Helicobacter pylori metabolites exacerbate gastritis through C-type lectin receptors.
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ABSTRACT:
SUBMITTER: Nagata M
PROVIDER: S-EPMC7527975 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:The interleukin-17 (IL-17) family of cytokines (IL-17A to IL-17F) is involved in many inflammatory diseases. Although IL-17A is recognized as being involved in the pathophysiology of Helicobacter pylori-associated diseases, the role of other IL-17 cytokine family members remains unclear. Microarray analysis of IL-17 family cytokines was performed in H. pylori-infected and uninfected gastric biopsy specimens. IL-17C mRNA was upregulated approximately 4.5-fold in H. pylori-infected gastric biopsy specimens. This was confirmed by quantitative reverse transcriptase PCR in infected and uninfected gastric mucosa obtained from Bhutan and from the Dominican Republic. Immunohistochemical analysis showed that IL-17C expression in H. pylori-infected gastric biopsy specimens was predominantly localized to epithelial and chromogranin A-positive endocrine cells. IL-17C mRNA levels were also significantly greater among cagA-positive than cagA-negative H. pylori infections (P = 0.012). In vitro studies confirmed an increase in IL-17C mRNA and protein levels in cells infected with cagA-positive infections compared to cells infected with either cagA-negative or cag pathogenicity island (PAI) mutant. Chemical inhibition of I?B kinase (IKK), mitogen-activated protein extracellular signal-regulated kinase (MEK), and Jun N-terminal kinase (JNK) inhibited induction of IL-17C proteins in infected cells, whereas p38 inhibition had no effect on IL-17C protein secretion. In conclusion, H. pylori infection was associated with a significant increase in IL-17C expression in human gastric mucosa. The role of IL-17C in the pathogenesis of H. pylori-induced diseases remains to be determined.
| S-EPMC5607407 | biostudies-literature
Project description:ObjectiveTo present results of the Kyoto Global Consensus Meeting, which was convened to develop global consensus on (1) classification of chronic gastritis and duodenitis, (2) clinical distinction of dyspepsia caused by Helicobacter pylori from functional dyspepsia, (3) appropriate diagnostic assessment of gastritis and (4) when, whom and how to treat H. pylori gastritis.DesignTwenty-three clinical questions addressing the above-mentioned four domains were drafted for which expert panels were asked to formulate relevant statements. A Delphi method using an anonymous electronic system was adopted to develop the consensus, the level of which was predefined as ≥80%. Final modifications of clinical questions and consensus were achieved at the face-to-face meeting in Kyoto.ResultsAll 24 statements for 22 clinical questions after extensive modifications and omission of one clinical question were achieved with a consensus level of >80%. To better organise classification of gastritis and duodenitis based on aetiology, a new classification of gastritis and duodenitis is recommended for the 11th international classification. A new category of H. pylori-associated dyspepsia together with a diagnostic algorithm was proposed. The adoption of grading systems for gastric cancer risk stratification, and modern image-enhancing endoscopy for the diagnosis of gastritis, were recommended. Treatment to eradicate H. pylori infection before preneoplastic changes develop, if feasible, was recommended to minimise the risk of more serious complications of the infection.ConclusionsA global consensus for gastritis was developed for the first time, which will be the basis for an international classification system and for further research on the subject.
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Project description:Autoimmune atrophic gastritis (AAG) is associated with an increased risk of certain types of gastric cancer (GC). Helicobacter pylori (H. pylori) infection may have a role in the induction and/or maintenance of AAG and GC. Toll-like receptors (TLR) are essential for H. pylori recognition and subsequent innate and adaptive immunity responses. This study therefore aimed to characterize TLR polymorphisms, and features of bacterial flagellin A in samples from patients with AAG (n = 67), GC (n = 114) and healthy donors (HD; n = 97). TLR5 rs5744174 C/C genotype was associated with GC, lower IgG anti H. pylori response and a higher H. pylori flagellin A abundance and motility. In a subset of patients with AAG, H. pylori strains showed a reduction of the flagellin A abundance and a moderate motility compared with strains from GC patients, a prerequisite for active colonization of the deeper layers of the mucosa, host immune response and inflammation. TLR9 rs5743836 T allele showed an association with serum gastrin G17. In conclusion, our study suggests that alterations of flaA protein, moderate motility in H. pylori and two polymorphisms in TLR5 and TLR9 may favor the onset of AAG and GC, at least in a subset of patients. These findings corroborate the function of pathogen-host cell interactions and responses, likely influencing the pathogenetic process.
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Project description:Background & aimsThe association between cellular senescence and Helicobacter pylori-induced atrophic gastritis is not clear. Here, we explore the role of cellular senescence in H pylori-induced atrophic gastritis and the underlying mechanism.MethodsC57BL/6J mice were infected with H pylori for biological and mechanistic studies in vivo. Gastric precancerous lesions from patients and mouse models were collected and analyzed using senescence-associated beta-galactosidase, Sudan Black B, and immunohistochemical staining to analyze senescent cells, signaling pathways, and H pylori infection. Chromatin immunoprecipitation, luciferase reporter assays, and other techniques were used to explore the underlying mechanism in vitro.ResultsGastric mucosa atrophy was highly associated with cellular senescence. H pylori promoted gastric epithelial cell senescence in vitro and in vivo in a manner that depended on C-X-C motif chemokine receptor 2 (CXCR2) signaling. Interestingly, H pylori infection not only up-regulated the expression of CXCR2 ligands, C-X-C motif chemokine ligands 1 and 8, but also transcriptionally up-regulated the expression of CXCR2 via the nuclear factor-κB subunit 1 directly. In addition, CXCR2 formed a positive feedback loop with p53 to continually enhance senescence. Pharmaceutical inhibition of CXCR2 in an H pylori-infected mouse model attenuated mucosal senescence and atrophy, and delayed further precancerous lesion progression.ConclusionsOur study showed a new mechanism of H pylori-induced atrophic gastritis through CXCR2-mediated cellular senescence. Inhibition of CXCR2 signaling is suggested as a potential preventive therapy for targeting H pylori-induced atrophic gastritis. GEO data set accession numbers: GSE47797 and GSE3556.
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Project description:Caveolin-1 (Cav1) is a scaffold protein and pathogen receptor in the mucosa of the gastrointestinal tract. Chronic infection of gastric epithelial cells by Helicobacter pylori (H. pylori) is a major risk factor for human gastric cancer (GC) where Cav1 is frequently down-regulated. However, the function of Cav1 in H. pylori infection and pathogenesis of GC remained unknown. We show here that Cav1-deficient mice, infected for 11 months with the CagA-delivery deficient H. pylori strain SS1, developed more severe gastritis and tissue damage, including loss of parietal cells and foveolar hyperplasia, and displayed lower colonisation of the gastric mucosa than wild-type B6129 littermates. Cav1-null mice showed enhanced infiltration of macrophages and B-cells and secretion of chemokines (RANTES) but had reduced levels of CD25+ regulatory T-cells. Cav1-deficient human GC cells (AGS), infected with the CagA-delivery proficient H. pylori strain G27, were more sensitive to CagA-related cytoskeletal stress morphologies ("humming bird") compared to AGS cells stably transfected with Cav1 (AGS/Cav1). Infection of AGS/Cav1 cells triggered the recruitment of p120 RhoGTPase-activating protein/deleted in liver cancer-1 (p120RhoGAP/DLC1) to Cav1 and counteracted CagA-induced cytoskeletal rearrangements. In human GC cell lines (MKN45, N87) and mouse stomach tissue, H. pylori down-regulated endogenous expression of Cav1 independently of CagA. Mechanistically, H. pylori activated sterol-responsive element-binding protein-1 (SREBP1) to repress transcription of the human Cav1 gene from sterol-responsive elements (SREs) in the proximal Cav1 promoter. These data suggested a protective role of Cav1 against H. pylori-induced inflammation and tissue damage. We propose that H. pylori exploits down-regulation of Cav1 to subvert the host's immune response and to promote signalling of its virulence factors in host cells.
| S-EPMC3623771 | biostudies-other
Project description:Infection of the gastric antrum by Helicobacter pylori is characterised by a cellular inflammatory infiltrate. Whether cytokines are involved in the pathogenesis of this gastritis has been investigated by studying the effect of eradicating H pylori on the expression of genes encoding the cytokines interleukin 8 (IL-8) and tumour necrosis factor alpha (TNF-alpha) in the antral mucosa. Gastric antral biopsy specimens were taken from nine patients with duodenal ulcers and cytokine transcripts were identified and quantified by northern blotting. After H pylori had been eradicated the chronic inflammatory infiltrate decreased in all the patients and the polymorphonuclear infiltrate virtually disappeared. Expression of genes also decreased. After eradication, the median TNF-alpha mRNA/rRNA fell to 48% (p = 0.02) and the median IL-8 mRNA/rRNA fell to 5% (p = 0.004) of initial values. These results support the role of increased synthesis of these cytokines in the pathogenesis of the gastritis.
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Project description:Atrophic autoimmune gastritis (AAG) is a condition of chronic inflammation and atrophy of stomach mucosa, for which development can be partially triggered by the bacterial pathogen Helicobacter pylori (HP). HP can cause a variety of gastric diseases, such as duodenal ulcer (DU) or gastric cancer (GC). In this study, a comparative proteomic approach was used by two-dimensional fluorescence difference gel electrophoresis (DIGE) to identify differentially expressed proteins of HP strains isolated from patients with AAG, to identify markers of HP strain associated with AAG. Proteome profiles of HP isolated from GC or DU were used as a reference to compare proteomic levels. Proteomics analyses revealed 27 differentially expressed spots in AAG-associated HP in comparison with GC, whereas only 9 differential spots were found in AAG-associated HP profiles compared with DU. Proteins were identified after matrix-assisted laser desorption ionization (MALDI)-TOF and peptide mass fingerprinting. Some AAG-HP differential proteins were common between DU- and GC-HP (peroxiredoxin, heat shock protein 70 [HSP70], adenosine 5'-triphosphate [ATP] synthase subunit α, flagellin A). Our results presented here may suggest that comparative proteomes of HP isolated from AAG and DU share more common protein expression than GC and provide subsets of putative AAG-specific upregulated or downregulated proteins that could be proposed as putative markers of AAG-associated HP. Other comparative studies by two-dimensional maps integrated with functional genomics of candidate proteins will undoubtedly contribute to better decipher the biology of AAG-associated HP strains.
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Project description:Chronic gastritis caused by Helicobacter pylori (H. pylori) infection has been widely recognized as the most important risk factor for gastric cancer. Analysis of the interaction between the key participants in gastric mucosal immunity and H. pylori infection is expected to provide important insights for the treatment of chronic gastritis and the prevention of gastric cancer. Heparanase is an endoglycosidase that degrades heparan sulfate, resulting in remodeling of the extracellular matrix thereby facilitating the extravasation and migration of immune cells towards sites of inflammation. Heparanase also releases heparan sulfate-bound cytokines and chemokines that further promote directed motility and recruitment of immune cells. Heparanase is highly expressed in a variety of inflammatory conditions and diseases, but its role in chronic gastritis has not been sufficiently explored. In this study, we report that H. pylori infection promotes up-regulation of heparanase in gastritis, which in turn facilitates the colonization of H. pylori in the gastric mucosa, thereby aggravating gastritis. By sustaining continuous activation, polarization and recruitment of macrophages that supply pro-inflammatory and pro-tumorigenic cytokines (i.e., IL-1, IL-6, IL-1β, TNF-α, MIP-2, iNOS), heparanase participates in the generation of a vicious circle, driven by enhanced NFκB and p38-MAPK signaling, that supports the development and progression of gastric cancer. These results suggest that inhibition of heparanase may block this self-sustaining cycle, and thereby reduce the risk of gastritis and gastric cancer.
| S-EPMC8248549 | biostudies-literature
Project description:BACKGROUND:The management of Helicobacter pylori (H. pylori) infection raises important challenges, still being the most common chronic infection worldwide in all age groups. In high-prevalence regions, paediatric patients need a specific focus, as the acquisition of the infection takes place in childhood. The objective of this study was to analyze the endoscopic and histopathologic changes of the gastric mucosa in H. pylori infected children. MATERIAL AND METHODS:A retrospective study was performed on consecutive paediatric patients, ranging from 0 to 18 years of age, who underwent an upper gastrointestinal endoscopy (UGE) for a period of 5 years, regardless of their symptomatology. Endoscopy reports and histological slides were reviewed and clinical, endoscopic, and histologic data were recorded. RESULTS:A total of 248 patients were included in the study, 82 (33.06%) of them being H. pylori infected. There was no difference in age and symptoms between the infected and noninfected group. A significant association was found between the H. pylori infection and histopathological parameters such as acute and chronic inflammatory infiltrate. The bacterial load influences the intensity of inflammation (p < 0.001). The chronic inflammation was predominant, only 23.2% of the patients displayed acute inflammation (p < 0.0001). The topographic distribution of inflammation was dominated by pangastritis (p = 0.04) with 58.6% of the patients presenting similar degrees of inflammation both in the antrum and corpus. CONCLUSION:Endoscopic features such as nodularity of the antral mucosa (p < 0.05) along with histological findings as lymphoid follicles (p < 0.05) are suggestive of H. pylori infection. However, the concordance between the endoscopic and histological diagnosis is still far from perfect (Cohen's k coefficient = 0.42), maintaining the need for an invasive approach in children.
| S-EPMC7141205 | biostudies-literature
Project description:Helicobacter pylori (H. pylori)-induced oxidative stress has been shown to play a very important role in the inflammation of the gastric mucosa and increases the risk of developing gastric cancer. Resveratrol has many biological functions and activities, including antioxidant and anti-inflammatory effect. The purpose of this study was to probe whether resveratrol inhibits H. pylori-induced gastric inflammation and to elucidate the underlying mechanisms of any effect in mice. A mouse model of H. pylori infection was established via oral inoculation with H. pylori. After one week, mice were administered resveratrol (100 mg/kg body weight/day) orally for six weeks. The mRNA and protein levels of iNOS and IL-8 were assessed using RT-PCR, Western blot and ELISA. The expression levels of I?B? and phosphorylated I?B? (which embodies the level and activation of NF-?B), Heme Oxygenase-1 (HO-1; a potent antioxidant enzyme) and nuclear factor-erythroid 2 related factor 2 (Nrf2) were determined using Western blot, and lipid peroxide (LPO) level and myeloperoxidase (MPO) activity were examined using an MPO colorimetric activity assay, thiobarbituric acid reaction, and histological-grade using HE staining of the gastric mucosa. The results showed that resveratrol improved the histological infiltration score and decreased LPO level and MPO activity in the gastric mucosa. Resveratrol down-regulated the H. pylori-induced mRNA transcription and protein expression levels of IL-8 and iNOS, suppressed H. pylori-induced phosphorylation of I?B?, and increased the levels of HO-1 and Nrf2. In conclusion, resveratrol treatment exerted significant effects against oxidative stress and inflammation in H. pylori-infected mucosa through the suppression of IL-8, iNOS, and NF-?B, and moreover through the activation of the Nrf2/HO-1 pathway.
| S-EPMC4661919 | biostudies-literature