Helicobacter pylori-Specific Antibodies Impair the Development of Gastritis, Facilitate Bacterial Colonization, and Counteract Resistance against Infection

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.

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Multiple in vivo passages enhance the ability of a clinical Helicobacter pylori isolate to colonize the stomach of Mongolian gerbils and to induce gastritis

Laboratory Animals ◽

10.1258/0023677053739800 ◽

2005 ◽

Vol 39 (2) ◽

pp. 221-229 ◽

Cited By ~ 10

Author(s):

A Bleich ◽

I Köhn ◽

S Glage ◽

W Beil ◽

S Wagner ◽

...

Keyword(s):

Helicobacter Pylori ◽

Bacterial Colonization ◽

Underlying Mechanism ◽

Mongolian Gerbils ◽

Histopathological Changes ◽

Genetic Changes ◽

Colonization Ability ◽

Colonization Factors ◽

H Pylori

The Mongolian gerbil is an excellent animal model for Helicobacter pylori-induced gastritis in humans. In this study, initially low colonization rates of the H. pylori strains ATCC 43504, SS1, or HP87 inoculated into gerbils caused difficulties in establishing this model. In order to increase the colonization ability and pathogenicity, the clinical HP87 isolate was selected for adaptation to the gerbil stomach by multiple in vivo passages through gerbils. Development of gastritis was examined histologically at 4–52 weeks after infection. The proportion of gerbils which tested positive for H. pylori by culture at four weeks after inoculation gradually increased from 11.1% of gerbils inoculated with HP87 without prior in vivo passage (P0) to 100% of gerbils inoculated with HP87 with seven in vivo passages (P7). In addition, adaptation of HP87 resulted in more severe histopathological changes. Gerbils infected with adapted HP87 (P7) exhibited severe infiltration by monomorphonuclear and polymorphonuclear leukocytes in the mucosa, submucosa, and subserosa of the gastric antrum, as well as epithelial changes consisting of hyperplasia, erosion, and ulceration. Histopathological changes increased in severity from four to 52 weeks after infection. Adaptation of HP87 during its passages through gerbils could be due to genetic changes in bacterial colonization factors. Identification of these changes might be useful to understand the underlying mechanism of gastric adaptation and pathogenesis of H. pylori.

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Helicobacter pylori Protein–Specific Antibodies and Risk of Colorectal Cancer

Cancer Epidemiology Biomarkers & Prevention ◽

10.1158/1055-9965.epi-13-0702 ◽

2013 ◽

Vol 22 (11) ◽

pp. 1964-1974 ◽

Cited By ~ 26

Author(s):

Meira Epplein ◽

Michael Pawlita ◽

Angelika Michel ◽

Richard M. Peek ◽

Qiuyin Cai ◽

...

Keyword(s):

Colorectal Cancer ◽

Helicobacter Pylori ◽

Specific Antibodies

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Therapeutic Vaccination against Helicobacter pylori in the Beagle Dog Experimental Model: Safety, Immunogenicity, and Efficacy

Infection and Immunity ◽

10.1128/iai.72.6.3252-3259.2004 ◽

2004 ◽

Vol 72 (6) ◽

pp. 3252-3259 ◽

Cited By ~ 65

Author(s):

Giacomo Rossi ◽

Paolo Ruggiero ◽

Samuele Peppoloni ◽

Laura Pancotto ◽

Damiano Fortuna ◽

...

Keyword(s):

Helicobacter Pylori ◽

Bacterial Colonization ◽

Human Infection ◽

Human Gastric Mucosa ◽

Therapeutic Vaccination ◽

Beagle Dogs ◽

Beagle Dog ◽

Vaccine Approach ◽

H Pylori ◽

Different Doses

ABSTRACT Helicobacter pylori is a gram-negative bacterium that colonizes the human gastric mucosa causing gastritis and peptic ulcer and increasing the risk of gastric cancer. The efficacy of current antibiotic-based therapies can be limited by problems of patient compliance and increasing antibiotic resistance; the vaccine approach can overcome these limits. The present study describes the therapeutic vaccination of experimentally H. pylori-infected beagle dogs, an animal model that reproduces several aspects of the human infection with H. pylori. The vaccine consisted of three recombinant H. pylori antigens, CagA, VacA, and NAP, formulated at different doses (10, 25, or 50 μg each) with alum and administered intramuscularly either weekly or monthly. No adverse effects were observed after vaccination and a good immunoglobulin G response was generated against each of the three antigens. Bacterial colonization and gastritis were decreased after the completion of the vaccination cycle, especially in the case of the monthly immunization schedule. In conclusion, therapeutic vaccination in the beagle dog model was safe and immunogenic and was able to limit H. pylori colonization and the related gastric pathology.

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Cure of Helicobacter pylori Infection and Resolution of Gastritis by Adoptive Transfer of Splenocytes in Mice

Infection and Immunity ◽

10.1128/iai.69.2.1025-1031.2001 ◽

2001 ◽

Vol 69 (2) ◽

pp. 1025-1031 ◽

Cited By ~ 39

Author(s):

Kathryn A. Eaton ◽

Megan E. Mefford

Keyword(s):

Helicobacter Pylori ◽

Immune Responses ◽

Adoptive Transfer ◽

Host Response ◽

Bacterial Colonization ◽

Scid Mice ◽

Humoral Immune ◽

Cellular Immune Responses ◽

H Pylori ◽

Cellular Immune

ABSTRACT Vaccination suppresses Helicobacter pylori colonization but does not cure infection. Furthermore, postvaccination gastritis, likely induced by enhanced host response to residual colonization, may exacerbate disease. The goal of this study was to determine if adoptive transfer of C57BL/6 splenocytes to C57BL/6scid/scid (severe combined immunodeficient [SCID]) mice cures infection without exacerbating gastritis. H. pylori-infected and uninfected C57BL/6 mice and SCID recipients of normal splenocytes were killed at intervals between 5 and 51 weeks after infection. Colonization and gastritis were quantified, humoral immune responses were determined by enzyme-linked immunosorbent assay, and cellular immune responses were determined by delayed-type hypersensitivity response and by a proliferative response of cultured splenocytes to H. pylorisonicate. In infected C57BL/6 mice, gastritis developed gradually and bacterial colonization diminished but persisted throughout the experiment. In contrast, gastritis in infected recipient SCID mice developed rapidly and bacterial colonization decreased precipitously. Gastritis in those mice peaked 9 weeks after adoptive transfer, however, and began to resolve. By 45 weeks after transfer, gastritis had returned to background levels and bacteria were no longer detectable. Resolution of gastritis and elimination of infection were associated with a cellular but not humoral immune response to H. pylori antigens. These results demonstrate that although the host response fails to clear bacterial colonization in normal mice, enhanced cellular immune responses in recipient SCID mice are capable of clearing H. pylori infection and allowing resolution of gastritis. Thus, immune mechanisms of cure exist, and effective and safe vaccination protocols may be feasible.

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Endoscopic Nodular Gastritis: An Endoscopic Indicator of High-Grade Bacterial Colonization and Severe Gastritis in Children With Helicobacter pylori

Journal of Pediatric Gastroenterology and Nutrition ◽

10.1097/00005176-200302000-00011 ◽

2003 ◽

Vol 36 (2) ◽

pp. 217-222 ◽

Cited By ~ 53

Author(s):

Maria da Graça Soares Bahú ◽

Themis Reverbel da Silveira ◽

Ismael Maguilnick ◽

Jane Ulbrich-Kulczynski

Keyword(s):

Helicobacter Pylori ◽

Bacterial Colonization ◽

High Grade ◽

Nodular Gastritis

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Endoscopic nodular gastritis with helicobacter pylori infection: An indicator of high-grade bacterial colonization and severe gastritis in children

International Journal of Infectious Diseases ◽

10.1016/j.ijid.2016.02.211 ◽

2016 ◽

Vol 45 ◽

pp. 75

Author(s):

K.K. Prasad ◽

S.B. Lal ◽

B.R. Thapa ◽

U. Debi ◽

A.K. Sharma

Keyword(s):

Helicobacter Pylori ◽

Bacterial Colonization ◽

Helicobacter Pylori Infection ◽

High Grade ◽

Nodular Gastritis

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Specific Antibodies in Sera and Gastric Aspirates of Symptomatic and Asymptomatic Helicobacter pylori-Infected Subjects

Clinical and Diagnostic Laboratory Immunology ◽

10.1128/cdli.5.3.288-293.1998 ◽

1998 ◽

Vol 5 (3) ◽

pp. 288-293 ◽

Cited By ~ 68

Author(s):

A. Mattsson ◽

A. Tinnert ◽

A. Hamlet ◽

H. Lönroth ◽

I. Bölin ◽

...

Keyword(s):

Duodenal Ulcer ◽

Helicobacter Pylori ◽

Membrane Proteins ◽

Immunosorbent Assay ◽

Antibody Responses ◽

Enzyme Linked Immunosorbent Assay ◽

Duodenal Ulcers ◽

Specific Antibodies ◽

Antibody Titers ◽

H Pylori

ABSTRACT In this study we have determined systemic and local antibody responses against different Helicobacter pylori antigens inH. pylori-infected and noninfected subjects. In addition, we studied whether differences in antibody responses between patients with duodenal ulcers and asymptomatic H. pylori carriers might explain the different outcomes of infection. Sera and in most instances gastric aspirates were collected from 19 duodenal ulcer patients, 15 asymptomatic H. pylori carriers, and 20 noninfected subjects and assayed for specific antibodies against different H. pylori antigens, i.e., whole membrane proteins (MP), lipopolysaccharides, flagellin, urease, the neuraminyllactose binding hemagglutinin HpaA, and a 26-kDa protein, by enzyme-linked immunosorbent assay. The H. pylori-infected subjects had significantly higher antibody titers against MP, flagellin, and urease in both sera and gastric aspirates compared with the noninfected subjects. Furthermore, the antibody titers against HpaA were significantly elevated in sera but not in gastric aspirates from the infected subjects. However, no differences in antibody titers against any of the tested antigens could be detected between the duodenal ulcer patients and the asymptomatic H. pyloricarriers, either in sera or in gastric aspirates.

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Mechanisms of interacting Helicobacter pylori with gastric mucosal epithelium. II. A reaction of gastric epithelium on Helicobacter pylori colonization and persistence

Russian Journal of Infection and Immunity ◽

10.15789/2220-7619-2019-2-253-261 ◽

2019 ◽

Vol 9 (2) ◽

pp. 253-261

Author(s):

O. K. Pozdeev ◽

A. O. Pozdeeva ◽

Yu. V. Valeeva ◽

P. E. Gulyaev ◽

A. N. Savinova

Keyword(s):

Helicobacter Pylori ◽

T Cell ◽

Epithelial Cell ◽

Gastric Mucosa ◽

Mapk Pathway ◽

Bacterial Colonization ◽

Gastric Epithelium ◽

T Cell Subsets ◽

H Pylori ◽

Apoptotic Factors

Gastric and duodenal recurrent inflammatory diseases have a high prevalence, but the role played by microbes in its development remained unclear. However, the data published in 1983 by Marshall and Warren about isolatingHelicobacter pylorifrom the stomach mucosa of the patient with gastritis and proposing relevant cultivation methods was the turning point in investigating etiology of the upper digestive tract inflammatory disorders. Moreover, it was shown that the majority ofH. pylorispp. are found within the gastric lumen upon colonization, whereas around 20% of them are attached to the epithelial cells in the stomach. In addition, effects of interacting H. pylori with gastric epithelium and activation of some defense mechanisms due to bacterial colonization and spreading were analyzed. It was found that along with triggering pro-inflammatory response induced by proteins VacA as well as phosphorylated/unphosphorylated CagA, wherein the latter is able to induce a set of protective reactionsH. pyloridisrupts intercellular contacts, affects epithelial cell polarity and proliferation, and activates SHP-2 phosphatase resulting in emerging diverse types of cellular responses. The activation mechanisms for the mitogen-activated protein kinase (MAPK) pathway were discussed. The ability ofH. pylorito regulate apoptosis, particularly via its suppression, by expressing ERK kinase and protein MCL1 facilitating bacterial survival in the gastric mucosa as well as beneficial effects related to bacterial circulation on gastric epithelial cell survival elicited by anti-apoptotic factors were also examined. Of note, persistence of H. pylori are mainly determined by activating transcriptional factors including NF-κB, NFAT, SRF, T-cell lymphoid enhancing factor (TCF/LEF), regulating activity of MCL1 protein, in turn, being one of the main anti-apoptotic factors, as well as induced production of the migration inhibitory factor (MIF). The role of VacA cytotoxin in triggering epithelial cell apoptosis via caspase-mediated pathways was also considered. Infection withH. pyloriis accompanied by release of proinflammatory cytokine cocktail detected bothin vitroandin vivo. In particular, bacterial urease activating transcriptional factor NF-κB was shown to play a crucial role in inducing cytokine production. Moreover, such signaling pathways may be activated afterH. pyloriis attached to the cognate receptor in the gastric epithelial surface by interacting with CD74 and MHC class II molecules. Finally, a role for various CD4+T cell subsets, particularly type 17 T helper cells (Th17) in inducing immune response against H. pylori antigens in gastric mucosa was revealed were also discussed.

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