated incomplete recovery of biofilm-forming ability. We therefore inferred that the variable region of AlpB (amino acid positions 121 to 146) was involved in TK1402 biofilm formation. In addition, diversification of the AlpB sequence was shown to affect the ability to adhere to AGS cells. These results demonstrate a new insight into the molecular mechanisms of host colonization by H. pylori. IMPORTANCE Bacterial biofilm is critical not only for environmental survival but also for successful infection. The mechanism of Helicobacter pylori adherence to host cells mediated by cell surface adhesins has been the focus of many studies, but little is known regarding factors involved in H. pylori biofilm formation. Our study demonstrated that AlpB plays an important role in biofilm formation and that this property depends upon the specific sequence of alpB. This in turn was shown to be important in the ability to adhere to gastric cells. We anticipate that these results will provide new insight into the molecular mechanisms of H. pylori colonization.
Collapse
|
|
37
|
Abstract
Coxiella burnetii is an intracellular bacterial pathogen and a significant cause of culture-negative endocarditis in the United States. Upon infection, the nascent Coxiella phagosome fuses with the host endocytic pathway to form a large lysosome-like vacuole called the parasitophorous vacuole (PV). The PV membrane is rich in sterols, and drugs perturbing host cell cholesterol homeostasis inhibit PV formation and bacterial growth. Using cholesterol supplementation of a cholesterol-free cell model system, we found smaller PVs and reduced Coxiella growth as cellular cholesterol concentration increased. Further, we observed in cells with cholesterol a significant number of nonfusogenic PVs that contained degraded bacteria, a phenotype not observed in cholesterol-free cells. Cholesterol had no effect on axenic Coxiella cultures, indicating that only intracellular bacteria are sensitive to cholesterol. Live-cell microscopy revealed that both plasma membrane-derived cholesterol and the exogenous cholesterol carrier protein low-density lipoprotein (LDL) traffic to the PV. To test the possibility that increasing PV cholesterol levels affects bacterial survival, infected cells were treated with U18666A, a drug that traps cholesterol in lysosomes and PVs. U18666A treatment led to PVs containing degraded bacteria and a significant loss in bacterial viability. The PV pH was significantly more acidic in cells with cholesterol or cells treated with U18666A, and the vacuolar ATPase inhibitor bafilomycin blocked cholesterol-induced PV acidification and bacterial death. Additionally, treatment of infected HeLa cells with several FDA-approved cholesterol-altering drugs led to a loss of bacterial viability, a phenotype also rescued by bafilomycin. Collectively, these data suggest that increasing PV cholesterol further acidifies the PV, leading to Coxiella death. The intracellular Gram-negative bacterium Coxiella burnetii is a significant cause of culture-negative infectious endocarditis, which can be fatal if untreated. The existing treatment strategy requires prolonged antibiotic treatment, with a 10-year mortality rate of 19% in treated patients. Therefore, new clinical therapies are needed and can be achieved by better understanding C. burnetii pathogenesis. Upon infection of host cells, C. burnetii grows within a specialized replication niche, the parasitophorous vacuole (PV). Recent data have linked cholesterol to intracellular C. burnetii growth and PV formation, leading us to further decipher the role of cholesterol during C. burnetii-host interaction. We observed that increasing PV cholesterol concentration leads to increased acidification of the PV and bacterial death. Further, treatment with FDA-approved drugs that alter host cholesterol homeostasis also killed C. burnetii through PV acidification. Our findings suggest that targeting host cholesterol metabolism might prove clinically efficacious in controlling C. burnetii infection.
Collapse
|
|
38
|
Huang Y, Wang QL, Cheng DD, Xu WT, Lu NH. Adhesion and Invasion of Gastric Mucosa Epithelial Cells by Helicobacter pylori. Front Cell Infect Microbiol 2016; 6:159. [PMID: 27921009 PMCID: PMC5118847 DOI: 10.3389/fcimb.2016.00159] [Citation(s) in RCA: 94] [Impact Index Per Article: 10.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/27/2016] [Accepted: 11/04/2016] [Indexed: 12/11/2022] Open
Abstract
Helicobacter pylori is the main pathogenic bacterium involved in chronic gastritis and peptic ulcer and a class 1 carcinogen in gastric cancer. Current research focuses on the pathogenicity of H. pylori and the mechanism by which it colonizes the gastric mucosa. An increasing number of in vivo and in vitro studies demonstrate that H. pylori can invade and proliferate in epithelial cells, suggesting that this process might play an important role in disease induction, immune escape and chronic infection. Therefore, to explore the process and mechanism of adhesion and invasion of gastric mucosa epithelial cells by H. pylori is particularly important. This review examines the relevant studies and describes evidence regarding the adhesion to and invasion of gastric mucosa epithelial cells by H. pylori.
Collapse
Affiliation(s)
- Ying Huang
- Department of Gastroenterology, The First Affiliated Hospital of Nanchang University Nanchang, China
| | - Qi-Long Wang
- Department of General Surgery, Tianjin Haihe Hospital Tianjin, China
| | - Dan-Dan Cheng
- Department of Gastroenterology, The First Affiliated Hospital of Nanchang University Nanchang, China
| | - Wen-Ting Xu
- Department of Gastroenterology, The First Affiliated Hospital of Nanchang University Nanchang, China
| | - Nong-Hua Lu
- Department of Gastroenterology, The First Affiliated Hospital of Nanchang University Nanchang, China
| |
Collapse
|
|
39
|
Chiu KH, Wang LH, Tsai TT, Lei HY, Liao PC. Secretomic Analysis of Host-Pathogen Interactions Reveals That Elongation Factor-Tu Is a Potential Adherence Factor of Helicobacter pylori during Pathogenesis. J Proteome Res 2016; 16:264-273. [PMID: 27764940 DOI: 10.1021/acs.jproteome.6b00584] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/25/2023]
Abstract
The secreted proteins of bacteria are usually accompanied by virulence factors, which can cause inflammation and damage host cells. Identifying the secretomes arising from the interactions of bacteria and host cells could therefore increase understanding of the mechanisms during initial pathogenesis. The present study used a host-pathogen coculture system of Helicobacter pylori and monocytes (THP-1 cells) to investigate the secreted proteins associated with initial H. pylori pathogenesis. The secreted proteins from the conditioned media from H. pylori, THP-1 cells, and the coculture were collected and analyzed using SDS-PAGE and LC-MS/MS. Results indicated the presence of 15 overexpressed bands in the coculture. Thirty-one proteins were identified-11 were derived from THP-1 cells and 20 were derived from H. pylori. A potential adherence factor from H. pylori, elongation factor-Tu (EF-Tu), was selected for investigation of its biological function. Results from confocal microscopic and flow cytometric analyses indicated the contribution of EF-Tu to the binding ability of H. pylori in THP-1. The data demonstrated that fluorescence of EF-Tu on THP-1 cells increased after the addition of the H. pylori-conditioned medium. This study reports a novel secretory adherence factor in H. pylori, EF-Tu, and further elucidates mechanisms of H. pylori adaptation for host-pathogen interaction during pathogenesis.
Collapse
Affiliation(s)
- Kuo-Hsun Chiu
- Department and Graduate Institute of Aquaculture, National Kaohsiung Marine University , Kaohsiung 81157, Taiwan
| | - Ling-Hui Wang
- Department of Environmental and Occupational Health, College of Medicine, National Cheng Kung University , Tainan 70428, Taiwan
| | - Tsung-Ting Tsai
- Department of Microbiology and Immunology, College of Medicine, National Cheng Kung University , Tainan 70101, Taiwan
| | - Huan-Yao Lei
- Department of Microbiology and Immunology, College of Medicine, National Cheng Kung University , Tainan 70101, Taiwan
| | - Pao-Chi Liao
- Department of Environmental and Occupational Health, College of Medicine, National Cheng Kung University , Tainan 70428, Taiwan
| |
Collapse
|
|
40
|
Raei N, Latifi-Navid S, Zahri S. Helicobacter pylori cag Pathogenicity Island cagL and orf17 Genotypes Predict Risk of Peptic Ulcerations but not Gastric Cancer in Iran. Asian Pac J Cancer Prev 2016; 16:6645-50. [PMID: 26434889 DOI: 10.7314/apjcp.2015.16.15.6645] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/10/2022] Open
Abstract
BACKGROUND Gastric cancer (GC) is the third most common cancer regarding mortality in the world. The cag pathogenicity island (PAI) of Helicobacter pylori which contains genes associated with a more aggressive phenotype may involve in the pathogenesis of gastrointestinal disease. We here aimed to examine the associations of cagH, cagL, orf17, and cagG genotypes of H. pylori cag PAI with severe gastrointestinal disease. MATERIALS AND METHODS A total of 242 H. pylori strains were genotyped. Histopathological examination and classification of subjects were performed. RESULTS The frequencies of the cagH, cagL, cagG, and orf17 genotypes were 40/54 (74.1%), 53/54 (98.1%), 38/54 (70.4%), and 43/54 (79.6%), respectively, in patients with peptidic ulceration (PU),while in the control group, the frequencies were 87/147 (59.6%) for cagH, 121/146 (82.9%) for cagL, 109/146 (74.7%) for cagG, and 89/146 (61.0%) for orf17. The results of simple logistic regression analysis showed that the cagL and orf17 genotypes were significantly associated with an increased risk of PU not GC; the ORs (95% CI) were 10.950 (1.446-82.935), and 2.504 (1.193-5.253), respectively. No significant association was found between the cagH and cagG genotypes and the risk of both the PU and the GC in Iran (P>0.05). Finally, multiple logistic regression analysis showed that the cagL genotype was independently and significantly associated with the age- and sex-adjusted risk for PU; the OR (95% CI) was 9.557 (1.219-17.185). CONCLUSIONS We conclude that the orf17 and especially cagL genotypes of H. pylori cag PAI could be factors for risk prediction of PU, but not GC in Iran.
Collapse
Affiliation(s)
- Negin Raei
- Department of Biology, Faculty of Sciences, University of Mohaghegh Ardabili, Ardabil, Iran E-mail :
| | | | | |
Collapse
|
|
41
|
Lactobacilli Reduce Helicobacter pylori Attachment to Host Gastric Epithelial Cells by Inhibiting Adhesion Gene Expression. Infect Immun 2016; 84:1526-1535. [PMID: 26930708 DOI: 10.1128/iai.00163-16] [Citation(s) in RCA: 47] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2016] [Accepted: 02/25/2016] [Indexed: 02/06/2023] Open
Abstract
The human gastrointestinal tract, including the harsh environment of the stomach, harbors a large variety of bacteria, of which Lactobacillus species are prominent members. The molecular mechanisms by which species of lactobacilli interfere with pathogen colonization are not fully characterized. In this study, we aimed to study the effect of lactobacillus strains upon the initial attachment of Helicobacter pylori to host cells. Here we report a novel mechanism by which lactobacilli inhibit adherence of the gastric pathogen H. pylori In a screen with Lactobacillus isolates, we found that only a few could reduce adherence of H. pylori to gastric epithelial cells. Decreased attachment was not due to competition for space or to lactobacillus-mediated killing of the pathogen. Instead, we show that lactobacilli act on H. pylori directly by an effector molecule that is released into the medium. This effector molecule acts on H. pylori by inhibiting expression of the adhesin-encoding gene sabA Finally, we verified that inhibitory lactobacilli reduced H. pylori colonization in an in vivo model. In conclusion, certain Lactobacillus strains affect pathogen adherence by inhibiting sabA expression and thereby reducing H. pylori binding capacity.
Collapse
|
|
42
|
Vázquez-Jiménez FE, Torres J, Flores-Luna L, Cerezo SG, Camorlinga-Ponce M. Patterns of Adherence of Helicobacter pylori Clinical Isolates to Epithelial Cells, and its Association with Disease and with Virulence Factors. Helicobacter 2016; 21:60-8. [PMID: 25908566 DOI: 10.1111/hel.12230] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
BACKGROUND AND AIM Adherence to the gastric epithelium is one of the most important steps of Helicobacter pylori to remain and cause disease. The aim of this study was to analyze whether H. pylori isolates from patients with different gastroduodenal diseases present differences in the pattern of adherence to gastric epithelial cells (AGS), in the ability to induce IL-8, and in the presence of virulence genes. METHODS We tested 75 H. pylori strains isolated from nonatrophic gastritis, gastric cancer, and duodenal ulcer patients. The adhesion pattern and IL-8 induction were determined in AGS cells, and invasion of AGS cells was studied using a gentamicin protection assay. The IL-8 levels induced were determined by ELISA. RESULTS Helicobacter pylori strains presented diffuse adherence (DA) and localized (LA) adherence patterns, similar to those described for enteropathogenic E. coli (EPEC), were observed in AGS cells. A DA pattern was observed in 57% and LA in 43% of the strains, and DA was more frequent in isolates from patients with gastric cancer (p = 0.044). Strains with a LA pattern induced higher levels of IL-8 (p = 0.042) in AGS cells. CONCLUSION The adherence pattern was not associated with neither invasiveness nor with the presence of virulence genes. Our study shows that H. pylori strains present adherence patterns to AGS cells resembling those observed in EPEC and that these patterns may be associated with disease and with activity on AGS cells.
Collapse
Affiliation(s)
- Flor Elizabeth Vázquez-Jiménez
- Unidad de Investigación Médica en Enfermedades Infecciosas y Parasitarias UMAE, Hospital de Pediatria, IMSS., México, DF, Mexico
| | - Javier Torres
- Unidad de Investigación Médica en Enfermedades Infecciosas y Parasitarias UMAE, Hospital de Pediatria, IMSS., México, DF, Mexico
| | | | - Silvia Giono Cerezo
- Departamento de Microbiologia, Instituto Politecnico Nacional, Escuela Nacional de Ciencias Biologicas, Mexico, DF, Mexico
| | - Margarita Camorlinga-Ponce
- Unidad de Investigación Médica en Enfermedades Infecciosas y Parasitarias UMAE, Hospital de Pediatria, IMSS., México, DF, Mexico
| |
Collapse
|
|
43
|
Parreira P, Shi Q, Magalhaes A, Reis CA, Bugaytsova J, Borén T, Leckband D, Martins MCL. Atomic force microscopy measurements reveal multiple bonds between Helicobacter pylori blood group antigen binding adhesin and Lewis b ligand. J R Soc Interface 2015; 11:20141040. [PMID: 25320070 DOI: 10.1098/rsif.2014.1040] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/04/2023] Open
Abstract
The strength of binding between the Helicobacter pylori blood group antigen-binding adhesin (BabA) and its cognate glycan receptor, the Lewis b blood group antigen (Le(b)), was measured by means of atomic force microscopy. High-resolution measurements of rupture forces between single receptor-ligand pairs were performed between the purified BabA and immobilized Le(b) structures on self-assembled monolayers. Dynamic force spectroscopy revealed two similar but statistically different bond populations. These findings suggest that the BabA may form different adhesive attachments to the gastric mucosa in ways that enhance the efficiency and stability of bacterial adhesion.
Collapse
Affiliation(s)
- P Parreira
- INEB-Instituto de Engenharia Biomédica, Universidade do Porto, Porto, Portugal
| | - Q Shi
- Department of Chemical and Biomolecular Engineering, University of Illinois at Urbana-Champaign, Urbana, IL, USA
| | - A Magalhaes
- IPATIMUP-Instituto de Patologia e Imunologia Molecular da Universidade do Porto, Porto, Portugal
| | - C A Reis
- IPATIMUP-Instituto de Patologia e Imunologia Molecular da Universidade do Porto, Porto, Portugal Faculdade de Medicina, Universidade do Porto, Porto, Portugal Instituto de Ciências Biomédicas Abel Salazar, Universidade do Porto, Porto, Portugal
| | - J Bugaytsova
- Department of Medical Biochemistry and Biophysics, Umeå University, Umeå, Sweden
| | - T Borén
- Department of Medical Biochemistry and Biophysics, Umeå University, Umeå, Sweden
| | - D Leckband
- Department of Chemical and Biomolecular Engineering, University of Illinois at Urbana-Champaign, Urbana, IL, USA
| | - M C L Martins
- INEB-Instituto de Engenharia Biomédica, Universidade do Porto, Porto, Portugal Instituto de Ciências Biomédicas Abel Salazar, Universidade do Porto, Porto, Portugal
| |
Collapse
|
|
44
|
Ling SSM, Khoo LHB, Hwang LA, Yeoh KG, Ho B. Instrumental Role of Helicobacter pylori γ-Glutamyl Transpeptidase in VacA-Dependent Vacuolation in Gastric Epithelial Cells. PLoS One 2015; 10:e0131460. [PMID: 26111186 PMCID: PMC4482420 DOI: 10.1371/journal.pone.0131460] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/07/2015] [Accepted: 06/02/2015] [Indexed: 01/27/2023] Open
Abstract
Helicobacter pylori causes cellular vacuolation in host cells, a cytotoxic event attributed to vacuolating cytotoxin (VacA) and the presence of permeant weak bases such as ammonia. We report here the role of γ-glutamyl transpeptidase (GGT), a constitutively expressed secretory enzyme of H. pylori, in potentiating VacA-dependent vacuolation formation in H. pylori-infected AGS and primary gastric cells. The enhancement is brought about by GGT hydrolysing glutamine present in the extracellular medium, thereby releasing ammonia which accentuates the VacA-induced vacuolation. The events of vacuolation in H. pylori wild type (WT)- and Δggt-infected AGS cells were first captured and visualized by real-time phase-contrast microscopy where WT was observed to induce more vacuoles than Δggt. By using semi-quantitative neutral red uptake assay, we next showed that Δggt induced significantly less vacuolation in AGS and primary gastric epithelial cells as compared to the parental strain (P<0.05) indicating that GGT potentiates the vacuolating effect of VacA. Notably, vacuolation induced by WT was significantly reduced in the absence of GGT substrate, glutamine (P<0.05) or in the presence of a competitive GGT inhibitor, serine-borate complex. Furthermore, the vacuolating ability of Δggt was markedly restored when co-incubated with purified recombinant GGT (rGGT), although rGGT itself did not induce vacuolation independently. Similarly, the addition of exogenous ammonium chloride as a source of ammonia also rescued the ability of Δggt to induce vacuolation. Additionally, we also show that monoclonal antibodies against GGT effectively inhibited GGT activity and successfully suppressed H. pylori-induced vacuolation. Collectively, our results clearly demonstrate that generation of ammonia by GGT through glutamine hydrolysis is responsible for enhancing VacA-dependent vacuolation. Our findings provide a new perspective on GGT as an important virulence factor and a promising target in the management of H. pylori-associated gastric diseases.
Collapse
Affiliation(s)
- Samantha Shi Min Ling
- Department of Microbiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
| | | | - Le-Ann Hwang
- Monoclonal Antibody Unit, Institute of Molecular and Cell Biology, Singapore, Singapore
| | - Khay Guan Yeoh
- Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
| | - Bow Ho
- Department of Microbiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
- * E-mail:
| |
Collapse
|
|
45
|
Qadri Q, Rasool R, Gulzar GM, Naqash S, Shah ZA. H. pylori infection, inflammation and gastric cancer. J Gastrointest Cancer 2015; 45:126-32. [PMID: 24557546 DOI: 10.1007/s12029-014-9583-1] [Citation(s) in RCA: 37] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
INTRODUCTION A strong association between chronic infection, inflammation, and cancer has been suggested. DISCUSSION Helicobacter pylori, a microaerophilic gram negative bacterium, infects about half the world's population. It has been defined as a definitive carcinogen in the pathogenesis of gastric cancer. H. pylori evades the host immune responses and persists in the stomach leading to gastritis gastric atrophy and sometimes gastric cancer. CONCLUSION Chronic H. pylori infection causes gastric cancer via two mechanisms: the presence of virulence factors and the induction of chronic inflammation which ultimately leads to neoplastic transformation.
Collapse
Affiliation(s)
- Qurteeba Qadri
- Department of Immunology and Molecular Medicine, Sher-i-Kashmir Institute of Medical Sciences (SKIMS), Soura, Srinagar, Jammu and Kashmir, 190011, India,
| | | | | | | | | |
Collapse
|
|
46
|
El-Zahaby SA, Kassem AA, El-Kamel AH. Design and evaluation of gastroretentive levofloxacin floating mini-tablets-in-capsule system for eradication of Helicobacter pylori. Saudi Pharm J 2014; 22:570-9. [PMID: 25561871 PMCID: PMC4281621 DOI: 10.1016/j.jsps.2014.02.009] [Citation(s) in RCA: 43] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2013] [Accepted: 02/15/2014] [Indexed: 02/07/2023] Open
Abstract
Gastroretentive levofloxacin (LVF) floating mini-tablets for the eradication of Helicobacter pylori (H. pylori) were prepared using the matrix forming polymer hydroxypropyl methylcellulose (HPMC K100M), alone or with Carbopol 940P in different ratios by wet granulation technique. Buoyancy of mini-tablets was achieved by an addition of an effervescent mixture consisting of sodium bicarbonate and anhydrous citric acid to some formulations. The prepared mini-tablets were evaluated for weight variation, thickness, friability, hardness, drug content, in vitro buoyancy, water uptake and in vitro release. The optimized formula was subjected to further studies: FT-IR, DSC analysis and in vivo examination in healthy volunteers. The prepared mini-tablets exhibited satisfactory physicochemical characteristics. Incorporation of gas-generating agent improved the floating parameters. HPMC K100M mini-tablet formulation (F1) offered the best controlled drug release (>8 h) along with floating lag time <1 s and total floating time >24 h. The obtained DSC thermograms and FT-IR charts indicated that there is no positive evidence for the interaction between LVF and ingredients of the optimized formula. The in vivo test confirmed the success of the optimized formula F1 in being retained in the stomach of the volunteers for more than 4 h. LVF floating mini-tablets based on HPMC K100M is a promising formulation for eradication of H. pylori.
Collapse
Affiliation(s)
- Sally A. El-Zahaby
- Department of Pharmaceutics, Faculty of Pharmacy and Drug Manufacturing, Pharos University in Alexandria, Alexandria, Egypt
- Corresponding author. Address: Department of Pharmaceutics, Faculty of Pharmacy and Drug Manufacturing, Pharos University in Alexandria, Canal El-Mahmoudia Street, Smouha, Alexandria, Egypt. Tel.: +20 1223526283.
| | - Abeer A. Kassem
- Department of Pharmaceutics, Faculty of Pharmacy and Drug Manufacturing, Pharos University in Alexandria, Alexandria, Egypt
| | - Amal H. El-Kamel
- Department of Pharmaceutics, Faculty of Pharmacy, University of Alexandria, Alexandria, Egypt
| |
Collapse
|
|
47
|
El-Zahaby SA, Kassem AA, El-Kamel AH. Design and evaluation of gastroretentive levofloxacin floating mini-tablets-in-capsule system for eradication of Helicobacter pylori. Saudi Pharm J 2014. [DOI: https://doi.org/10.1016/j.jsps.2014.02.009] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/06/2022] Open
|
|
48
|
Rhee KH, Park JS, Cho MJ. Helicobacter pylori: bacterial strategy for incipient stage and persistent colonization in human gastric niches. Yonsei Med J 2014; 55:1453-66. [PMID: 25323880 PMCID: PMC4205683 DOI: 10.3349/ymj.2014.55.6.1453] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/21/2022] Open
Abstract
Helicobacter pylori (H. pylori) undergoes decades long colonization of the gastric mucosa of half the population in the world to produce acute and chronic gastritis at the beginning of infection, progressing to more severe disorders, including peptic ulcer disease and gastric cancer. Prolonged carriage of H. pylori is the most crucial factor for the pathogenesis of gastric maladies. Bacterial persistence in the gastric mucosa depends on bacterial factors as well as host factors. Herein, the host and bacterial components responsible for the incipient stages of H. pylori infection are reviewed and discussed. Bacterial adhesion and adaptation is presented to explain the persistence of H. pylori colonization in the gastric mucosa, in which bacterial evasion of host defense systems and genomic diversity are included.
Collapse
Affiliation(s)
- Kwang-Ho Rhee
- Department of Microbiology, Gyeongsang National University College of Medicine, Research Institute of Life Science, Gyeongsang National University, Jinju, Korea
| | - Jin-Sik Park
- Department of Microbiology, Gyeongsang National University College of Medicine, Research Institute of Life Science, Gyeongsang National University, Jinju, Korea
| | - Myung-Je Cho
- Department of Microbiology, Gyeongsang National University College of Medicine, Research Institute of Life Science, Gyeongsang National University, Jinju, Korea.
| |
Collapse
|
|
49
|
Menchicchi B, Fuenzalida JP, Bobbili KB, Hensel A, Swamy MJ, Goycoolea FM. Structure of chitosan determines its interactions with mucin. Biomacromolecules 2014; 15:3550-8. [PMID: 25122160 DOI: 10.1021/bm5007954] [Citation(s) in RCA: 123] [Impact Index Per Article: 11.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/28/2022]
Abstract
Synthetic and natural mucoadhesive biomaterials in optimized galenical formulations are potentially useful for the transmucosal delivery of active ingredients to improve their localized and prolonged effects. Chitosans (CS) have potent mucoadhesive characteristics, but the exact mechanisms underpinning such interactions at the molecular level and the role of the specific structural properties of CS remain elusive. In the present study we used a combination of microviscosimetry, zeta potential analysis, isothermal titration calorimetry (ITC) and fluorescence quenching to confirm that the soluble fraction of porcine stomach mucin interacts with CS in water or 0.1 M NaCl (at c < c*; relative viscosity, η(rel), ∼ 2.0 at pH 4.5 and 37 °C) via a heterotypic stoichiometric process significantly influenced by the degree of CS acetylation (DA). We propose that CS-mucin interactions are driven predominantly by electrostatic binding, supported by other forces (e.g., hydrogen bonds and hydrophobic association) and that the DA influences the overall conformation of CS and thus the nature of the resulting complexes. Although the conditions used in this model system are simpler than the typical in vivo environment, the resulting knowledge will enable the rational design of CS-based nanostructured materials for specific transmucosal drug delivery (e.g., for Helicobacter pylori stomach therapy).
Collapse
Affiliation(s)
- B Menchicchi
- Institute of Plant Biology and Biotechnology (IBBP), University of Münster , Schlossgarten 3, D-48149 Münster, Germany
| | | | | | | | | | | |
Collapse
|
|
50
|
Pastene E, Parada V, Avello M, Ruiz A, García A. Catechin-based Procyanidins from Peumus boldus
Mol. Aqueous Extract Inhibit Helicobacter pylori
Urease and Adherence to Adenocarcinoma Gastric Cells. Phytother Res 2014; 28:1637-45. [DOI: 10.1002/ptr.5176] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2013] [Revised: 04/28/2014] [Accepted: 04/29/2014] [Indexed: 11/08/2022]
Affiliation(s)
- Edgar Pastene
- Laboratory of Pharmacognosy, Department of Pharmacy, Faculty of Pharmacy; University of Concepción; Concepción Chile
| | - Víctor Parada
- Laboratory of Pharmacognosy, Department of Pharmacy, Faculty of Pharmacy; University of Concepción; Concepción Chile
| | - Marcia Avello
- Laboratory of Pharmacognosy, Department of Pharmacy, Faculty of Pharmacy; University of Concepción; Concepción Chile
| | - Antonieta Ruiz
- Laboratory of Chromatography, Department of Instrumental Analysis; University of Concepción; Concepción Chile
| | - Apolinaria García
- Laboratory of Bacterial Pathogenicity, Department of Microbiology, Faculty of Biological Sciences; University of Concepción; Concepción Chile
| |
Collapse
|