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Helicobacter: Infection, Diagnosis and Treatment

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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Microbiology".

Deadline for manuscript submissions: closed (28 February 2021) | Viewed by 33665

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Dr. Alessandra Tosco

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Department of Pharmacy, University of Salerno, Via Giovanni Paolo II, 132, 84084 Fisciano, Italy
Interests: Helicobacter pylori infection; host-pathogen interaction; gastrointestinal TFF1 protein; epigenetic mechanisms
Special Issues, Collections and Topics in MDPI journals

Prof. Dr. Amalia Porta

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Guest Editor

Department of Pharmacy, University of Salerno, Salerno, Italy
Interests: Helicobacter pylori infection; host-pathogen interaction; gastrointestinal TFF1 protein; epigentic mechanisms
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Helicobacter pylori is the most common infection in humans, with 50% of the world's population being affected. Chronic H. pylori infection is associated with increased risk for numerous diseases, including gastric cancer. The risk factors capable of influencing the outcome of a bacterial infection are a complex combination of host characteristics, bacterial virulence, and environmental factors. The human gastric mucosa appears to be the major site of infection, but recent findings demonstrate that H. pylori infection is also strongly associated with different extra-gastric diseases. Moreover, the anti-H. pylori therapeutic regimens currently available are encountering several problems due to the diffusion of multidrug resistance, highly correlated with specific geographical areas.

This Special Issue aims to highlight new contributions to the molecular mechanisms involved in H. pylori infection and host–pathogen interaction, so to understand the related pathologies and discover new anti-microbial agents.

Dr. Alessandra Tosco
Prof. Dr. Amalia Porta
Guest Editors

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Keywords

Helicobacter
gastric cancer
infection
diagnosis
symptoms
therapy
antibiotic resistance

Published Papers (10 papers)

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Research

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22 pages, 3916 KiB

Open AccessArticle

In Vitro Framework to Assess the Anti-Helicobacter pylori Potential of Lactic Acid Bacteria Secretions as Alternatives to Antibiotics

by Samantha A. Whiteside, Mahi M. Mohiuddin, Sargon Shlimon, Jaspreet Chahal, Chad W. MacPherson, Jana Jass, Thomas A. Tompkins and Carole Creuzenet

Int. J. Mol. Sci. 2021, 22(11), 5650; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22115650 - 26 May 2021

Cited by 6 | Viewed by 2951

Abstract

Helicobacter pylori is a prevalent bacterium that can cause gastric ulcers and cancers. Lactic acid bacteria (LAB) ameliorate treatment outcomes against H. pylori, suggesting that they could be a source of bioactive molecules usable as alternatives to current antibiotics for which resistance is mounting. We developed an in vitro framework to compare the anti-H. pylori properties of 25 LAB and their secretions against H. pylori. All studies were done at acidic and neutralized pH, with or without urea to mimic various gastric compartments. Eighteen LAB strains secreted molecules that curtailed the growth of H. pylori and the activity was urea-resistant in five LAB. Several LAB supernatants also reduced the urease activity of H. pylori. Pre-treatment of H. pylori with acidic LAB supernatants abrogated its flagella-mediated motility and decreased its ability to elicit pro-inflammatory IL-8 cytokine from human gastric cells, without reverting the H. pylori-induced repression of other pro-inflammatory cytokines. This study identified the LAB that have the most anti-H. pylori effects, decreasing its viability, its production of virulence factors, its motility and/or its ability to elicit pro-inflammatory IL-8 from gastric cells. Once identified, these molecules can be used as alternatives or complements to current antibiotics to fight H. pylori infections. Full article

(This article belongs to the Special Issue Helicobacter: Infection, Diagnosis and Treatment)

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20 pages, 2972 KiB

Open AccessArticle

Outer Membrane Vesicle Production by Helicobacter pylori Represents an Approach for the Delivery of Virulence Factors CagA, VacA and UreA into Human Gastric Adenocarcinoma (AGS) Cells

by Yongyu Chew, Hsin-Yu Chung, Po-Yi Lin, Deng-Chyang Wu, Shau-Ku Huang and Mou-Chieh Kao

Int. J. Mol. Sci. 2021, 22(8), 3942; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22083942 - 11 Apr 2021

Cited by 19 | Viewed by 3764

Abstract

Helicobacter pylori infection is the etiology of several gastric-related diseases including gastric cancer. Cytotoxin associated gene A (CagA), vacuolating cytotoxin A (VacA) and α-subunit of urease (UreA) are three major virulence factors of H. pylori, and each of them has a distinct entry pathway and pathogenic mechanism during bacterial infection. H. pylori can shed outer membrane vesicles (OMVs). Therefore, it would be interesting to explore the production kinetics of H. pylori OMVs and its connection with the entry of key virulence factors into host cells. Here, we isolated OMVs from H. pylori 26,695 strain and characterized their properties and interaction kinetics with human gastric adenocarcinoma (AGS) cells. We found that the generation of OMVs and the presence of CagA, VacA and UreA in OMVs were a lasting event throughout different phases of bacterial growth. H. pylori OMVs entered AGS cells mainly through macropinocytosis/phagocytosis. Furthermore, CagA, VacA and UreA could enter AGS cells via OMVs and the treatment with H. pylori OMVs would cause cell death. Comparison of H. pylori 26,695 and clinical strains suggested that the production and characteristics of OMVs are not only limited to laboratory strains commonly in use, but a general phenomenon to most H. pylori strains. Full article

(This article belongs to the Special Issue Helicobacter: Infection, Diagnosis and Treatment)

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23 pages, 5435 KiB

Open AccessArticle

Helicobacter pylori Infection Acts Synergistically with a High-Fat Diet in the Development of a Proinflammatory and Potentially Proatherogenic Endothelial Cell Environment in an Experimental Model

by Agnieszka Krupa, Weronika Gonciarz, Paulina Rusek-Wala, Tomasz Rechciński, Adrian Gajewski, Zuzanna Samsel, Anna Dziuba, Agnieszka Śmiech and Magdalena Chmiela

Int. J. Mol. Sci. 2021, 22(7), 3394; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22073394 - 25 Mar 2021

Cited by 18 | Viewed by 4179

Abstract

Classic atherosclerosis risk factors do not explain all cases of chronic heart disease. There is significant evidence that gut microbiota may influence the development of atherosclerosis. The widespread prevalence of chronic Helicobacter pylori (H. pylori, HP) infections suggests that HP can be the source of components that stimulate local and systemic inflammatory responses. Elevated production of reactive oxygen species during HP infection leads to cholesterol oxidation, which drives atherogenesis. The aim of this study is to explore the link between persistent HP infection and a high-fat diet in the development of proinflammatory conditions that are potentially proatherogenic. An in vivo model of Caviae porcellus infected with HP and exposed to an experimental diet was investigated for the occurrence of a proinflammatory and proatherogenic endothelial environment. Vascular endothelial primary cells exposed to HP components were tested in vitro for oxidative stress, cell activation and apoptosis. The infiltration of inflammatory cells into the vascular endothelium of animals infected with HP and exposed to a high-fat diet was observed in conjunction with an increased level of inflammatory markers systemically. The arteries of such animals were the least elastic, suggesting the role of HP in arterial stiffness. Soluble HP components induced transformation of macrophages to foam cells in vitro and influenced the endothelial life span, which was correlated with Collagen I upregulation. These preliminary results support the hypothesis that HP antigens act synergistically with a high-fat diet in the development of proatherogenic conditions. Full article

(This article belongs to the Special Issue Helicobacter: Infection, Diagnosis and Treatment)

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15 pages, 2170 KiB

Open AccessArticle

Evodiamine Inhibits Helicobacter pylori Growth and Helicobacter pylori-Induced Inflammation

by Ji Yeong Yang, Jong-Bae Kim, Pyeongjae Lee and Sa-Hyun Kim

Int. J. Mol. Sci. 2021, 22(7), 3385; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22073385 - 25 Mar 2021

Cited by 21 | Viewed by 3147

Abstract

Helicobacter pylori (H. pylori) classified as a class I carcinogen by the World Health Organization (WHO) plays an important role in the progression of chronic gastritis and the development of gastric cancer. A major bioactive component of Evodia rutaecarpa, evodiamine, has been known for its anti-bacterial effect and anti-cancer effects. However, the inhibitory effect of evodiamine against H. pylori is not yet known and the inhibitory mechanisms of evodiamine against gastric cancer cells are yet to be elucidated concretely. In this study, therefore, anti-bacterial effect of evodiamine on H. pylori growth and its inhibitory mechanisms as well as anti-inflammatory effects and its mechanisms of evodiamine on H. pylori-induced inflammation were investigated in vitr. Results of this study showed the growth of the H. pylori reference strains and clinical isolates were inhibited by evodiamine. It was considered one of the inhibitory mechanisms that evodiamine downregulated both gene expressions of replication and transcription machineries of H. pylori. Treatment of evodiamine also induced downregulation of urease and diminished translocation of cytotoxin-associated antigen A (CagA) and vacuolating cytotoxin A (VacA) proteins into gastric adenocarcinoma (AGS) cells. This may be resulted from the reduction of CagA and VacA expressions as well as the type IV secretion system (T4SS) components and secretion system subunit protein A (SecA) protein which are involved in translocation of CagA and VacA into host cells, respectively. In particular, evodiamine inhibited the activation of signaling proteins such as the nuclear factor κ-light-chain-enhancer of activated B cells (NF-κB) and the mitogen-activated protein kinase (MAPK) pathway induced by H. pylori infection. It consequently might contribute to reduction of interleukin (IL)-8 production in AGS cells. Collectively, these results suggest anti-bacterial and anti-inflammatory effects of evodiamine against H. pylori. Full article

(This article belongs to the Special Issue Helicobacter: Infection, Diagnosis and Treatment)

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13 pages, 1700 KiB

Open AccessArticle

TFF1 Induces Aggregation and Reduces Motility of Helicobacter pylori

by Daniela Eletto, Megi Vllahu, Fatima Mentucci, Pasquale Del Gaudio, Antonello Petrella, Amalia Porta and Alessandra Tosco

Int. J. Mol. Sci. 2021, 22(4), 1851; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22041851 - 12 Feb 2021

Cited by 3 | Viewed by 2199

Abstract

Gastric cancer is considered one of the most common malignancies in humans and Helicobacter pylori infection is the major environmental risk factor of gastric cancer development. Given the high spread of this bacterium whose infection is mostly asymptomatic, H. pylori colonization persists for a long time, becoming chronic and predisposing to malignant transformation. The first defensive barrier from bacterial infection is constituted by the gastric mucosa that secretes several protective factors, among which is the trefoil factor 1 (TFF1), that, as mucin 5AC, binds the bacterium. Even if the protective role of TFF1 is well-documented, the molecular mechanisms that confer a beneficial function to the interaction among TFF1 and H. pylori remain still unclear. Here we analyze the effects of this interaction on H. pylori at morphological and molecular levels by means of microscopic observation, chemiotaxis and motility assays and real-time PCR analysis. Our results show that TFF1 favors aggregation of H. pylori and significantly slows down the motility of the bacterium across the mucus. Such aggregates significantly reduce both flgE and flaB gene transcription compared with bacteria not incubated with TFF1. Finally, our results suggest that the interaction between TFF1 and the bacterium may explain the frequent persistence of H. pylori in the human host without inducing disease. Full article

(This article belongs to the Special Issue Helicobacter: Infection, Diagnosis and Treatment)

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15 pages, 2470 KiB

Open AccessArticle

Male-Dependent Promotion of Colitis in 129 Rag2^−/− Mice Co-Infected with Helicobacter pylori and Helicobacter hepaticus

by Zhongming Ge, Lili Ge, Sureshkumar Muthupalani, Yan Feng and James G. Fox

Int. J. Mol. Sci. 2020, 21(23), 8886; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21238886 - 24 Nov 2020

Cited by 3 | Viewed by 1760

Abstract

The prevalence of gastric Helicobacter pylori (Hp) infection is ~50% of the world population. However, how Hp infection influences inflammatory bowel disease in humans is not fully defined. In this study, we examined whether co-infection with Hp influenced Helicobacter hepaticus (Hh)–induced intestinal pathology in Rag2^−/− mice. Rag2^−/− mice of both sexes were infected with Hh, of which a subgroup was followed by infection with Hp two weeks later. Co-infected males, but not females, had significantly higher total colitis index scores in the colon at both 10 and 21 weeks post-Hh infection (WPI) and developed more severe dysplasia at 21 WPI compared with mono-Hh males. There were no significant differences in colonization levels of gastric Hp and colonic Hh between sexes or time-points. In addition, mRNA levels of colonic Il-1β, Ifnγ, Tnfα, Il-17A, Il-17F, Il-18, and Il-23, which play important roles in the development and function of proinflammatory innate lymphoid cell groups 1 and 3, were significantly up-regulated in the dually infected males compared with mono-Hh males at 21 WPI. These data suggest that concomitant Hp infection enhances the inflammatory responses in the colon of-Hh-infected Rag2^−/− males, which results in more severe colitis and dysplasia. Full article

(This article belongs to the Special Issue Helicobacter: Infection, Diagnosis and Treatment)

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13 pages, 1451 KiB

Open AccessArticle

An In Vitro Model to Investigate the Role of Helicobacter pylori in Type 2 Diabetes, Obesity, Alzheimer’s Disease and Cardiometabolic Disease

by Paola Cuomo, Marina Papaianni, Clementina Sansone, Antonio Iannelli, Domenico Iannelli, Chiara Medaglia, Debora Paris, Andrea Motta and Rosanna Capparelli

Int. J. Mol. Sci. 2020, 21(21), 8369; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21218369 - 08 Nov 2020

Cited by 18 | Viewed by 2946

Abstract

Helicobacter pylori (Hp) is a Gram-negative bacterium colonizing the human stomach. Nuclear Magnetic Resonance (NMR) analysis of intracellular human gastric carcinoma cells (MKN-28) incubated with the Hp cell filtrate (Hpcf) displays high levels of amino acids, including the branched chain amino acids (BCAA) isoleucine, leucine, and valine. Polymerase chain reaction (PCR) Array Technology shows upregulation of mammalian Target Of Rapamycin Complex 1 (mTORC1), inflammation, and mitochondrial dysfunction. The review of literature indicates that these traits are common to type 2 diabetes, obesity, Alzheimer’s diseases, and cardiometabolic disease. Here, we demonstrate how Hp may modulate these traits. Hp induces high levels of amino acids, which, in turn, activate mTORC1, which is the complex regulating the metabolism of the host. A high level of BCAA and upregulation of mTORC1 are, thus, directly regulated by Hp. Furthermore, Hp modulates inflammation, which is functional to the persistence of chronic infection and the asymptomatic state of the host. Finally, in order to induce autophagy and sustain bacterial colonization of gastric mucosa, the Hp toxin VacA localizes within mitochondria, causing fragmentation of these organelles, depletion of ATP, and oxidative stress. In conclusion, our in vitro disease model replicates the main traits common to the above four diseases and shows how Hp may potentially manipulate them. Full article

(This article belongs to the Special Issue Helicobacter: Infection, Diagnosis and Treatment)

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Review

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23 pages, 1673 KiB

Open AccessReview

Helicobacter pylori Outer Membrane Vesicles and Extracellular Vesicles from Helicobacter pylori-Infected Cells in Gastric Disease Development

by María Fernanda González, Paula Díaz, Alejandra Sandoval-Bórquez, Daniela Herrera and Andrew F. G. Quest

Int. J. Mol. Sci. 2021, 22(9), 4823; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22094823 - 01 May 2021

Cited by 24 | Viewed by 7097

Abstract

Extracellular vesicles (EVs) are cell-derived vesicles important in intercellular communication that play an essential role in host-pathogen interactions, spreading pathogen-derived as well as host-derived molecules during infection. Pathogens can induce changes in the composition of EVs derived from the infected cells and use them to manipulate their microenvironment and, for instance, modulate innate and adaptive inflammatory immune responses, both in a stimulatory or suppressive manner. Gastric cancer is one of the leading causes of cancer-related deaths worldwide and infection with Helicobacter pylori (H. pylori) is considered the main risk factor for developing this disease, which is characterized by a strong inflammatory component. EVs released by host cells infected with H. pylori contribute significantly to inflammation, and in doing so promote the development of disease. Additionally, H. pylori liberates vesicles, called outer membrane vesicles (H. pylori-OMVs), which contribute to atrophia and cell transformation in the gastric epithelium. In this review, the participation of both EVs from cells infected with H. pylori and H. pylori-OMVs associated with the development of gastric cancer will be discussed. By deciphering which functions of these external vesicles during H. pylori infection benefit the host or the pathogen, novel treatment strategies may become available to prevent disease. Full article

(This article belongs to the Special Issue Helicobacter: Infection, Diagnosis and Treatment)

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13 pages, 1029 KiB

Open AccessReview

The Role of Formyl Peptide Receptors in Permanent and Low-Grade Inflammation: Helicobacter pylori Infection as a Model

by Paola Cuomo, Marina Papaianni, Rosanna Capparelli and Chiara Medaglia

Int. J. Mol. Sci. 2021, 22(7), 3706; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22073706 - 02 Apr 2021

Cited by 9 | Viewed by 2558

Abstract

Formyl peptide receptors (FPRs) are cell surface pattern recognition receptors (PRRs), belonging to the chemoattractant G protein-coupled receptors (GPCRs) family. They play a key role in the innate immune system, regulating both the initiation and the resolution of the inflammatory response. FPRs were originally identified as receptors with high binding affinity for bacteria or mitochondria N-formylated peptides. However, they can also bind a variety of structurally different ligands. Among FPRs, formyl peptide receptor-like 1 (FPRL1) is the most versatile, recognizing N-formyl peptides, non-formylated peptides, and synthetic molecules. In addition, according to the ligand nature, FPRL1 can mediate either pro- or anti-inflammatory responses. Hp(2-20), a Helicobacter pylori-derived, non-formylated peptide, is a potent FPRL1 agonist, participating in Helicobacter pylori-induced gastric inflammation, thus contributing to the related site or not-site specific diseases. The aim of this review is to provide insights into the role of FPRs in H. pylori-associated chronic inflammation, which suggests this receptor as potential target to mitigate both microbial and sterile inflammatory diseases. Full article

(This article belongs to the Special Issue Helicobacter: Infection, Diagnosis and Treatment)

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11 pages, 434 KiB

Open AccessReview

Genetics of Host Protection against Helicobacter pylori Infections

by Rosanna Capparelli and Domenico Iannelli

Int. J. Mol. Sci. 2021, 22(6), 3192; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22063192 - 21 Mar 2021

Cited by 7 | Viewed by 2064

Abstract

This narrative review discusses the genetics of protection against Helicobacter pylori (Hp) infection. After a brief overview of the importance of studying infectious disease genes, we provide a detailed account of the properties of Hp, with a view to those relevant for our topic. Hp displays a very high level of genetic diversity, detectable even between single colonies from the same patient. The high genetic diversity of Hp can be evaded by stratifying patients according to the infecting Hp strain. This approach enhances the power and replication of the study. Scanning for single nucleotide polymorphisms is generally not successful since genes rarely work alone. We suggest selecting genes to study from among members of the same family, which are therefore inclined to cooperate. Further, extending the analysis to the metabolism would significantly enhance the power of the study. This combined approach displays the protective role of MyD88, TIRAP, and IL1RL1 against Hp infection. Finally, several studies in humans have demonstrated that the blood T cell levels are under the genetic control of the CD39⁺ T regulatory cells (T_REGS). Full article

(This article belongs to the Special Issue Helicobacter: Infection, Diagnosis and Treatment)

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