H. pylori down-regulates TRAIL (DR4)-receptors in the human gastric mucosa, a possible mechanism for chronic persistence

Helicobacter pylori has a number of well-characterized carbohydrate-binding adhesins (BabA, SabA, and LabA) that promote adhesion to the gastric mucosa. In contrast, information on the glycoconjugates present in the human stomach remains unavailable. Here, we used MS and binding of carbohydrate-recognizing ligands to characterize the glycosphingolipids of three human stomachs from individuals with different blood group phenotypes (O(Rh−)P, A(Rh+)P, and A(Rh+)p), focusing on compounds recognized by H. pylori. We observed a high degree of structural complexity, and the composition of glycosphingolipids differed among individuals with different blood groups. The type 2 chain was the dominating core chain of the complex glycosphingolipids in the human stomach, in contrast to the complex glycosphingolipids in the human small intestine, which have mainly a type 1 core. H. pylori did not bind to the O(Rh−)P stomach glycosphingolipids, whose major complex glycosphingolipids were neolactotetraosylceramide, the Lex, Lea, and H type 2 pentaosylceramides, and the Ley hexaosylceramide. Several H. pylori-binding compounds were present among the A(Rh+)P and A(Rh+)p stomach glycosphingolipids. Ligands for BabA-mediated binding of H. pylori were the Leb hexaosylceramide, the H type 1 pentaosylceramide, and the A type 1/ALeb heptaosylceramide. Additional H. pylori-binding glycosphingolipids recognized by BabA-deficient strains were lactosylceramide, lactotetraosylceramide, the x2 pentaosylceramide, and neolactohexaosylceramide. Our characterization of human gastric receptors required for H. pylori adhesion provides a basis for the development of specific compounds that inhibit the binding of this bacterium to the human gastric mucosa.

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Antigastric autoantibodies in Helicobacter pyloriinfection: implications of histological and clinical parameters of gastritis

Gut ◽

10.1136/gut.41.5.619 ◽

1997 ◽

Vol 41 (5) ◽

pp. 619-623 ◽

Cited By ~ 93

Author(s):

G Faller ◽

H Steininger ◽

J Kränzlein ◽

H Maul ◽

T Kerkau ◽

...

Keyword(s):

Gastric Mucosa ◽

Clinical Course ◽

Clinical Findings ◽

Gastric Biopsy ◽

Human Gastric Mucosa ◽

Serum Pepsinogen ◽

Luminal Membrane ◽

H Pylori ◽

Immunohistochemical Techniques ◽

Upper Abdominal

Background—It has recently been shown that humoral antigastric autoreactivities occur in a substantial number ofHelicobacter pylori infected patients.Aims—To analyse the relevance of such antigastric autoantibodies for histological and serological parameters of the infection as well as for the clinical course.Methods—Gastric biopsy samples and sera from 126 patients with upper abdominal complaints were investigated for evidence of H pylori infection using histology and serology. Autoantibodies against epitopes in human gastric mucosa were detected by immunohistochemical techniques. Histological and clinical findings of all patients were then correlated with the detection of antigastric autoantibodies.Results—H pylori infection was significantly associated with antigastric autoantibodies reactive with the luminal membrane of the foveolar epithelium and with canalicular structures within parietal cells. The presence of the latter autoantibodies was significantly correlated with the severity of body gastritis, gastric mucosa atrophy, elevated fasting gastrin concentrations, and a decreased ratio of serum pepsinogen I:II. Furthermore the presence of anticanalicular autoantibodies was associated with a greater than twofold reduced prevalence for duodenal ulcer.Conclusion—The data indicate that antigastric autoantibodies play a role in the pathogenesis and outcome of H pylori gastritis, in particular in the development of gastric mucosal atrophy.

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Gene structure of the Helicobacter pylori cytotoxin and evidence of its key role in gastric disease.

Journal of Experimental Medicine ◽

10.1084/jem.179.5.1653 ◽

1994 ◽

Vol 179 (5) ◽

pp. 1653-1658 ◽

Cited By ~ 383

Author(s):

J L Telford ◽

P Ghiara ◽

M Dell'Orco ◽

M Comanducci ◽

D Burroni ◽

...

Keyword(s):

Helicobacter Pylori ◽

Peptic Ulcer ◽

Gastric Mucosa ◽

Chronic Infection ◽

Gastric Disease ◽

Human Gastric Mucosa ◽

Gastric Lesions ◽

Gram Negative ◽

H Pylori ◽

Cytotoxin Gene

The gram negative, microaerophilic bacterium Helicobacter pylori colonizes the human gastric mucosa and establishes a chronic infection that is tightly associated with atrophic gastritis, peptic ulcer, and gastric carcinoma. Cloning of the H. pylori cytotoxin gene shows that the protein is synthesized as a 140-kD precursor that is processed to a 94-kD fully active toxin. Oral administration to mice of the purified 94-kD protein caused ulceration and gastric lesions that bear some similarities to the pathology observed in humans. The cloning of the cytotoxin gene and the development of a mouse model of human gastric disease will provide the basis for the understanding of H. pylori pathogenesis and the development of therapeutics and vaccines.

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Living cells of probiotic Bifidobacterium bifidum YIT 10347 detected on gastric mucosa in humans

Beneficial Microbes ◽

10.3920/bm2015.0138 ◽

2016 ◽

Vol 7 (3) ◽

pp. 319-326 ◽

Cited By ~ 5

Author(s):

H. Shibahara-Sone ◽

A. Gomi ◽

T. Iino ◽

M. Kano ◽

C. Nonaka ◽

...

Keyword(s):

Gastric Mucosa ◽

Human Study ◽

In Vitro Study ◽

Probiotic Strain ◽

Bifidobacterium Bifidum ◽

Human Gastric Mucosa ◽

Beneficial Effects ◽

H Pylori

The probiotic strain Bifidobacterium bifidum YIT 10347 has been demonstrated to inhibit Helicobacter pylori activity, prevent injury to the gastric mucosa, and improve general gastric malaise symptoms in H. pylori positive patients. This study aimed to investigate the adhering activity and localisation of B. bifidum YIT 10347 to gastric cells and tissue in vitro, and in human in vivo to clarify the mechanism of its beneficial effects on the stomach. The in vitro study found the adhesion rate of B. bifidum YIT 10347 to human gastric epithelial cells was about 10 times higher than that of lactic acid bacteria and other bifidobacteria. In the human study, 5 H. pylori negative and 12 H. pylori positive subjects ingested milk fermented with B. bifidum YIT 10347. B. bifidum YIT 10347 cells were measured by RT-qPCR for in gastric biopsy samples. Living B. bifidum YIT 10347 cells were detected in the biopsy samples in H. pylori negative subjects (105 cells/g and 104 cells/g at 1 h and 2 h after ingestion, respectively) and H. pylori positive subjects (104 cells/g at 1 h after the ingestion). Moreover, immunostaining analysis of tissue sections found that B. bifidum YIT 10347 cells were located at the interstitial mucin layer of the stomach. These results suggest that cells of probiotic B. bifidum YIT 10347 adhered to the human gastric mucosa in a live state, and that the higher adhering activity of B. bifidum YIT 10347 to the gastric mucosa may be involved in its beneficial effects on the human stomach.

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Downregulation of Interleukin- (IL-) 17 through Enhanced Indoleamine 2,3-Dioxygenase (IDO) Induction by Curcumin: A Potential Mechanism of Tolerance towards Helicobacter pylori

Journal of Immunology Research ◽

10.1155/2018/3739593 ◽

2018 ◽

Vol 2018 ◽

pp. 1-7 ◽

Cited By ~ 7

Author(s):

Tiziana Larussa ◽

Serena Gervasi ◽

Rita Liparoti ◽

Evelina Suraci ◽

Raffaella Marasco ◽

...

Keyword(s):

Helicobacter Pylori ◽

Gastric Mucosa ◽

Antimicrobial Properties ◽

Human Gastric Mucosa ◽

T Cell Apoptosis ◽

Indoleamine 2,3 Dioxygenase ◽

Treated Sample ◽

Tryptophan Catabolism ◽

Gastric Biopsies ◽

H Pylori

The anti-inflammatory and antimicrobial properties of curcumin suggest its use as an anti-Helicobacter pylori (H. pylori) agent, but mechanisms underlying its helpful activity are still not clear. Indoleamine 2,3-dioxygenase (IDO) promotes the effector T cell apoptosis by catalyzing the rate-limiting first step in tryptophan catabolism, and its high expression in H. pylori-infected human gastric mucosa attenuates Th1 and Th17 immune response. The aim of this study was to investigate the role of curcumin in modulating the expression of IL-17 and IDO in H. pylori-infected human gastric mucosa. In an organ culture chamber, gastric biopsies from 35 patients were treated with and without 200 μM curcumin. In H. pylori-infected patients (n=21), IL-17 was significantly lower, both in gastric biopsies (p=0.0003) and culture supernatant (p=0.0001) while IDO significantly increased (p<0.00001) in curcumin-treated sample compared with untreated samples. In a subgroup of H. pylori-infected patients (n=15), samples treated with curcumin in addition to IDO inhibitor 1-methyl-L-tryptophan (1-MT) showed a higher expression of IL-17 compared with untreated samples and curcumin-treated alone (p<0.00001). Curcumin downregulates IL-17 production through the induction of IDO in H. pylori-infected human gastric mucosa, suggesting its role in dampening H. pylori-induced immune-mediated inflammatory changes.

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Interleukin-12 Drives the Th1 Signaling Pathway in Helicobacter pylori-Infected Human Gastric Mucosa

Infection and Immunity ◽

10.1128/iai.01446-06 ◽

2007 ◽

Vol 75 (4) ◽

pp. 1738-1744 ◽

Cited By ~ 34

Author(s):

Antonia Pellicanò ◽

Ladislava Sebkova ◽

Giovanni Monteleone ◽

Giovanni Guarnieri ◽

Maria Imeneo ◽

...

Keyword(s):

Helicobacter Pylori ◽

Transcription Factors ◽

Gastric Mucosa ◽

Enzyme Linked Immunosorbent Assay ◽

Human Gastric Mucosa ◽

Organ Cultures ◽

Gastric Biopsies ◽

Ifn Γ ◽

H Pylori ◽

Cell Commitment

ABSTRACT In this study we examined mechanisms that regulate T-helper lymphocyte 1 (Th1) commitment in Helicobacter pylori-infected human gastric mucosa. The levels of gamma interferon (IFN-γ), interleukin-4 (IL-4), and IL-12 in total extracts of gastric biopsies taken from H. pylori-infected and uninfected patients were determined by an enzyme-linked immunosorbent assay. The levels of signal transducer and activator of transcription 4 (STAT4), STAT6, and T-box expressed in T cells (T-bet) in total proteins extracted from gastric biopsies were determined by Western blotting. Finally, the effect of a neutralizing IL-12 antibody on expression of Th1 transcription factors and the levels of IFN-γ in organ cultures of H. pylori-infected biopsies was examined. Increased levels of IFN-γ and IL-12 were found in gastric biopsy samples of H. pylori-infected patients compared to the levels in uninfected patients. In addition, H. pylori-infected biopsies exhibited high levels of expression of phosphorylated STAT4 and T-bet. Higher levels of IFN-γ and expression of Th1 transcription factors were associated with greater infiltration of mononuclear cells in the gastric mucosa. By contrast, production of IL-4 and expression of phosphorylated STAT6 were not associated with the intensity of mononuclear cell infiltration. In ex vivo organ cultures of H. pylori-infected biopsies, neutralization of endogenous IL-12 down-regulated the expression of phosphorylated STAT4 and T-bet and reduced IFN-γ production. Our data indicated that IL-12 contributes to the Th1 cell commitment in H. pylori-infected human gastric mucosa.

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Tissue transglutaminase activity in human gastric mucosa according to Helicobacter pylori infection

Experimental Biology and Medicine ◽

10.1177/1535370218819423 ◽

2018 ◽

Vol 243 (15-16) ◽

pp. 1161-1164

Author(s):

Maria Pina Dore ◽

Giovanni Mario Pes ◽

Alessandra Errigo ◽

Alessandra Manca ◽

Giuseppe Realdi

Keyword(s):

Helicobacter Pylori ◽

Animal Models ◽

Gastric Mucosa ◽

Natural History ◽

Tissue Transglutaminase ◽

Helicobacter Pylori Infection ◽

Human Gastric Mucosa ◽

Antral Mucosa ◽

History Of ◽

H Pylori

Tissue transglutaminase (t-TG) is a multifunctional protein involved in the healing of gastric erosions and ulcers in animal models. The aim of this study was to measure gastric t-TG activity in patients with dyspepsia according to Helicobacter pylori infection and cytotoxin-associated gene A (cagA) and vacuolating cytotoxin (vacA) subtype status. Patients undergoing upper endoscopy not taking any medications were enrolled. Tissue-TG activity was determined in homogenates of antral specimens using a radiometric assay and was expressed in pmol/mg. The cagA and vacA genotypes were determined by PCR amplification using gene-specific oligoprimers. Data from 46 patients were available (17 of them were positive for H. pylori). Antral t-TG activity was significantly increased in H. pylori positive patients compared to H. pylori negative patients (6437 ± 3691 vs. 3773 ± 1530 pmol/mg; P = 0.001) according to Mann–Whitney U test. Patients with H. pylori negative gastritis had higher t-TG activity than patients with normal gastric mucosa. The specimens infected with cagA positive strains (72%) displayed greater t-TG activity than cagA negative samples (7358 ± 4318 vs. 4895 ± 1062 pmol/mg; P = 0.237). Similarly, t-TG activity was higher in H. pylori vacA s1/m1 strains vs. vacA s1/m2 (7429 vs. 5045 pmol/mg; P = 0.744), and vacA s1/m1 vs. s2/m2 (7429 vs. 4489 pmol/mg; P = 0.651) but the results were not significant. No differences were found between histology, endoscopy features and t-TG activity. These results show that t-TG activity is significantly greater in gastritis associated with H. pylori infection, suggesting that this enzyme is induced by inflammation and may have an important role in the natural history of human gastritis. Impact statement Tissue transglutaminase (t-TG) is unique among TG enzymes because of its additional role in several physiological and pathological activities, including inflammation, fibrosis, and wound healing. The presence of t-TG has previously been described in the intestine of human and animal models, yet studies on t-TG activity in human gastric mucosa are missing. Helicobacter pylori infection is the major cause of gastritis and peptic ulcers. For the first time, our results show that t-TG activity was significantly higher in antral specimens of patients with chronic active gastritis associated with H. pylori infection compared to H. pylori negative chronic gastritis and normal antral mucosa. These findings suggest that t-TG has a role in the natural history of human gastritis, which requires further investigation but may be an avenue for new therapeutic options.

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Variations in Helicobacter pylori Lipopolysaccharide To Evade the Innate Immune Component Surfactant Protein D

Infection and Immunity ◽

10.1128/iai.73.11.7677-7686.2005 ◽

2005 ◽

Vol 73 (11) ◽

pp. 7677-7686 ◽

Cited By ~ 38

Author(s):

Wafa Khamri ◽

Anthony P. Moran ◽

Mulugeta L. Worku ◽

Q. Najma Karim ◽

Marjorie M. Walker ◽

...

Keyword(s):

Helicobacter Pylori ◽

Gastric Mucosa ◽

Phase Variation ◽

Surfactant Protein ◽

Clinical Isolates ◽

Surfactant Protein D ◽

Human Gastric Mucosa ◽

H Pylori

ABSTRACT Helicobacter pylori is a common and persistent human pathogen of the gastric mucosa. Surfactant protein D (SP-D), a component of innate immunity, is expressed in the human gastric mucosa and is capable of aggregating H. pylori. Wide variation in the SP-D binding affinity to H. pylori has been observed in clinical isolates and laboratory-adapted strains. The aim of this study was to reveal potential mechanisms responsible for evading SP-D binding and establishing persistent infection. An escape variant, J178V, was generated in vitro, and the lipopolysaccharide (LPS) structure of the variant was compared to that of the parental strain, J178. The genetic basis for structural variation was explored by sequencing LPS biosynthesis genes. SP-D binding to clinical isolates was demonstrated by fluorescence-activated cell sorter analyses. Here, we show that H. pylori evades SP-D binding through phase variation in lipopolysaccharide. This phenomenon is linked to changes in the fucosylation of the O chain, which was concomitant with slipped-strand mispairing in a poly(C) tract of the fucosyltransferase A (fucT1) gene. SP-D binding organisms are predominant in mucus in vivo (P = 0.02), suggesting that SP-D facilitates physical elimination. Phase variation to evade SP-D contributes to the persistence of this common gastric pathogen.

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