RESUMEN

A bibliometric analysis of studies dedicated to autoimmune gastritis (AIG) recently published demonstrated a noteworthy surge in publications over the last three years. This can be explained by numerous publications from different regions of the world reporting the results of several studies that stimulated reassessment of our view of AIG as a precancerous condition. Follow-up studies and retrospective analyses showed that the risk of gastric cancer (GC) in AIG patients is much lower than expected if the patients ever being infected with Helicobacter pylori (H. pylori) were excluded. The low prevalence of precancerous lesions, such as the incomplete type of intestinal metaplasia, may explain the low risk of GC in AIG patients because the spasmolytic polypeptide-expressing metaplasia commonly observed in AIG does not involve clonal reprogramming of the gastric gland and can be considered as an adaptive change rather than a true precancerous lesion. However, changes in gastric secretion due to the progression of gastric atrophy during the course of AIG cause changes in the gastric mic-robiome, stimulating the growth of bacterial species such as streptococci, which may promote the development of precancerous lesions and GC. Thus, Streptococcus anginosus exhibited a robust proinflammatory response and induced the gastritis-atrophy-metaplasia-dysplasia sequence in mice, reproducing the well-established process for carcinogenesis associated with H. pylori. Prospective studies in H. pylori-naïve patients evaluating gastric microbiome changes during the long-term course of AIG might provide an explanation for the enigmatic increase in GC incidence in the last decades in younger cohorts, which has been reported in economically developed countries.

Asunto(s)

Enfermedades Autoinmunes , Bibliometría , Mucosa Gástrica , Gastritis , Infecciones por Helicobacter , Helicobacter pylori , Lesiones Precancerosas , Neoplasias Gástricas , Neoplasias Gástricas/inmunología , Neoplasias Gástricas/patología , Neoplasias Gástricas/microbiología , Neoplasias Gástricas/epidemiología , Humanos , Gastritis/inmunología , Gastritis/microbiología , Gastritis/epidemiología , Gastritis/patología , Infecciones por Helicobacter/epidemiología , Infecciones por Helicobacter/inmunología , Infecciones por Helicobacter/microbiología , Infecciones por Helicobacter/patología , Helicobacter pylori/aislamiento & purificación , Helicobacter pylori/inmunología , Helicobacter pylori/patogenicidad , Lesiones Precancerosas/inmunología , Lesiones Precancerosas/microbiología , Lesiones Precancerosas/patología , Lesiones Precancerosas/epidemiología , Animales , Enfermedades Autoinmunes/inmunología , Enfermedades Autoinmunes/epidemiología , Mucosa Gástrica/patología , Mucosa Gástrica/inmunología , Mucosa Gástrica/microbiología , Metaplasia , Factores de Riesgo , Estómago/patología , Estómago/inmunología , Estómago/microbiología , Microbioma Gastrointestinal/inmunología , Ratones

RESUMEN

The mucus serves as a protective barrier in the gastrointestinal tract against microbial attacks. While its role extends beyond merely being a physical barrier, the extent of its active bactericidal properties remains unclear, and the mechanisms regulating these properties are not yet understood. We propose that inflammation induces epithelial cells to secrete antimicrobial peptides, transforming mucus into an active bactericidal agent. To investigate the properties of mucus, we previously developed mucosoid culture models that mimic the healthy human stomach epithelium. Similar to organoids, mucosoids are stem cell-driven cultures; however, the cells are cultivated on transwells at air-liquid interface. The epithelial cells of mucosoids form a polarized monolayer, allowing differentiation into all stomach lineages, including mucus-secreting cells. This setup facilitates the secretion and accumulation of mucus on the apical side of the mucosoids, enabling analysis of its bactericidal effects and protein composition, including antimicrobial peptides. Our findings show that TNFα, IL1ß, and IFNγ induce the secretion of antimicrobials such as lactotransferrin, lipocalin2, complement component 3, and CXCL9 into the mucus. This antimicrobial-enriched mucus can partially eliminate Helicobacter pylori, a key stomach pathogen. The bactericidal activity depends on the concentration of each antimicrobial and their gene expression is higher in patients with inflammation and H.pylori-associated chronic gastritis. However, we also find that H. pylori infection can reduce the expression of antimicrobial encoding genes promoted by inflammation. These findings suggest that controlling antimicrobial secretion in the mucus is a critical component of epithelial immunity. However, pathogens like H. pylori can overcome these defenses and survive in the mucosa.

Asunto(s)

Péptidos Antimicrobianos , Mucosa Gástrica , Helicobacter pylori , Inflamación , Moco , Humanos , Moco/metabolismo , Moco/microbiología , Péptidos Antimicrobianos/metabolismo , Mucosa Gástrica/microbiología , Mucosa Gástrica/metabolismo , Mucosa Gástrica/inmunología , Inflamación/metabolismo , Células Epiteliales/microbiología , Células Epiteliales/metabolismo , Infecciones por Helicobacter/microbiología , Infecciones por Helicobacter/metabolismo , Infecciones por Helicobacter/inmunología , Estómago/microbiología , Organoides/metabolismo , Organoides/microbiología

RESUMEN

Helicobacter pylori infection predisposes carriers to a high risk of developing gastric cancer. The cell-of-origin of antral gastric cancer is the Lgr5+ stem cell. Here, we show that infection of antrum-derived gastric organoid cells with H. pylori increases the expression of the stem cell marker Lgr5 as determined by immunofluorescence microscopy, qRT-PCR, and Western blotting, both when cells are grown and infected as monolayers and when cells are exposed to H. pylori in 3D structures. H. pylori exposure increases stemness properties as determined by spheroid formation assay. Lgr5 expression and the acquisition of stemness depend on a functional type IV secretion system (T4SS) and at least partly on the T4SS effector CagA. The pharmacological inhibition or genetic ablation of NF-κB reverses the increase in Lgr5 and spheroid formation. Constitutively active Wnt/ß-catenin signaling because of Apc inactivation exacerbates H. pylori-induced Lgr5 expression and stemness, both of which persist even after eradication of the infection. The combined data indicate that H. pylori has stemness-inducing properties that depend on its ability to activate NF-κB signaling.

Asunto(s)

Infecciones por Helicobacter , Helicobacter pylori , FN-kappa B , Receptores Acoplados a Proteínas G , Neoplasias Gástricas , Vía de Señalización Wnt , Animales , Ratones , Antígenos Bacterianos/metabolismo , Antígenos Bacterianos/genética , Proteínas Bacterianas/metabolismo , Proteínas Bacterianas/genética , Mucosa Gástrica/metabolismo , Mucosa Gástrica/microbiología , Infecciones por Helicobacter/metabolismo , Infecciones por Helicobacter/microbiología , Células Madre Neoplásicas/metabolismo , Células Madre Neoplásicas/microbiología , FN-kappa B/metabolismo , Organoides/metabolismo , Organoides/microbiología , Receptores Acoplados a Proteínas G/metabolismo , Receptores Acoplados a Proteínas G/genética , Células Madre/metabolismo , Estómago/microbiología , Estómago/patología , Neoplasias Gástricas/microbiología , Neoplasias Gástricas/metabolismo , Neoplasias Gástricas/genética , Neoplasias Gástricas/patología , Sistemas de Secreción Tipo IV/metabolismo , Sistemas de Secreción Tipo IV/genética , Vía de Señalización Wnt/genética

RESUMEN

Helicobacter pylori (Hp) is a Gram-negative bacterium that colonizes in the gastric mucosa. Hp induces the production of cancer-associated fibroblasts (CAF) in the stomach. The virulence factors of Hp and CAF trigger epithelial-mesenchymal transition (EMT), leading to local inflammation, damage to the gastric mucosa, and the occurrence of chronic gastritis. Here, we summarize the molecular mechanisms of CAF mediated gastric EMT after Hp infection, providing new insights into potential molecular targets and strategies for the future treatment of Hp infection associated gastric cancer.

Asunto(s)

Transición Epitelial-Mesenquimal , Mucosa Gástrica , Infecciones por Helicobacter , Helicobacter pylori , Neoplasias Gástricas , Humanos , Infecciones por Helicobacter/complicaciones , Helicobacter pylori/fisiología , Neoplasias Gástricas/microbiología , Neoplasias Gástricas/patología , Neoplasias Gástricas/etiología , Mucosa Gástrica/microbiología , Mucosa Gástrica/patología , Fibroblastos Asociados al Cáncer/metabolismo , Fibroblastos Asociados al Cáncer/fisiología , Animales

RESUMEN

BACKGROUND: Helicobacter pylori infection is one of the most common chronic bacterial infections, especially in developing countries. MicroRNA-148a is involved in the regulation of various genes, including Rock1, which is altered in gastric cancer. Decreased expression of mir-148a leads to tumor metastasis and increased Rock1 gene expression in gastric cancer. This study aimed to investigate the expression of these genes in biopsies collected from patients with H. pylori induced gastritis. METHODS: Informed consent forms were gotten from the studied patients with gastritis who needed endoscopy. Gastric biopsies were taken by a gastroenterologist from patients with inflammation. Rapid urease test, stool antigen detection, and histopathological staining were used to determine the H. pylori infected patients. Real time PCR was used to evaluate the miRNA and Rock1 expression levels. RESULTS: The Rock1 expression level in biopsies that were positive for H. pylori was significantly increased compared to our control gastritis group that were H. pylori-negative, but the results were not statistically significant. Moreover, the mir-148a expression level in H. pylori-positive patients with gastritis was increased compared to our control group. However, the results were not statistically significant. We did not find a significant relation between the expression levels of Rock1 and mir-148a in samples with gastritis infected or uninfected by H. pylori. This result may be due to the small sample size. CONCLUSION: We suggest that this test should be carried out with more samples, and the comparison should be done between biopsies with inflammation and no inflammation in a patient.

Asunto(s)

Gastritis , Infecciones por Helicobacter , Helicobacter pylori , MicroARNs , Quinasas Asociadas a rho , Humanos , Gastritis/microbiología , Gastritis/patología , Gastritis/metabolismo , MicroARNs/metabolismo , MicroARNs/genética , Infecciones por Helicobacter/patología , Quinasas Asociadas a rho/metabolismo , Quinasas Asociadas a rho/genética , Helicobacter pylori/aislamiento & purificación , Biopsia , Masculino , Femenino , Persona de Mediana Edad , Adulto , Mucosa Gástrica/patología , Mucosa Gástrica/microbiología , Anciano

RESUMEN

Emerging evidence suggests differential antagonism of lactic acid-producing bacteria (LAB) to Helicobacter pylori, posing challenges to human health and food safety due to unclear mechanisms. This study assessed 21 LAB strains from various sources on H. pylori growth, urease activity, and coaggregation. Composite scoring revealed that Latilactobacillus sakei LZ217, derived from fresh milk, demonstrates strong inhibitory effects on both H. pylori growth and urease activity. L. sakei LZ217 significantly reduced H. pylori adherence of gastric cells in vitro, with inhibition ratios of 47.62%. Furthermore, in vivo results showed that L. sakei LZ217 alleviated H. pylori-induced gastric mucosa damage and inflammation in mice. Metabolomic exploration revealed metabolic perturbations in H. pylori induced by L. sakei LZ217, including reduced amino acid levels (e.g., isoleucine, leucine, glutamate, aspartate, and phenylalanine) and impaired carbohydrate and nucleotide synthesis, contributing to the suppression of ureA (28.30%), ureE (84.88%), and ureF (59.59%) expressions in H. pylori. This study underscores the efficacy of LAB against H. pylori and highlights metabolic pathways as promising targets for future interventions against H. pylori growth and colonization.

Asunto(s)

Mucosa Gástrica , Infecciones por Helicobacter , Helicobacter pylori , Ureasa , Ureasa/metabolismo , Animales , Infecciones por Helicobacter/microbiología , Mucosa Gástrica/microbiología , Mucosa Gástrica/metabolismo , Ratones , Humanos , Adhesión Bacteriana , Femenino , Probióticos , Masculino

RESUMEN

INTRODUCTION: Helicobacter pylori is a major risk factor for gastric cancer. In addition to eradication therapy, early-phase detection of gastric cancer through screening programs using high-vision endoscopy is also widely known to reduce mortality. Although European and US guidelines recommend evaluation of atrophy and intestinal metaplasia by high-vision endoscopy and pathological findings, the guideline used in Japan - the Kyoto classification of gastritis - is based on endoscopic evaluation, and recommends the grading of risk factors. This system requires classification into three endoscopic groups: H. pylori-negative, previous H. pylori infection (inactive gastritis), and current H. pylori infection (active gastritis). Major endoscopic findings in active gastritis are diffuse redness, enlarged folds, nodularity, mucosal swelling, and sticky mucus, while those in H pylori-related gastritis - irrespective of active or inactive status - are atrophy, intestinal metaplasia, and xanthoma. AREAS COVERED: This review describes the endoscopic characteristics of current H. pylori infection, and how characteristic endoscopic findings should be evaluated. EXPERT OPINION: Although the correct evaluation of endoscopic findings related to H. pylori remains necessary, if findings of possible infection are observed, it is important to diagnose infection by detection methods with high sensitivity and specificity, including the stool antigen test and urea breath test.

Asunto(s)

Infecciones por Helicobacter , Helicobacter pylori , Humanos , Infecciones por Helicobacter/diagnóstico , Infecciones por Helicobacter/microbiología , Helicobacter pylori/aislamiento & purificación , Gastritis/microbiología , Gastritis/diagnóstico , Mucosa Gástrica/patología , Mucosa Gástrica/microbiología , Pruebas Respiratorias , Metaplasia , Gastroscopía , Valor Predictivo de las Pruebas , Neoplasias Gástricas/microbiología , Neoplasias Gástricas/diagnóstico , Neoplasias Gástricas/patología

RESUMEN

Gastrointestinal mucosal surface is frequently under challenge due to it's the large surface area and most common entry of microbes. IL-37, an anti-inflammatory cytokine, regulates local and systemic host immunity. H. pylori infection leads to the inhibition of IL-37 in the gastric mucosa, contributing to heightened mucosal inflammation and destruction, thereby facilitating increased proliferation of H. pylori. Food allergy, due to immune dysregulation, also contribute to GI injury. On the other hand, elevated levels of IL-37 observed in gastric cancer patients align with reduced host immunity at the cellular and humoral levels, indicating that IL-37 may contribute to the development of gastric cancer via suppressing pro-inflammatory responses. While IL-37 provides protection in an IBD animal model, the detection of highly produced IL-37 in IBD patients suggests a stage-dependent role, being protective in acute inflammation but potentially exacerbates the development of IBD in chronic conditions. Moreover, elevated colonic IL-37 in CRC correlates with overall survival time and disease time, indicating a protective role for IL-37 in CRC. The differential regulation and expression of IL-37 between upper- and lower-GI organs may be attributed to variations in the microbial flora. This information suggests that IL-37 could be a potential therapeutic agent, depending on the stage and location.

Asunto(s)

Enfermedades Gastrointestinales , Interleucina-1 , Humanos , Interleucina-1/metabolismo , Animales , Enfermedades Gastrointestinales/inmunología , Enfermedades Gastrointestinales/metabolismo , Infecciones por Helicobacter/inmunología , Infecciones por Helicobacter/metabolismo , Mucosa Gástrica/metabolismo , Mucosa Gástrica/inmunología , Mucosa Gástrica/microbiología , Helicobacter pylori/inmunología , Microbioma Gastrointestinal/inmunología

RESUMEN

Helicobacter pylori (H. pylori) infection is the primary risk factor for the progress of gastric diseases. The persistent stomach colonization of H. pylori is closely associated with the development of gastritis and malignancies. Although the involvement of progranulin (PGRN) in various cancer types has been well-documented, its functional role and underlying mechanisms in gastric cancer (GC) associated with H. pylori infection remain largely unknown. This report demonstrated that PGRN was up-regulated in GC and associated with poor prognosis, as determined through local and public database analysis. Additionally, H. pylori induced the up-regulation of PGRN in gastric epithelial cells both in vitro and in vivo. Functional studies have shown that PGRN promoted the intracellular colonization of H. pylori. Mechanistically, H. pylori infection induced autophagy, while PGRN inhibited autophagy to promote the intracellular colonization of H. pylori. Furthermore, PGRN suppressed H. pylori-induced autophagy by down-regulating decorin (DCN) through the mTOR pathway. In general, PGRN inhibited autophagy to facilitate intracellular colonization of H. pylori via the PGRN/mTOR/DCN axis. This study provides new insights into the molecular mechanisms underlying the progression of gastric diseases, suggesting PGRN as a potential therapeutic target and prognostic predictor for these disorders.

Asunto(s)

Autofagia , Células Epiteliales , Mucosa Gástrica , Infecciones por Helicobacter , Helicobacter pylori , Progranulinas , Neoplasias Gástricas , Serina-Treonina Quinasas TOR , Progranulinas/metabolismo , Serina-Treonina Quinasas TOR/metabolismo , Humanos , Células Epiteliales/microbiología , Células Epiteliales/metabolismo , Infecciones por Helicobacter/microbiología , Infecciones por Helicobacter/metabolismo , Animales , Neoplasias Gástricas/microbiología , Neoplasias Gástricas/metabolismo , Neoplasias Gástricas/patología , Mucosa Gástrica/microbiología , Mucosa Gástrica/metabolismo , Ratones , Transducción de Señal

RESUMEN

OBJECTIVES: We aimed to identify predictive markers for metachronous gastric cancer (MGC) in early gastric cancer (EGC) patients curatively treated with endoscopic submucosal dissection (ESD). MATERIALS AND METHODS: From EGC patients who underwent ESD, bulk RNA sequencing was performed on non-cancerous gastric mucosa samples at the time of initial EGC diagnosis. This included 23 patients who developed MGC, and 23 control patients without additional gastric neoplasms for over 3 years (1:1 matched by age, sex, and Helicobacter pylori infection state). Candidate differentially-expressed genes were identified, from which biomarkers were selected using real-time quantitative polymerase chain reaction and cell viability assays using gastric cell lines. An independent validation cohort of 55 MGC patients and 125 controls was used for marker validation. We also examined the severity of gastric intestinal metaplasia, a known premalignant condition, at initial diagnosis. RESULTS: From the discovery cohort, 86 candidate genes were identified of which KDF1 and CDK1 were selected as markers for MGC, which were confirmed in the validation cohort. CERB5 and AKT2 isoform were identified as markers related to intestinal metaplasia and were also highly expressed in MGC patients compared to controls (p < 0.01). Combining these markers with clinical data (age, sex, H. pylori and severity of intestinal metaplasia) yielded an area under the curve (AUC) of 0.91 (95% CI, 0.85-0.97) for MGC prediction. CONCLUSION: Assessing biomarkers in non-cancerous gastric mucosa may be a useful method for predicting MGC in EGC patients and identifying patients with a higher risk of developing MGC, who can benefit from rigorous surveillance.

Asunto(s)

Biomarcadores de Tumor , Neoplasias Primarias Secundarias , Neoplasias Gástricas , Humanos , Neoplasias Gástricas/cirugía , Neoplasias Gástricas/patología , Neoplasias Gástricas/genética , Masculino , Femenino , Biomarcadores de Tumor/genética , Persona de Mediana Edad , Anciano , Neoplasias Primarias Secundarias/genética , Neoplasias Primarias Secundarias/patología , Resección Endoscópica de la Mucosa , Proteína Quinasa CDC2/genética , Proteína Quinasa CDC2/metabolismo , Mucosa Gástrica/patología , Mucosa Gástrica/cirugía , Mucosa Gástrica/microbiología , Mucosa Gástrica/metabolismo , Infecciones por Helicobacter/complicaciones , Infecciones por Helicobacter/genética , Gastroscopía , Regulación Neoplásica de la Expresión Génica , Metaplasia/genética , Metaplasia/patología , Helicobacter pylori/aislamiento & purificación , Estudios de Casos y Controles

RESUMEN

BACKGROUND: Theoretically, a rapid urease test (RUT) using a swab of the gastric wall (Swab-RUT) for Helicobacter pylori (H. pylori) is safe. However, the validity and utility of Swab-RUT remain unclear. Therefore, we assessed the validity and utility of Swab-RUT compared to RUT using mucosal forceps of the gastric wall (Forceps-RUT) and 13C-urea breath test (UBT). METHODS: This study was a multicenter prospective observational study. When the examinees were suspected of H. pylori infection during esophagogastroduodenoscopy, we performed Swab-RUT and Forceps-RUT continuously. When the examinees were not suspected of H. pylori infection, we performed Swab-RUT alone. We validated the status of H. pylori infection using UBT. RESULTS: Ninety-four examinees were enrolled from four institutions between May 2016 and December 2020 (median age [range], 56.5 [26-88] years). In this study, the sensitivity, specificity, and accuracy of Swab-RUT to UBT were 0.933 (95% confidence interval: 0.779-0.992), 0.922 (0.827-0.974), and 0.926 (0.853-0.970), respectively. The Kappa coefficient of Swab-RUT to UBT was 0.833, and that of Swab-RUT to forceps-RUT was 0.936. No complications were observed in this study. CONCLUSIONS: Swab-RUT is a valid examination for the status of H. pylori infection compared to the conventional Forceps-RUT.

Asunto(s)

Pruebas Respiratorias , Infecciones por Helicobacter , Helicobacter pylori , Sensibilidad y Especificidad , Ureasa , Humanos , Pruebas Respiratorias/métodos , Pruebas Respiratorias/instrumentación , Infecciones por Helicobacter/diagnóstico , Infecciones por Helicobacter/microbiología , Persona de Mediana Edad , Estudios Prospectivos , Ureasa/análisis , Ureasa/metabolismo , Masculino , Femenino , Anciano , Helicobacter pylori/aislamiento & purificación , Helicobacter pylori/enzimología , Adulto , Anciano de 80 o más Años , Mucosa Gástrica/microbiología , Endoscopía del Sistema Digestivo , Reproducibilidad de los Resultados , Isótopos de Carbono , Instrumentos Quirúrgicos/microbiología

RESUMEN

BACKGROUND: Helicobacter pylori (H. pylori) infection is critical in the development and occurrence of gastric cancer. H. pylori secretes gamma-glutamyl transferase (GGT), which affects energy metabolism and histone methylation in mesenchymal stem cells. However, its effect on human gastric epithelial cells remains unclear. This study aimed to investigate the effects of GGT on energy metabolism and histone methylation in gastric epithelial cells and determine its role in the development and progression of H. pylori-induced gastric cancer. METHODS: A GGT knockout H. pylori strain and mouse gastric cancer model were constructed, and alpha-ketoglutarate (α-KG) was added. The underlying mechanism was investigated using proteomics, immunohistochemistry, Western blotting, and other experimental assays. RESULTS: H. pylori can colonize the host's stomach and destroy the gastric epithelium. GGT secreted by H. pylori decreased the concentration of glutamine in the stomach and increased H3K9me3 and H3K27me3 expression, which promoted the proliferation and migration of gastric epithelial cells. Additionally, α-KG reversed this effect. GGT increased the tumorigenic ability of nude mice. GGT, secreted by H. pylori, promoted the expression of ribosomal protein L15 (RPL15), while GGT knockout and supplementation with α-KG and trimethylation inhibitors reduced RPL15 expression and Wnt signaling pathway expression. CONCLUSIONS: H. pylori secreted GGT decreased the expression of glutamine and α-KG in gastric epithelial cells, increased the expression of histones H3K9me3 and H3K27me3, and activated the Wnt signaling pathway through RPL15 expression, ultimately changing the biological characteristics of the gastric epithelium and promoting the occurrence of gastric cancer. Altered energy metabolism and histone hypermethylation are important factors involved in this process.

Asunto(s)

Metabolismo Energético , Células Epiteliales , Helicobacter pylori , Histonas , Neoplasias Gástricas , gamma-Glutamiltransferasa , Neoplasias Gástricas/microbiología , Neoplasias Gástricas/patología , Neoplasias Gástricas/metabolismo , Neoplasias Gástricas/genética , Animales , Histonas/metabolismo , Metilación , Células Epiteliales/metabolismo , Células Epiteliales/microbiología , Células Epiteliales/patología , gamma-Glutamiltransferasa/metabolismo , gamma-Glutamiltransferasa/genética , Ratones , Humanos , Ratones Desnudos , Mucosa Gástrica/metabolismo , Mucosa Gástrica/microbiología , Mucosa Gástrica/patología , Proliferación Celular , Infecciones por Helicobacter/metabolismo , Infecciones por Helicobacter/microbiología , Infecciones por Helicobacter/patología , Infecciones por Helicobacter/complicaciones , Ácidos Cetoglutáricos/metabolismo

RESUMEN

BACKGROUND: Changes in gastric microbiome are associated with gastric carcinogenesis. Studies on the association between gastric mucosa-associated gastric microbiome (MAM) and metachronous gastric cancer are limited. This study aimed to identify gastric MAM as a predictive factor for metachronous recurrence following endoscopic resection of gastric neoplasms. METHOD: Microbiome analyses were conducted for 81 patients in a prospective cohort to investigate surrogate markers to predict metachronous recurrence. Gastric MAM in non-cancerous corporal biopsy specimens was evaluated using Illumina MiSeq platform targeting 16S ribosomal DNA. RESULTS: Over a median follow-up duration of 53.8 months, 16 metachronous gastric neoplasms developed. Baseline gastric MAM varied with Helicobacter pylori infection status, but was unaffected by initial pathologic diagnosis, presence of atrophic gastritis, intestinal metaplasia, or synchronous lesions. The group with metachronous recurrence did not exhibit distinct phylogenetic diversity compared with the group devoid of recurrence but showed significant difference in ß-diversity. The study population could be classified into two distinct gastrotypes based on baseline gastric MAM: gastrotype 1, Helicobacter-abundant; gastrotype 2: Akkermansia-abundant. Patients in gastrotype 2 showed higher risk of metachronous recurrence than gastrotype (Cox proportional hazard analysis, adjusted hazard ratio [95% confidence interval]: 5.10 [1.09-23.79]). CONCLUSIONS: Gastric cancer patients can be classified into two distinct gastrotype groups by their MAM profiles, which were associated with different risk of metachronous recurrence.

Asunto(s)

Microbioma Gastrointestinal , Infecciones por Helicobacter , Recurrencia Local de Neoplasia , Neoplasias Primarias Secundarias , Neoplasias Gástricas , Humanos , Neoplasias Gástricas/cirugía , Neoplasias Gástricas/patología , Neoplasias Gástricas/microbiología , Masculino , Femenino , Persona de Mediana Edad , Anciano , Recurrencia Local de Neoplasia/microbiología , Recurrencia Local de Neoplasia/patología , Estudios Prospectivos , Neoplasias Primarias Secundarias/microbiología , Neoplasias Primarias Secundarias/patología , Infecciones por Helicobacter/microbiología , Infecciones por Helicobacter/patología , Helicobacter pylori/aislamiento & purificación , Mucosa Gástrica/microbiología , Mucosa Gástrica/patología , Mucosa Gástrica/cirugía , Estudios de Seguimiento , Pronóstico

RESUMEN

Impaired E-cadherin (Cdh1) functions are closely associated with cellular dedifferentiation, infiltrative tumor growth and metastasis, particularly in gastric cancer. The class-I carcinogen Helicobacter pylori (H. pylori) colonizes gastric epithelial cells and induces Cdh1 shedding, which is primarily mediated by the secreted bacterial protease high temperature requirement A (HtrA). In this study, we used human primary epithelial cell lines derived from gastroids and mucosoids from different healthy donors to investigate HtrA-mediated Cdh1 cleavage and the subsequent impact on bacterial pathogenesis in a non-neoplastic context. We found a severe impairment of Cdh1 functions by HtrA-induced ectodomain cleavage in 2D primary cells and mucosoids. Since mucosoids exhibit an intact apico-basal polarity, we investigated bacterial transmigration across the monolayer, which was partially depolarized by HtrA, as indicated by microscopy, the analyses of the transepithelial electrical resistance (TEER) and colony forming unit (cfu) assays. Finally, we investigated CagA injection and observed efficient CagA translocation and tyrosine phosphorylation in 2D primary cells and, to a lesser extent, similar effects in mucosoids. In summary, HtrA is a crucially important factor promoting the multistep pathogenesis of H. pylori in non-transformed primary gastric epithelial cells and organoid-based epithelial models.

Asunto(s)

Proteínas Bacterianas , Cadherinas , Células Epiteliales , Mucosa Gástrica , Helicobacter pylori , Organoides , Humanos , Cadherinas/metabolismo , Organoides/metabolismo , Células Epiteliales/metabolismo , Células Epiteliales/microbiología , Mucosa Gástrica/metabolismo , Mucosa Gástrica/microbiología , Mucosa Gástrica/patología , Proteínas Bacterianas/metabolismo , Proteínas Bacterianas/genética , Antígenos Bacterianos/metabolismo , Infecciones por Helicobacter/metabolismo , Infecciones por Helicobacter/microbiología , Infecciones por Helicobacter/patología , Antígenos CD/metabolismo , Estómago/microbiología , Estómago/patología , Línea Celular , Neoplasias Gástricas/metabolismo , Neoplasias Gástricas/patología , Neoplasias Gástricas/microbiología , Serina Proteasas

RESUMEN

Mycobacterium bovis (M. bovis) Bacillus Calmette-Guerin (BCG) strain used in immunotherapy of bladder cancer (onco-BCG) due to its acid tolerance can be a candidate for prevention or reversion of deleterious effects towards gastric cell barrier initiated by gastric pathogen Helicobacter pylori (Hp) with high resistance to commonly used antibiotics. Colonization of gastric mucosa by Hp promotes oxidative stress, apoptosis resulting in the gastric barrier damage. The aim of this study was to examine the ability of onco-BCG bacilli to control the Hp driven gastric damage using the model of Cavia porcellus primary gastric epithelial cells or fibroblasts in vitro. These cells were treated with Hp surface antigens (glycine acid extract-GE or lipopolysaccharide-LPS) alone or with onco-BCG bacilli and evaluated for cell apoptosis and proliferation in conjunction with the level of soluble lipid peroxidation marker (s4HNE). The cell migration was determined by "wound healing assay", while cytokine response of cells, including interleukin (IL)-33, IL-1ß, IL-8 and tumor necrosis factor alpha (TNF-α), by the ELISA. The apoptosis of cells pulsed in vitro with Hp surface components present in GE or with LPS was reduced after exposure of cells to mycobacteria. Similarly, the cell regeneration which was diminished by Hp LPS has been improved in response to mycobacteria. This study reveals that vaccine mycobacteria may reduce gastric barrier damage induced by Hp infection.

Asunto(s)

Apoptosis , Mucosa Gástrica , Helicobacter pylori , Mycobacterium bovis , Helicobacter pylori/efectos de los fármacos , Animales , Apoptosis/efectos de los fármacos , Mucosa Gástrica/efectos de los fármacos , Mucosa Gástrica/microbiología , Mucosa Gástrica/patología , Lipopolisacáridos , Citocinas/metabolismo , Proliferación Celular/efectos de los fármacos , Células Epiteliales/efectos de los fármacos , Células Epiteliales/microbiología , Movimiento Celular/efectos de los fármacos , Células Cultivadas , Peroxidación de Lípido/efectos de los fármacos , Fibroblastos/efectos de los fármacos

RESUMEN

A wealth of research indicates that superficial gastritis (SG) and atrophic gastritis (AG) are precursors to gastric cancer (GC). While Helicobacter pylori (H. pylori) has long been recognized as a key player in GC development, recent findings by Fu et al. have identified Streptococcus anginosus (S. anginosus) as an emerging pathogen that can trigger SG, AG and GC. S. anginosus, a gram-positive coccus, leverages its surface protein T. pallidum membrane protein C (TMPC) to engage with the annexin A2 (ANXA2) receptor of gastric epithelial cells, facilitating its colonization and invasion in the gastric mucosa. This leads to an upregulation of proinflammatory chemokines Ccl20 and Ccl8, causing prolonged effects on gastric barrier function and microbiota homeostasis, leading to SG. Moreover, these bacteria activate the mitogen-activated protein kinase (MAPK) signaling pathway, which is associated with the development of AG and GC. Importantly, inhibiting TMPC or knocking down ANXA2 can reduce S. anginosus colonization and invasion, lowering the chances of SG, AG, and GC. This paper highlights the molecular mechanisms of S. anginosus in SG, AG and GC, emphasizing the importance of a multi-pathogen strategy in gastric disease management and the need for further investigation into the role of S. anginosus in GC progression.

Asunto(s)

Gastritis Atrófica , Neoplasias Gástricas , Streptococcus anginosus , Humanos , Neoplasias Gástricas/microbiología , Neoplasias Gástricas/patología , Gastritis Atrófica/microbiología , Gastritis Atrófica/patología , Anexina A2/metabolismo , Infecciones Estreptocócicas/inmunología , Infecciones Estreptocócicas/microbiología , Mucosa Gástrica/microbiología , Mucosa Gástrica/patología , Mucosa Gástrica/metabolismo , Gastritis/microbiología , Gastritis/patología , Gastritis/inmunología , Animales

RESUMEN

INTRODUCTION: Cytokeratins (CKs) have been associated with precancerous and cancerous gastric lesions in patients with Helicobacter pylori-associated chronic gastritis, making them useful for diagnosing epithelial tumors. METHODOLOGY: A retrospective study was conducted utilizing 200 formalin-fixed paraffin-embedded gastric biopsy samples collected from the lesser curvature of the stomach. Samples from the control group, patients with H. pylori infection, and patients with H. pylori-associated gastritis, with complete and incomplete intestinal metaplasia (IM) were immunostained. Monoclonal antibodies were utilized to determine the expression of CK7, CK20, and Ki-67. RESULTS: Patients infected with H. pylori had strong CK20 expression on the surface, and weak CK7 expression on the surface and deep glands; while non-specific chronic gastritis patients had weak focal CK7 expression and strong CK20 expression. The normal gastric mucosa of patients in the control group had relatively weak CK7 expression, restricted to a few cells in the neck and deep glands. CK20 showed diffuse strong reactivity on the surface. On the other hand, patients with complete IM showed a CK7 staining pattern that was either negative or weakly focal on the surface and crypts associated with diffuse surface CK20 and focal crypt staining corresponding to gastric type IM. The Ki67 proliferating index was low (≤ 15%) in H. pylori infected patients, high (> 30%) in patients with incomplete IM, and intermediate (16-30%) in patients with complete IM. CONCLUSIONS: These results indicate a significant link between the expressions of CK7/CK20 and Ki67 in patients afflicted with H. pylori and IM.

Asunto(s)

Gastritis , Infecciones por Helicobacter , Helicobacter pylori , Queratina-20 , Queratina-7 , Antígeno Ki-67 , Metaplasia , Adulto , Anciano , Femenino , Humanos , Masculino , Persona de Mediana Edad , Biopsia , Mucosa Gástrica/patología , Mucosa Gástrica/microbiología , Mucosa Gástrica/metabolismo , Gastritis/microbiología , Gastritis/patología , Infecciones por Helicobacter/patología , Infecciones por Helicobacter/microbiología , Inmunohistoquímica , Queratina-20/metabolismo , Queratina-7/metabolismo , Antígeno Ki-67/metabolismo , Metaplasia/patología , Metaplasia/microbiología , Estudios Retrospectivos

RESUMEN

Glucocorticoids are steroid hormones well known for their potent anti-inflammatory effects. However, their immunomodulatory properties are multifaceted. Increasing evidence suggests that glucocorticoid signaling promotes effective immunity and that disruption of glucocorticoid signaling impairs immune function. In this study, we conditionally deleted the glucocorticoid receptor (GR) in the myeloid lineage using the LysM-Cre driver (myGRKO). We examined the impact on macrophage activation and gastric immune responses to Helicobacter pylori, the best-known risk factor of gastric cancer. Our results indicate that, compared with wild type (WT), glucocorticoid receptor knockout (GRKO) macrophages exhibited higher expression of proinflammatory genes in steroid-free conditions. However, when challenged in vivo, GRKO macrophages exhibited aberrant chromatin landscapes and impaired proinflammatory gene expression profiles. Moreover, gastric colonization with H. pylori revealed impaired gastric immune responses and reduced T cell recruitment in myGRKO mice. As a result, myGRKO mice were protected from atrophic gastritis and pyloric metaplasia development. These results demonstrate a dual role for glucocorticoid signaling in preparing macrophages to respond to bacterial infection but limiting their pathogenic activation. In addition, our results support that macrophages are critical for gastric H. pylori immunity.NEW & NOTEWORTHY Signaling by endogenous glucocorticoids primes macrophages toward more robust responses to pathogens. Disruption of glucocorticoid signaling caused dysregulation of the chromatin landscape, blunted proinflammatory gene activation upon bacterial challenge, and impaired the gastric inflammatory response to Helicobacter pylori infection.

Asunto(s)

Glucocorticoides , Infecciones por Helicobacter , Helicobacter pylori , Activación de Macrófagos , Macrófagos , Ratones Noqueados , Receptores de Glucocorticoides , Animales , Infecciones por Helicobacter/inmunología , Infecciones por Helicobacter/metabolismo , Infecciones por Helicobacter/microbiología , Receptores de Glucocorticoides/metabolismo , Receptores de Glucocorticoides/genética , Macrófagos/inmunología , Macrófagos/metabolismo , Ratones , Glucocorticoides/farmacología , Mucosa Gástrica/metabolismo , Mucosa Gástrica/inmunología , Mucosa Gástrica/microbiología , Transducción de Señal

RESUMEN

BACKGROUND: Chronic gastritis caused by Helicobacter pylori (Hp) infection is a common gastrointestinal disorder. Despite the high prevalence of Hp infection and chronic gastritis in the Tibetan Plateau, there is a lack of studies elucidating the influence of plateau hypoxia on Hp-induced gastritis. This study aimed to investigate the impact of high-altitude hypoxia on Hp-induced gastritis, particularly focusing on pathological manifestations and inflammatory responses. METHODS: This study was conducted from July 2023 to March 2024 at the Department of Gastroenterology, Affiliated Hospital of Qinghai University. Ninety patients diagnosed with chronic gastritis were enrolled in the study and divided into four groups based on their residential altitude and Hp infection status. Data on endoscopic and pathological characteristics were collected, along with serum oxidative stress and inflammatory markers. RESULTS: Patients with Hp gastritis exhibit distinctive features in the gastric mucosa, including diffuse erythema, enlarged folds, and white turbid mucus during endoscopy. Notably, individuals with Hp gastritis at high altitudes show a higher prevalence of diffuse erythema and enlarged folds. Pathological analysis reveals that these patients have elevated gastric mucosal inflammation scores and increased chronic and active inflammation. Furthermore, individuals with Hp gastritis at high altitudes demonstrate elevated levels of serum TNF-α, IL-1ß, IL-6, and MDA, as well as reduced serum SOD and GSH-Px activities. CONCLUSIONS: High-altitude hypoxia may exacerbate gastric mucosal damage by enhancing oxidative stress and inflammatory response induced by Hp infection.

Asunto(s)

Altitud , Gastritis , Infecciones por Helicobacter , Helicobacter pylori , Estrés Oxidativo , Humanos , Gastritis/microbiología , Gastritis/patología , Masculino , Infecciones por Helicobacter/complicaciones , Infecciones por Helicobacter/patología , Femenino , Adulto , Persona de Mediana Edad , Hipoxia , Inflamación , Adulto Joven , Mucosa Gástrica/patología , Mucosa Gástrica/microbiología , Tibet/epidemiología

RESUMEN

BACKGROUND: Helicobacter pylori (H. pylori) infection is closely associated with gastrointestinal diseases. Our preliminary studies have indicated that H. pylori infection had a significant impact on the mucosal microbiome structure in patients with gastric ulcer (GU) or duodenal ulcer (DU). AIM: To investigate the contributions of H. pylori infection and the mucosal microbiome to the pathogenesis and progression of ulcerative diseases. METHODS: Patients with H. pylori infection and either GU or DU, and healthy individuals without H. pylori infection were included. Gastric or duodenal mucosal samples was obtained and subjected to metagenomic sequencing. The compositions of the microbial communities and their metabolic functions in the mucosal tissues were analyzed. RESULTS: Compared with that in the healthy individuals, the gastric mucosal microbiota in the H. pylori-positive patients with GU was dominated by H. pylori, with significantly reduced biodiversity. The intergroup differential functions, which were enriched in the H. pylori-positive GU patients, were all derived from H. pylori, particularly those concerning transfer RNA queuosine-modification and the synthesis of demethylmenaquinones or menaquinones. A significant enrichment of the uibE gene was detected in the synthesis pathway. There was no significant difference in microbial diversity between the H. pylori-positive DU patients and healthy controls. CONCLUSION: H. pylori infection significantly alters the gastric microbiota structure, diversity, and biological functions, which may be important contributing factors for GU.

Asunto(s)

Úlcera Duodenal , Mucosa Gástrica , Microbioma Gastrointestinal , Infecciones por Helicobacter , Helicobacter pylori , Úlcera Gástrica , Humanos , Infecciones por Helicobacter/microbiología , Helicobacter pylori/aislamiento & purificación , Helicobacter pylori/genética , Úlcera Duodenal/microbiología , Úlcera Duodenal/diagnóstico , Masculino , Femenino , Persona de Mediana Edad , Mucosa Gástrica/microbiología , Mucosa Gástrica/patología , Úlcera Gástrica/microbiología , Adulto , Estudios de Casos y Controles , Anciano , Metagenómica/métodos , Duodeno/microbiología , Disbiosis/microbiología