RESUMEN

BACKGROUND: Recent studies have suggested an association between H. pylori and metabolic-disfunction associated fatty liver disease (MASLD). However, epidemiologic studies have yielded inconsistent results. We aim to evaluate the association of H. pylori and G-allele PNPLA3 in MASLD diagnosis, and markers of severity. METHODS: A multi-center cross-sectional study was conducted. A total 224 functional dyspepsia (FD) patients cohort who underwent gastroscopy was selected. Biochemical, clinical parameters, ultrasound, FIB-4 score, LSM by VCTE, gastric biopsies, H. pylori status, and rs738409 PNPLA3 were evaluated. A second retrospective cohort of 86 patients with biopsy-proven MASLD who underwent gastroscopy with gastric biopsies was analyzed. RESULTS: In the FD cohort MASLD was observed in 52%, and H. pylori-positive in 51%. H. pylori infection was associated with MASLD prevalence, but in multivariate analyses adjusted for G-allele PNPLA3, it became not significant. Then in MASLD-only dyspeptic cohort, H. pylori infection was significantly linked to elevated serum AST levels and increased liver stiffness measurements, suggesting a potential role in liver injury and fibrosis. Histopathological analysis in biopsy-proven MASLD patients further supported these findings, showing a significant association between H. pylori infection and increased NAS score, fibrosis stage, and prevalence of MASH. Notably, the combination of H. pylori infection and G-allele PNPLA3 appeared to exacerbate MASLD severity beyond individual effects. CONCLUSIONS: Our results suggest that H. pylori infection may play a role in the progression of liver injury and fibrosis in patients with MASLD, especially in those with specific genetic predispositions.

Asunto(s)

Infecciones por Helicobacter , Helicobacter pylori , Lipasa , Proteínas de la Membrana , Humanos , Masculino , Femenino , Lipasa/genética , Proteínas de la Membrana/genética , Persona de Mediana Edad , Infecciones por Helicobacter/complicaciones , Infecciones por Helicobacter/genética , Adulto , Estudios Transversales , Estudios Retrospectivos , Hígado Graso/genética , Hígado Graso/complicaciones , Alelos , Polimorfismo de Nucleótido Simple , Dispepsia/microbiología , Dispepsia/genética , Dispepsia/complicaciones , Hígado/patología , Hígado/metabolismo , Aciltransferasas , Fosfolipasas A2 Calcio-Independiente

RESUMEN

BACKGROUND: A 100-bp insertion/deletion polymorphism in the pepsinogen C gene has been associated with the risk of gastric cancer (GC). OBJECTIVE: We analyzed the relationships of the 100-bp insertion/deletion polymorphism with GC, atrophic gastritis (AG), and intestinal metaplasia (IM) in the Mexican general population (MGP). METHODS: We studied the genomic DNA of subjects with GC n = 80, AG and IM n = 60, controls n = 110, and the MGP n = 97. PGC gene insertion/deletion polymorphism was identified by means of PCR, capillary electrophoresis and GeneScan software. RESULTS: Different allele sizes of PGC polymorphism were observed in the studied groups, from 266 bp to 499 bp, which were grouped for the analysis as short alleles of 266-399 bp, medium alleles of 400-433 bp and large alleles of 434-499 bp. Carriers of one or two medium alleles, had an increased risk of GC, with OR of 1.99 (CI95% 1.08-3.67 p = 0.026) compared to homozygotes (no medium/no medium). CONCLUSIONS: Previous studies have related PGC short alleles to risk for or protection against GC depending on the ethnic origin of the population. In our study, medium alleles were related to risk for GC. Further studies are required to establish the importance of this polymorphism in the origin of gastric neoplasia.

Asunto(s)

Gastritis Atrófica , Pepsinógeno C , Neoplasias Gástricas , Humanos , Alelos , Gastritis Atrófica/genética , Gastritis Atrófica/complicaciones , Infecciones por Helicobacter/complicaciones , Infecciones por Helicobacter/genética , Polimorfismo Genético/genética , Factores de Riesgo , Neoplasias Gástricas/genética , Pepsinógeno C/genética

RESUMEN

Helicobacter pylori is a kind of Gram-negative bacteria that parasitizes on human gastric mucosa. Helicobacter pylori infection is very common in human beings, which often causes gastrointestinal diseases, including chronic gastritis, duodenal ulcer and gastric cancer. MicroRNAs are a group of endogenous non-coding single stranded RNAs, which play an important role in cell proliferation, differentiation, autophagy, apoptosis and inflammation. In recent years, relevant studies have found that the expression of microRNA is changed after Helicobacter pylori infection, and then regulate the biological process of host cells. This paper reviews the regulation role of microRNAs on cell biological behavior through different signal pathways after Helicobacter pylori infection.

Asunto(s)

Infecciones por Helicobacter , Helicobacter pylori , MicroARNs , Humanos , MicroARNs/genética , MicroARNs/metabolismo , Helicobacter pylori/genética , Helicobacter pylori/metabolismo , Infecciones por Helicobacter/genética , Infecciones por Helicobacter/microbiología , Inflamación , Transducción de Señal , Mucosa Gástrica/metabolismo

RESUMEN

BACKGROUND: The association between H. pylori infection and coronary artery disease (CAD) is well-known. Alterations in DNA methylation in CAD have been reported, which can be induced by H. pylori through the DNA demethylases (DNMTs). The objective was to analyze the association and interaction of H. pylori infection and DMNT3a gene polymorphisms with premature CAD (pCAD) and subclinical atherosclerosis (SA). METHODS: The study included 561 patients with pCAD, 318 subjects with SA, and 599 healthy controls. Antibodies against H. pylori and DNMT3a rs13420827, rs752208, and rs1550117 polymorphisms were determined. RESULTS: The pCAD group presented the highest seroprevalence of H. pylori infection (87.7%) compared to the SA (74.5%, p = 1 × 10-6) and the control group (63.1%, p = 7 × 10-23). A significant association was observed between H. pylori infection and pCAD (OR = 2.729, p = 1.0 × 10-6). The rs13420827 polymorphism was associated with a high risk of H. pylori infection in the whole population (padditive = 0.009, pdominant = 0.018, and pcodominant2 = 0.013) and in individuals with SA (padditive = 0.003, pdominant = 0.020, precessive = 0.013, and pcodominant2 = 0.005). The coexistence of H. pylori infection and the rs13420827GG genotype increases the risk of pCAD (pinteraction = 1.1 × 10-5). CONCLUSIONS: According to the model adjusted for more confounding variables, H. pylori infection was associated with almost three times the risk of developing pCAD. The rs13420827G allele was associated with an increased risk of H. pylori infection in the whole population and in individuals with SA. Individuals in whom H. pylori infection and the rs13420827GG genotype coexist are at increased risk of pCAD.

Asunto(s)

Aterosclerosis , Enfermedad de la Arteria Coronaria , ADN Metiltransferasa 3A/genética , Infecciones por Helicobacter , Helicobacter pylori , Aterosclerosis/epidemiología , Aterosclerosis/genética , Enfermedad de la Arteria Coronaria/epidemiología , Enfermedad de la Arteria Coronaria/genética , Predisposición Genética a la Enfermedad , Infecciones por Helicobacter/complicaciones , Infecciones por Helicobacter/epidemiología , Infecciones por Helicobacter/genética , Helicobacter pylori/genética , Humanos , Polimorfismo de Nucleótido Simple , Factores de Riesgo , Estudios Seroepidemiológicos

RESUMEN

OBJECTIVE: The objective of the present study was to estimate the frequency of CYP2C19 cytochrome variants *1, *2, *3 and *17 among Helicobacter pylori carriers from Manaus, Amazonas state, who were treated at Fundação de Medicina Tropical Dr. Heitor Vieira Dourado (FMT-HVD). METHODS: From the 78 recruited individuals who underwent upper gastrointestinal endoscopy with biopsy and histopathological test, 50 tested positive for H. pylori. Peripheral blood was collected from this group and CYP2C19 *2, *3 and *17 alleles were genotyped using qPCR. RESULTS: Of the 50 H. pylori + individuals, 22 were male and 28 were female. Their age varied from 18 to 67 years old, with the mean age being 40.24. Racial groups were classified by self-declaration, based on the official Instituto Brasileiro de Geografia e Estatística (IBGE) categories: 16% (8) were white, 78% (39) were brown, 4% (2) were black, and 2% (1) were indigenous. H. pylori infection was classified using the system of crosses, with 30% (15) of infections being classified as mild (+), 30% (15) as moderate (++), and 40% (20) as severe (+++). The CYP2C19 genotype results showed an allelic frequency of 11% for *2 (20% of the subjects), 6% for *3 (10% of the subjects) and 17% for *17 (30% of the subjects). Based on the phenotypic profiles, the individuals were classified as poor metabolizers (PM, 10%), intermediate metabolizers (IM, 2%), extensive metabolizers (EM, 58%) and ultra-rapid metabolizers (UM, 20%). CONCLUSIONS: Even though the percentage of allele *3 was higher than expected, the percentage of allele *17, a possible contributor to H. pylori eradication failure, was also significant. The population that self-declared as brown showed a unique genotypic pattern, unlike any other population described in previous studies. Our results show that small populations may have genetic particularities that are relevant to therapeutic outcomes.
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Asunto(s)

Citocromo P-450 CYP2C19/genética , Infecciones por Helicobacter/genética , Adolescente , Adulto , Anciano , Alelos , Biopsia , Brasil , Femenino , Gastroscopía , Variación Genética , Genotipo , Infecciones por Helicobacter/tratamiento farmacológico , Helicobacter pylori , Humanos , Masculino , Persona de Mediana Edad , Inhibidores de la Bomba de Protones/uso terapéutico

RESUMEN

Helicobacter pylori (H. pylori) induces an intense inflammatory response, mediated by proinflammatory cytokines, including interleukin (IL)-6 and its membrane receptor (IL-6R), which activates important signaling pathways in the development of gastric disease and cancer. We investigated the gene and protein expression of IL-6 and IL-6R and the influence of polymorphisms rs1800795, rs1800796, and rs1800797 on its gene expression together with H. pylori infection. Furthermore, an in-silico analysis was performed to support our results. Gastric biopsies were obtained from patients with gastric symptoms and patients with gastric cancer (GC) and were divided into groups (Control, Gastritis, and Cancer). H. pylori was detected by PCR. Real-time-qPCR was employed to determine gene expression, and western blot assay was used to analyze protein expression levels. PCR-RFLP was used to characterize IL-6 polymorphisms. Bioinformatics analyses were performed using the Gene Expression Omnibus (GEO) database and GEO2R to screen out differentially expressed genes (DEGs). H. pylori was detected in 43.3% of the samples. Statistically significant differences were found for IL-6 (P=0.0001) and IL-6R (P=0.0005) genes among the three groups, regardless of the presence of H. pylori. Among patients with H. pylori infection, the IL-6 and IL-6R gene and protein expressions were significantly increased, highlighting IL-6 gene overexpression in patients with GC. No statistically significant differences were found for the rs1800795, rs1800796, and rs1800797 polymorphisms compared to IL-6 gene expression. The results indicated that the IL-6 polymorphisms do not influence its expression, but IL-6 and IL-6R expression seems to be altered by the presence of H. pylori.

Asunto(s)

Gastritis , Infecciones por Helicobacter , Helicobacter pylori , Interleucina-6/genética , Neoplasias Gástricas , Mucosa Gástrica , Gastritis/genética , Infecciones por Helicobacter/genética , Humanos , Interleucina-8 , Neoplasias Gástricas/genética

RESUMEN

BACKGROUND: Helicobacter pylori is detected by pathogen recognition receptors including toll-like receptors (TLR) and nucleotide-binding oligomerization domain (NOD)-like receptors, eliciting an innate immune response against this bacteria. The aim of this study was to assess if polymorphisms of TLR2, TLR4, TLR5, NOD1 and NOD2 genes are associated with gastric cancer, in particular in individuals infected with H. pylori. RESULTS: A case-control study of 297 gastric cancer patients and 300 controls was performed to assess the association of 17 polymorphisms. Analyses performed under the allele model did not find association with gastric cancer. However, NOD1 rs2075820 (p.E266K) showed association with intestinal-type gastric cancer among H. pylori infected subjects (OR = 2.69, 95% CI 1.41-5.13, p = 0.0026). The association was not statistically significant in diffuse-type gastric cancer cases (OR = 1.26, 95% CI 0.63-2.52, p = 0.51). When the analyses were performed in patients carrying H. pylori strains harboring the cag pathogenicity island (cagPAI), we noticed significant association with NOD1 rs2075820 (OR = 4.90, 95% CI 1.80-3.36, p = 0.0019), in particular for intestinal-type gastric cancer cases (OR = 7.16, 95% CI 2.40-21.33, p = 4.1 × 10- 4) but not among diffuse-type gastric cancer cases (OR = 3.39, 95% CI 1.13-0.10, p = 0.03). CONCLUSIONS: NOD1 rs2075820 increases the risk of intestinal-type gastric cancer among individuals infected with H. pylori, particularly in those harboring the cagPAI.

Asunto(s)

Infecciones por Helicobacter , Proteína Adaptadora de Señalización NOD1/genética , Neoplasias Gástricas , Estudios de Casos y Controles , Islas Genómicas , Infecciones por Helicobacter/genética , Helicobacter pylori , Humanos , Neoplasias Gástricas/genética

RESUMEN

INTRODUCTION: Proton pump inhibitors (PPIs) are a group of drugs that are essential for the treatment of acid-related disorders, such as gastroesophageal reflux (GERD), dyspepsia, gastric ulcers and Helicobacter pylori (H. pylori) infection. PPIs such as omeprazole, esomeprazole, pantoprazole and lansoprazole are metabolized by the CYP2C19 enzyme, which is encoded by a polymorphic gene. Four polymorphisms have an impact on the speed of PPI metabolism: CYP2C19*1/*1 (extensive metabolizers), CYP2C19*2/*2 (intermediate metabolizers), CYP2C19*3/*3 (poor metabolizers) and CYP2C19*17/*17 (ultrarapid metabolizers). Extensive and ultrarapid metabolizers inactivate PPIs quickly, which consequently causes low plasma concentrations of PPIs, while intermediate or poor metabolizers have higher plasma concentrations of PPIs and, therefore, PPIs have greater therapeutic efficacy in individuals with these polymorphisms. OBJECTIVE: To determine the frequency of genetic polymorphisms of the CPY2C19 enzyme in Bogotá, Colombia. METHODS: This observational study was conducted in Bogotá between 2012 and 2015 and was part of a clinical trial (ID: NCT03650543). It included 239 subjects with dyspepsia, H. pylori infection, or GERD symptoms. CYP2C19 genotyping was performed on gastric biopsy samples. Polymorphisms *1, *2, and *3 were analyzed by real-time PCR (Roche®), and PCR-RFLP was used to determine the presence of polymorphism *17. RESULTS: The distribution of different types of PPI metabolizers was as follows: extensive (70.7%), ultrarapid (12.9%), intermediate (8.8%) and poor (0.8%). CONCLUSION: The population studied consisted mainly of extensive and ultrarapid PPI metabolizers. These findings show that it is necessary to increase PPI doses in this group of subjects or to use PPIs that are not metabolized by CYP2C19 (rabeprazole). This is the first Colombian work to identify ultrarapid metabolizers.

Asunto(s)

Citocromo P-450 CYP2C19/genética , Polimorfismo Genético , Adulto , Alelos , Colombia , Dispepsia/tratamiento farmacológico , Dispepsia/genética , Femenino , Reflujo Gastroesofágico/tratamiento farmacológico , Infecciones por Helicobacter/tratamiento farmacológico , Infecciones por Helicobacter/genética , Humanos , Masculino , Persona de Mediana Edad , Inhibidores de la Bomba de Protones/farmacología , Inhibidores de la Bomba de Protones/uso terapéutico , Úlcera Gástrica/tratamiento farmacológico , Úlcera Gástrica/genética

RESUMEN

PURPOSE: Analyze the expression of caspase-9, Smac/DIABLO, XIAP, let-7a, and let-7b in patients with normal gastric tissue, chronic gastritis, and gastric adenocarcinoma. METHODS: The expression of caspase-9, Smac/DIABLO, XIAP, let-7a, and let-7b by qRT-PCR was analyzed in 158 samples from 53 patients with normal gastric mucosa, 86 with chronic gastritis, and 19 with gastric cancer. RESULTS: The comparison between the gastric cancer and the control group revealed a decreased expression of caspase-9 in gastric cancer tissues; considering the Helicobacter pylor presence, comparable results were revealed. Smac/DIABLO was increased in gastric cancer cells, while XIAP demonstrated no significant difference in the gene expression. The microRNA analysis revealed a decreased expression of let-7a and let-7b in samples positive to H. pylori infection and in gastric cancer group, regardless of the presence of the bacterium. CONCLUSION: Our study provided some evidence of low activity of the intrinsic apoptosis pathway, as well as the influence of H. pylori on let-7a and let-7b expression.

Asunto(s)

Adenocarcinoma/genética , Apoptosis/genética , Biomarcadores de Tumor/genética , Carcinogénesis/genética , Neoplasias Gástricas/genética , Adenocarcinoma/patología , Adulto , Anciano , Proteínas Reguladoras de la Apoptosis/genética , Biopsia , Caspasa 9/genética , Femenino , Mucosa Gástrica/microbiología , Mucosa Gástrica/patología , Gastritis/genética , Gastritis/microbiología , Gastritis/patología , Perfilación de la Expresión Génica , Regulación Neoplásica de la Expresión Génica , Infecciones por Helicobacter/genética , Infecciones por Helicobacter/microbiología , Infecciones por Helicobacter/patología , Helicobacter pylori/aislamiento & purificación , Humanos , Masculino , MicroARNs/genética , Persona de Mediana Edad , Proteínas Mitocondriales/genética , Neoplasias Gástricas/microbiología , Neoplasias Gástricas/patología , Proteína Inhibidora de la Apoptosis Ligada a X/genética

RESUMEN

PURPOSE: The aim of this study was to evaluate the expression of miR-125a-5p in patients with dyspeptic symptoms and gastric cancer, correlating them with the development of this cancer and H. pylori. METHODS: Patients were divided in groups according to histopathological analysis (control, gastritis, and cancer groups). Polymerase chain reaction was performed to detect H. pylori and real-time quantitative PCR to determine miR-125a-5p expression. RESULTS: H. pylori was detected in 44% of the patients, with prevalence in the gastritis and cancer groups. A statistically significant decrease of miR-125a-5p expression was found in the control positive (p = 0.0183*), gastritis positive (p = 0.0380*), and cancer positive (p = 0.0288*) groups when compared with the control negative group. CONCLUSION: We suggest that decreased expression of the miRNA-125a-5p associated with the presence of the H. pylori is an important mechanism in gastric diseases and could be a possible marker for early diagnosis of gastric cancer.

Asunto(s)

Biomarcadores de Tumor/metabolismo , Gastritis/genética , Infecciones por Helicobacter/genética , MicroARNs/metabolismo , Neoplasias Gástricas/genética , Adulto , Anciano , Biomarcadores de Tumor/análisis , Brasil/epidemiología , Línea Celular Tumoral , Proliferación Celular , Detección Precoz del Cáncer/métodos , Femenino , Mucosa Gástrica/microbiología , Mucosa Gástrica/patología , Gastritis/microbiología , Gastritis/patología , Perfilación de la Expresión Génica , Predisposición Genética a la Enfermedad , Infecciones por Helicobacter/epidemiología , Infecciones por Helicobacter/microbiología , Infecciones por Helicobacter/patología , Helicobacter pylori/aislamiento & purificación , Humanos , Masculino , MicroARNs/análisis , Persona de Mediana Edad , Prevalencia , Neoplasias Gástricas/diagnóstico , Neoplasias Gástricas/microbiología , Neoplasias Gástricas/patología

RESUMEN

Helicobacter pylori (H. pylori) induces an intense inflammatory response, mediated by proinflammatory cytokines, including interleukin (IL)-6 and its membrane receptor (IL-6R), which activates important signaling pathways in the development of gastric disease and cancer. We investigated the gene and protein expression of IL-6 and IL-6R and the influence of polymorphisms rs1800795, rs1800796, and rs1800797 on its gene expression together with H. pylori infection. Furthermore, an in-silico analysis was performed to support our results. Gastric biopsies were obtained from patients with gastric symptoms and patients with gastric cancer (GC) and were divided into groups (Control, Gastritis, and Cancer). H. pylori was detected by PCR. Real-time-qPCR was employed to determine gene expression, and western blot assay was used to analyze protein expression levels. PCR-RFLP was used to characterize IL-6 polymorphisms. Bioinformatics analyses were performed using the Gene Expression Omnibus (GEO) database and GEO2R to screen out differentially expressed genes (DEGs). H. pylori was detected in 43.3% of the samples. Statistically significant differences were found for IL-6 (P=0.0001) and IL-6R (P=0.0005) genes among the three groups, regardless of the presence of H. pylori. Among patients with H. pylori infection, the IL-6 and IL-6R gene and protein expressions were significantly increased, highlighting IL-6 gene overexpression in patients with GC. No statistically significant differences were found for the rs1800795, rs1800796, and rs1800797 polymorphisms compared to IL-6 gene expression. The results indicated that the IL-6 polymorphisms do not influence its expression, but IL-6 and IL-6R expression seems to be altered by the presence of H. pylori.

Asunto(s)

Humanos , Neoplasias Gástricas/genética , Helicobacter pylori , Infecciones por Helicobacter/genética , Interleucina-6/genética , Gastritis/genética , Interleucina-8 , Mucosa Gástrica

RESUMEN

BACKGROUND: Helicobacter pylori is detected by pathogen recognition receptors including toll-like receptors (TLR) and nucleotide-binding oligomerization domain (NOD)-like receptors, eliciting an innate immune response against this bacteria. The aim of this study was to assess if polymorphisms of TLR2, TLR4, TLR5, NOD1 and NOD2 genes are associated with gastric cancer, in particular in individuals infected with H. pylori. RESULTS: A case-control study of 297 gastric cancer patients and 300 controls was performed to assess the association of 17 polymorphisms. Analyses performed under the allele model did not find association with gastric cancer. However, NOD1 rs2075820 (p.E266K) showed association with intestinal-type gastric cancer among H. pylori infected subjects (OR = 2.69, 95% CI 1.41-5.13, p = 0.0026). The association was not statistically significant in diffuse-type gastric cancer cases (OR = 1.26, 95% CI 0.63-2.52, p = 0.51). When the analyses were performed in patients carrying H. pylori strains harboring the cag pathogenicity island (cagPAI), we noticed significant association with NOD1 rs2075820 (OR = 4.90, 95% CI 1.80-3.36, p = 0.0019), in particular for intestinal-type gastric cancer cases (OR = 7.16, 95% CI 2.40-21.33, p = 4.1 × 10- 4) but not among diffuse-type gastric cancer cases (OR = 3.39, 95% CI 1.13-0.10, p = 0.03). CONCLUSIONS: NOD1 rs2075820 increases the risk of intestinal-type gastric cancer among individuals infected with H. pylori, particularly in those harboring the cagPAI.

Asunto(s)

Humanos , Neoplasias Gástricas/genética , Infecciones por Helicobacter/genética , Proteína Adaptadora de Señalización NOD1/genética , Estudios de Casos y Controles , Helicobacter pylori , Islas Genómicas

RESUMEN

Helicobacter pylori (H. pylori) is one of the main causes of gastric gancer. TNF-related apoptosis-inducing ligand (TRAIL) is a protein able to promote apoptosis in cancer cells, however not in gastric cancer, which presents resistance to apoptosis via TRAIL. It is believed that MicroRNA-106b-5p might be involved in this resistance, although its role in Gastric Cancer is unclear. We aimed to determine the expression of microRNA-106b-5p and TRAIL in patients with gastric diseases, infected by H. pylori, and understand the relationship between these genes and their role in apoptosis and the gastric cancer pathways. H. pylori was detected by PCR, gene expression analysis was performed by real-time-qPCR, and bioinformatics analysis was performed using the Kyoto Encyclopedia of Genes and Genomes (KEGG) and Cytoscape software. A total of 244 patients were divided into groups (Control, Gastritis, and Cancer); H. pylori was detected in 42.2% of the samples. The cancer group had a poor expression of TRAIL (p < 0.0001) and overexpression of microRNA-106b-5p (p=0.0005), however, our results confirmed that these genes are not directly related to each other although both are apoptosis-related regulators. Our results also indicated that H. pylori decreases microRNA-106b-5p expression and that this is a carcinogenic bacterium responsible for gastric diseases.

Asunto(s)

Infecciones por Helicobacter/genética , MicroARNs/genética , Neoplasias Gástricas/genética , Ligando Inductor de Apoptosis Relacionado con TNF/genética , Apoptosis/genética , Femenino , Gastritis/genética , Gastritis/microbiología , Gastritis/patología , Regulación Neoplásica de la Expresión Génica/genética , Infecciones por Helicobacter/microbiología , Infecciones por Helicobacter/patología , Helicobacter pylori/genética , Helicobacter pylori/patogenicidad , Humanos , Masculino , Persona de Mediana Edad , Transducción de Señal/genética , Neoplasias Gástricas/microbiología , Neoplasias Gástricas/patología

RESUMEN

The present study aimed to evaluate the influence of the IL1B -31C/T polymorphism on gastric inflammatory response and precancerous lesions development - atrophic gastritis (AG) and intestinal metaplasia (IM) - in patients positive for Helicobacter pylori infection with functional dyspepsia (FD). The diagnosis of FD followed the Rome III criteria, and the H. pylori infection was evaluated by urease test and histological examination of gastric biopsies (corpus, antrum, and incisura). The severity of chronic inflammation and inflammatory activity, as well as the presence of precancerous lesions were evaluated accordingly to the updated Sydney System. Genotyping of the IL1B -31C/T polymorphism (rs1143627) was performed by polymerase chain reaction-restriction fragment length polymorphism. A total of 303 patients positive for H. pylori infection with FD were analyzed (81.8% women; mean age of 46.3 ± 12.3 years). No differences were observed in overall genotype frequencies among outcomes evaluated. However, in the dominant -31C allele model (CC+CT vs. TT), the frequency of the TT genotype was significantly higher among patients with moderate/severe chronic inflammation of the antrum than the frequency of the CC+CT genotypes (80.8% vs. 65.2%; OR = 2.25; 95% CI = 1.23-4.24; P = .005). The presence of AG and IM in the gastric mucosa of patients was of 19.5% and 19.1%, respectively. No significant association was observed concerning the frequencies of the genotypes of IL1B -31C/T polymorphism with development of precancerous lesions. In conclusion, our data suggest that genetic variants of the IL1B -31C/T polymorphism play a role in chronic inflammation of the gastric mucosa in H. pylori-infected FD patients.

Asunto(s)

Dispepsia/genética , Gastritis/genética , Genotipo , Infecciones por Helicobacter/genética , Helicobacter pylori/fisiología , Inflamación/genética , Interleucina-1beta/genética , Adulto , Femenino , Frecuencia de los Genes , Estudios de Asociación Genética , Predisposición Genética a la Enfermedad , Infecciones por Helicobacter/inmunología , Humanos , Masculino , Persona de Mediana Edad , Polimorfismo de Nucleótido Simple , Lesiones Precancerosas

RESUMEN

BACKGROUND AND AIMS: Nodular gastropathy (NG) is an inflammatory condition of the gastric mucosa characterized by the endoscopic detection of multiple millimeter protrusions. A strong association between NG and Helicobacter pylori and a possible role of NG as a risk factor for undifferentiated gastric cancer have been described. The aim of this study was to characterize the pathogenic and inflammatory profile of patients with NG. METHODS: Adult patients referred for upper gastrointestinal endoscopy were prospectively enrolled in this study. H. pylori infection status was determined by rapid urease test. Biopsies were stained with hematoxylin-eosin. Sydney and OLGA scores were used to assess gastritis characteristics and gastric cancer risk. PCR analysis was performed to determine bacterial load and virulence factors CagA (and its EPIYA motifs) and VacA alleles. Finally, gastric mucosa cytokine gene expression (IL-8, IL-1ß, and TNF-α) was determined by real-time RT-PCR. RESULTS: Forty-eight patients, mean age of 36 years, were recruited. All NG patients were infected by H. pylori. OLGA score was similar in both groups (NG patients and non-NG patients). NG patients had higher bacterial load in the gastric corpus (p = 0.01) and significantly less pro-inflammatory cytokine levels than non-NG infected patients (p = 0.01). CONCLUSIONS: In our study, NG is not associated with preneoplastic lesions. An increase in bacterial load without a concomitant increase in mucosal inflammatory cytokine responses in H. pylori-infected subjects with NG may represent a general dampening of immune responses or an additional mechanism of H. pylori active immune evasion.

Asunto(s)

Carga Bacteriana , Citocinas/genética , Mucosa Gástrica/microbiología , Gastritis/microbiología , Infecciones por Helicobacter/microbiología , Adulto , Antígenos Bacterianos , Proteínas Bacterianas , Estudios de Casos y Controles , Citocinas/metabolismo , Endoscopía del Sistema Digestivo , Endosonografía , Femenino , Mucosa Gástrica/metabolismo , Mucosa Gástrica/patología , Gastritis/genética , Gastritis/metabolismo , Gastritis/patología , Infecciones por Helicobacter/genética , Infecciones por Helicobacter/metabolismo , Infecciones por Helicobacter/patología , Helicobacter pylori/genética , Helicobacter pylori/patogenicidad , Humanos , Interleucina-1beta/genética , Interleucina-1beta/metabolismo , Interleucina-8/genética , Interleucina-8/metabolismo , Masculino , Persona de Mediana Edad , Imagen de Banda Estrecha , ARN Mensajero/metabolismo , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Factor de Necrosis Tumoral alfa/genética , Factor de Necrosis Tumoral alfa/metabolismo , Adulto Joven

RESUMEN

BACKGROUND & AIMS: Gastric carcinoma is related mostly to CagA+-Helicobacter pylori infection, which disrupts the gastric mucosa turnover and elicits an epithelial-mesenchymal transition (EMT) and preneoplastic transdifferentiation. The tumor suppressor Hippo pathway controls stem cell homeostasis; its core, constituted by the large tumor suppressor 2 (LATS2) kinase and its substrate Yes-associated protein 1 (YAP1), was investigated in this context. METHODS: Hippo, EMT, and intestinal metaplasia marker expression were investigated by transcriptomic and immunostaining analyses in human gastric AGS and MKN74 and nongastric immortalized RPE1 and HMLE epithelial cell lines challenged by H pylori, and on gastric tissues of infected patients and mice. LATS2 and YAP1 were silenced using small interfering RNAs. A transcriptional enhanced associated domain (TEAD) reporter assay was used. Cell proliferation and invasion were evaluated. RESULTS: LATS2 and YAP1 appear co-overexpressed in the infected mucosa, especially in gastritis and intestinal metaplasia. H pylori via CagA stimulates LATS2 and YAP1 in a coordinated biphasic pattern, characterized by an early transient YAP1 nuclear accumulation and stimulated YAP1/TEAD transcription, followed by nuclear LATS2 up-regulation leading to YAP1 phosphorylation and targeting for degradation. LATS2 and YAP1 reciprocally positively regulate each other's expression. Loss-of-function experiments showed that LATS2 restricts H pylori-induced EMT marker expression, invasion, and intestinal metaplasia, supporting a role of LATS2 in maintaining the epithelial phenotype of gastric cells and constraining H pylori-induced preneoplastic changes. CONCLUSIONS: H pylori infection engages a number of signaling cascades that alienate mucosa homeostasis, including the Hippo LATS2/YAP1/TEAD pathway. In the host-pathogen conflict, which generates an inflammatory environment and perturbations of the epithelial turnover and differentiation, Hippo signaling appears as a protective pathway, limiting the loss of gastric epithelial cell identity that precedes gastric carcinoma development.

Asunto(s)

Transición Epitelial-Mesenquimal/inmunología , Mucosa Gástrica/patología , Infecciones por Helicobacter/patología , Lesiones Precancerosas/patología , Proteínas Serina-Treonina Quinasas/metabolismo , Proteínas Supresoras de Tumor/metabolismo , Proteínas Adaptadoras Transductoras de Señales/metabolismo , Adenocarcinoma/genética , Adenocarcinoma/inmunología , Adenocarcinoma/patología , Anciano , Anciano de 80 o más Años , Animales , Proteínas de Ciclo Celular/metabolismo , Femenino , Mucosa Gástrica/microbiología , Regulación Neoplásica de la Expresión Génica/inmunología , Infecciones por Helicobacter/genética , Infecciones por Helicobacter/microbiología , Helicobacter pylori/patogenicidad , Interacciones Huésped-Patógeno/genética , Humanos , Masculino , Metaplasia/genética , Metaplasia/microbiología , Metaplasia/patología , Ratones , Lesiones Precancerosas/genética , Lesiones Precancerosas/inmunología , Factores Protectores , Proteínas Serina-Treonina Quinasas/genética , Transducción de Señal/genética , Transducción de Señal/inmunología , Neoplasias Gástricas/genética , Neoplasias Gástricas/inmunología , Neoplasias Gástricas/patología , Factores de Transcripción/metabolismo , Proteínas Supresoras de Tumor/genética , Proteínas Señalizadoras YAP

RESUMEN

BACKGROUND: IL-27 has dual roles in the immune response either stimulating Th1 or inhibiting Th17 cells. Because there is a particular link of IL-23/Th17 axis in the development of cancer and IL-27 has been considered a potential treatment for cancer, we evaluated the gastric and serum concentrations of IL-27 in two mutually exclusive Helicobacter pylori-associated diseases, gastric cancer (GC) and duodenal ulcer (DU). MATERIAL AND METHODS: We prospectively studied 110 H pylori-positive patients and 40 healthy blood donors. Serum and gastric concentrations of IL-27 and cytokines of the Th1/Th17 cells were assessed by ELISA. RESULTS: IL-27 was not detected in GC patients, but the cytokine concentration was very high in the patients with DU. IL-27 was also detected in the gastritis patients and in the H pylori-positive blood donors. IL27RA mRNA expression in peripheral blood mononuclear cells, evaluated by rt-PCR, was stimulated by H pylori strains. The cytokine concentration positively correlated with the Th1 and negatively with Th17 cell representative cytokine levels. Gastric IL-27 concentrations were positively correlated with increased degree of mononuclear and polymorphonuclear cells on the antral gastric mucosa of DU patients in consonance with the DU gastritis pattern. IL-12p70 and IFN-γ gastric concentrations were significantly higher in DU than in GC. Conversely, gastric concentrations of Th17 cell-associated cytokines (IL-1ß, IL-6, IL-17A, IL-23, and TGF-ß) were significantly higher in GC than in DU patients. CONCLUSION: Although H pylori infection is able to elicit IL-27 and IL-27Rα secretion, DU and GC have diametrically opposed cytokine patterns.

Asunto(s)

Infecciones por Helicobacter/genética , Helicobacter pylori/fisiología , Interleucina-27/genética , Adulto , Anciano , Anciano de 80 o más Años , Úlcera Duodenal/genética , Úlcera Duodenal/inmunología , Úlcera Duodenal/microbiología , Femenino , Infecciones por Helicobacter/inmunología , Infecciones por Helicobacter/microbiología , Helicobacter pylori/genética , Humanos , Interleucina-17/genética , Interleucina-17/inmunología , Interleucina-27/inmunología , Leucocitos Mononucleares/inmunología , Masculino , Persona de Mediana Edad , Estudios Prospectivos , Neoplasias Gástricas/genética , Neoplasias Gástricas/inmunología , Neoplasias Gástricas/microbiología , Células TH1/inmunología , Células Th17/inmunología , Adulto Joven

RESUMEN

BACKGROUND AND AIM: The relationship between race/ethnicity and H pylori infection has been extensively reported, with a higher prevalence of infection observed in black individuals. Whether such differences are due to genetic factors underlying African ancestry remains to be clarified. In the present study, we evaluated the association between the proportion of individual African ancestry and H pylori infection in a sample of 1046 children living in a large Latin American urban center. MATERIALS AND METHODS: Estimation of individual biogeographical ancestry was based on 370,539 SNPs and performed using the ADMIXTURE software. Multivariate logistic regression models and mediation analysis considering the influence of previously recognized socioenvironmental risk factors to H pylori infection were performed. All analyses were conducted using the statistical package STATA v.14.0. RESULTS: Each 10% increase in the proportion of individual African ancestry was positively and independently associated with H pylori infection in our population (adjusted OR = 1.22, 95% CI = 1.10-1.36, P < .001). Mediation analysis demonstrated that only 9.23% of the effect of the individual African ancestry on H pylori infection was explained by factors such as household income, the absence of street paving and crowding. CONCLUSIONS: The results suggest that genetic variants that covariate with African ancestry may explain an important part of the racial differences observed for the prevalence of H pylori infection.

Asunto(s)

Negro o Afroamericano/genética , Infecciones por Helicobacter/etnología , Infecciones por Helicobacter/genética , Negro o Afroamericano/estadística & datos numéricos , Anticuerpos Antibacterianos/sangre , Niño , Preescolar , Estudios de Cohortes , Femenino , Predisposición Genética a la Enfermedad , Infecciones por Helicobacter/epidemiología , Infecciones por Helicobacter/microbiología , Helicobacter pylori/inmunología , Helicobacter pylori/aislamiento & purificación , Helicobacter pylori/fisiología , Humanos , América Latina/epidemiología , América Latina/etnología , Masculino , Polimorfismo de Nucleótido Simple , Población Urbana/estadística & datos numéricos

RESUMEN

Because of its association with severe gastric pathologies, including gastric cancer, Helicobacter pylori has been subject of research for more than 30 years. Its capacity to adapt and survive in the human stomach can be attributed to its genetic flexibility. Its natural competence and its capacity to turn genes on and off allows H. pylori to adapt rapidly to the changing conditions of its host. Because of its genetic variability, it is difficult to establish the uniqueness of each strain obtained from a human host. The methods considered to-date to deliver the best result for differentiation of strains are Rapid Amplification of Polymorphic DNA (RAPD), Multilocus Sequence Typing (MLST) and Whole Genome Sequencing (WGS) analysis. While RAPD analysis is cost-effective, it requires a stable genome for its reliability. MLST and WGS are optimal for strain identification, however, they require analysis of data at the bioinformatics level. Using the StainFree method, which modifies tryptophan residues on proteins using 2, 2, 2, - trichloroethanol (TCE), we observed a strain specific pattern of tryptophan in 1D acrylamide gels. In order to establish the effectiveness of tryptophan fingerprinting for strain identification, we compared the graphic analysis of tryptophan-labelled bands in the gel images with MLST results. Based on this, we find that tryptophan banding patterns can be used as an alternative method for the differentiation of H. pylori strains. Furthermore, investigating the origin for these differences, we found that H. pylori strains alters the number and/or position of tryptophan present in several proteins at the genetic code level, with most exchanges taking place in membrane- and cation-binding proteins, which could be part of a novel response of H. pylori to host adaptation.

Asunto(s)

Helicobacter pylori/genética , Helicobacter pylori/metabolismo , Triptófano/metabolismo , ADN Bacteriano/genética , Etilenclorhidrina/análogos & derivados , Genoma Bacteriano/genética , Genotipo , Infecciones por Helicobacter/genética , Humanos , Tipificación de Secuencias Multilocus/métodos , Técnica del ADN Polimorfo Amplificado Aleatorio/métodos , Reproducibilidad de los Resultados , Análisis de Secuencia de ADN/métodos , Neoplasias Gástricas/genética

RESUMEN

The process of combating neoplasms and mononuclear cells, and during H. pylori infection, several pro-inflammatory and anti-inflammatory cytokines are synthesized. In view of the involvement of the IL-6 law and the presence of H. pylori in the development of gastric diseases, the present study aimed to characterize the promoter-region polymorphism -597 (G/A) (rs1800797), -572 (C/G) (rs1800796), and -174 (G/C) (rs1800795) by PCR-RFLP in 375 gastric biopsy specimens from patients with peptic symptoms. A total of 375 samples were analyzed: 87 patients (without lesion without gastric tissue); 236 patients with gastritis and 52 patients with gastric cancer analyzed the PCR-RFLP techniques. All the results were normalized in relation to the presence of H. pylori. The frequencies of the three polymorphisms were compared in the Control vs Gastritis groups and a statistically significant test observed: -174 (G/C) (OR: 1.27; 95% CI: 0.84-1.93; P = 0.26), 572 (C/G) (OR: 1.42; 95% CI: 0.78-2.59; P = 0.25), and 597 (G/A) (OR: 0.98; 95% CI, 0.64-1.52; P = 0.94). Similar results were obtained when the gastric cancer group was compared to the control group: -174 (G/C) (OR: 1.27; 95% CI: 0.66-2.47; P = 0.47), -572 (C/G) (OR: 1.07; 95% CI: 0.43-2.68; P = 0.88), and -597 (G/A) (OR: 1.01; 95% CI, 0.5-0.9; P = 0.99). The haplotypes were and were not observed statistically significant differences. In conclusion, we found no correlations between any of the three polymorphisms in the IL-6 gene analyzed in this study and a higher risk of gastritis or gastric cancer.

Asunto(s)

Predisposición Genética a la Enfermedad , Infecciones por Helicobacter/genética , Interleucina-6/genética , Neoplasias Gástricas/genética , Femenino , Estudios de Asociación Genética , Genotipo , Haplotipos/genética , Infecciones por Helicobacter/microbiología , Infecciones por Helicobacter/patología , Helicobacter pylori/patogenicidad , Humanos , Masculino , Polimorfismo de Nucleótido Simple/genética , Neoplasias Gástricas/microbiología , Neoplasias Gástricas/patología