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1.
Minerva Med ; 110(5): 464-470, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31368293

RESUMO

INTRODUCTION: Helicobacter pylori is a gram-negative bacterium that is colonized in the stomach. H. pylori infection can lead to a series of stomach diseases. However, the relationship between H. pylori infection and colorectal cancer is currently controversial. Therefore, we performed this meta-analysis to further understand the relationship between H. pylori infection and colorectal cancer. EVIDENCE ACQUISITION: We conducted a comprehensive retrieval from electronic databases, included the PubMed, Medline, China National Knowledge Infrastructure (CNKI), and China Wanfang Data Knowledge Service Platform databases (Wanfang Databases) through May 1st, 2018. We used the search terms H. pylori and colorectal cancer or colorectal carcinoma and collected all relevant studies to explore the association between H. pylori infection and colorectal cancer. EVIDENCE SYNTHESIS: Twenty-seven studies including 14357 cases were included. H. pylori infection was associated with an increased risk of colorectal cancer. A pooled odds ratio (OR) of 1.27 with a 95% CI of 1.17-1.37 (P<0.001) was calculated by using a fixed-effects model (I2=45.5%, P=0.006). The subgroup analysis revealed that H. pylori infection was associated with an increased risk of colorectal cancer in the subgroups of Western countries (OR=1.34, 95% CI: 1.14-1.57) (P<0.001), serological testing (OR=1.20, 95% CI: 1.08-1.34) (P=0.001), multiple methods of testing (OR=2.63, 95% CI: 1.09-6.31) (P=0.031), cross-sectional studies (OR=1.92, 95% CI: 1.17-3.16) (P=0.010) and case-control studies (OR 1.26, 95% CI: 1.16-1.36) (P<0.001). CONCLUSIONS: The present meta-analysis provides evidence suggests that a positive association between H. pylori infection and the risk of colorectal cancer.


Assuntos
Neoplasias Colorretais/etiologia , Gastrite/epidemiologia , Infecções por Helicobacter/complicações , Helicobacter pylori/patogenicidade , Neoplasias Colorretais/diagnóstico , Neoplasias Colorretais/epidemiologia , Neoplasias Colorretais/microbiologia , Comorbidade , Suscetibilidade a Doenças , Estudos Epidemiológicos , Gastrite/microbiologia , Infecções por Helicobacter/epidemiologia , Humanos , Razão de Chances , Viés de Publicação , Fatores de Risco , Sensibilidade e Especificidade
2.
Ann Hematol ; 98(8): 1981-1987, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31177299

RESUMO

Infection with Helicobacter pylori (H. pylori) is associated with an increased risk of gastric malignant lymphoma. The chronic inflammation of gastric mucosa by H. pylori infection induces lymphomagenesis. Although this chronic mucosal inflammation also results in atrophic gastritis, evidence supporting the possible significance of atrophic gastritis in gastric lymphomagenesis is scarce. Here, to evaluate the association between gastric mucosal atrophy and the risk of gastric lymphoma, we conducted a matched case-control study at Aichi Cancer Center focusing on the attribution of H. pylori infection status and pepsinogen (PG) serum levels. In total, 86 patients with gastric lymphoma (including 49 cases of extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue (MALT lymphoma) and 24 cases of diffuse large B cell lymphoma (DLBCL)) and 1720 non-cancer controls were included. Odds ratios (ORs) and 95% confidence intervals (CIs) were assessed by conditional logistic regression analysis with adjustment for potential confounders. Results failed to show a statistically significant association between atrophic gastritis and the risk of gastric lymphoma. The adjusted ORs of positive atrophic gastritis relative to negative for overall gastric lymphoma, MALT lymphoma, DLBCL, and other lymphomas were 0.77 (95% CI 0.45-1.33), 0.65 (0.30-1.39), 1.03 (0.38-2.79), and 0.84 (0.22-3.29), respectively. In contrast, a positive association between overall gastric lymphoma and H. pylori infection was observed (OR = 2.14, 95% CI 1.30-3.54). A consistent association was observed for MALT lymphoma, DLBCL, and other lymphomas with ORs of 1.96 (1.00-3.86), 1.92 (0.74-4.95), and 5.80 (1.12-30.12), respectively. These findings suggest that H. pylori infection triggers gastric lymphoma but that epithelial changes due to atrophic gastritis do not inherently affect the development of gastric lymphoma.


Assuntos
Infecções por Helicobacter/diagnóstico , Helicobacter pylori/patogenicidade , Linfoma de Zona Marginal Tipo Células B/diagnóstico , Linfoma Difuso de Grandes Células B/diagnóstico , Linfoma não Hodgkin/diagnóstico , Neoplasias Gástricas/diagnóstico , Adulto , Idoso , Carcinogênese/patologia , Estudos de Casos e Controles , Feminino , Mucosa Gástrica/microbiologia , Mucosa Gástrica/patologia , Gastrite Atrófica/complicações , Gastrite Atrófica/diagnóstico , Gastrite Atrófica/microbiologia , Gastrite Atrófica/patologia , Infecções por Helicobacter/complicações , Infecções por Helicobacter/microbiologia , Infecções por Helicobacter/patologia , Helicobacter pylori/fisiologia , Humanos , Japão , Modelos Logísticos , Linfoma de Zona Marginal Tipo Células B/etiologia , Linfoma de Zona Marginal Tipo Células B/microbiologia , Linfoma de Zona Marginal Tipo Células B/patologia , Linfoma Difuso de Grandes Células B/etiologia , Linfoma Difuso de Grandes Células B/microbiologia , Linfoma Difuso de Grandes Células B/patologia , Linfoma não Hodgkin/etiologia , Linfoma não Hodgkin/microbiologia , Linfoma não Hodgkin/patologia , Masculino , Pessoa de Meia-Idade , Razão de Chances , Pepsinogênio A/sangue , Fatores de Risco , Neoplasias Gástricas/etiologia , Neoplasias Gástricas/microbiologia , Neoplasias Gástricas/patologia
3.
Microbiol Immunol ; 63(6): 199-205, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31045263

RESUMO

Success in eradication of Helicobacter pylori is declining globally because H. pylori has developed resistance against most of the antibiotics proposed for eradication regimens, mainly through point mutations. The present study included 200 patients with dyspepsia attending Taif Hospital. Gastric biopsies were obtained during gastroscopy and subjected to rapid urease testing. Molecular methods were used to confirm diagnoses of H. pylori infection and to identify resistance gene variants of four antibiotics; namely, clarithromycin, metronidazole, fluoroquinolones and tetracycline (23S rRNA, gyrA, rdxA and 16S rRNA respectively). Of all investigated patients, Molecular diagnoses were made in 143 of all investigated patients; thus, the prevalence was .5%. The overall rate of resistance to clarithromycin among the H. pylori-positive patients was high (39.9%) and the rate of resistance significantly greater (48.2%) among the secondary resistance group, secondary resistance being defined as resistance as a result of previous exposure to the relevant antibiotic. The rate of resistance to fluoroquinolones was considered moderate; the difference in rate of resistance between the primary and secondary resistance groups (8.4% and 9.5%, respectively) was not significant Also, there was a low prevalence of both primary and the secondary tetracycline resistance in the study cohort. In contrast, the prevalence of metronidazole resistance was considered high with no significant difference between the two resistance groups. H. pylori showed an increased prevalence of resistance to all four of the commonly used therapeutic agents. Thus, eradication therapy should be based on the regional results of susceptibility testing. Moreover, treatment tailored according to individually determined H. pylori susceptibility may be a reasonable future goal.


Assuntos
Farmacorresistência Bacteriana Múltipla/genética , Infecções por Helicobacter/diagnóstico , Helicobacter pylori/genética , Helicobacter pylori/isolamento & purificação , Patologia Molecular , Adulto , Idoso , Antibacterianos/farmacologia , Proteínas de Bactérias/genética , Claritromicina/farmacologia , Estudos de Coortes , DNA Girase/genética , Farmacorresistência Bacteriana Múltipla/efeitos dos fármacos , Feminino , Fluoroquinolonas/farmacologia , Infecções por Helicobacter/epidemiologia , Helicobacter pylori/efeitos dos fármacos , Helicobacter pylori/patogenicidade , Humanos , Masculino , Metronidazol/farmacologia , Testes de Sensibilidade Microbiana , Pessoa de Meia-Idade , Epidemiologia Molecular , Nitrorredutases/genética , Prevalência , RNA Ribossômico 16S/genética , RNA Ribossômico 23S/genética , Arábia Saudita/epidemiologia , Tetraciclina/farmacologia , Adulto Jovem
4.
Nat Commun ; 10(1): 2273, 2019 05 22.
Artigo em Inglês | MEDLINE | ID: mdl-31118420

RESUMO

The human pathogen Helicobacter pylori displays extensive genetic diversity. While H. pylori is known to evolve during infection, population dynamics inside the gastric environment have not been extensively investigated. Here we obtained gastric biopsies from multiple stomach regions of 16 H. pylori-infected adults, and analyze the genomes of 10 H. pylori isolates from each biopsy. Phylogenetic analyses suggest location-specific evolution and bacterial migration between gastric regions. Migration is significantly more frequent between the corpus and the fundus than with the antrum, suggesting that physiological differences between antral and oxyntic mucosa contribute to spatial partitioning of H. pylori populations. Associations between H. pylori gene polymorphisms and stomach niches suggest that chemotaxis, regulatory functions and outer membrane proteins contribute to specific adaptation to the antral and oxyntic mucosa. Moreover, we show that antibiotics can induce severe population bottlenecks and likely play a role in shaping the population structure of H. pylori.


Assuntos
Adaptação Biológica/genética , Mucosa Gástrica/microbiologia , Infecções por Helicobacter/microbiologia , Helicobacter pylori/genética , Taxa de Mutação , Adulto , Idoso , Biópsia , Quimiotaxia/genética , Mucosa Gástrica/patologia , Genoma Bacteriano/genética , Infecções por Helicobacter/patologia , Helicobacter pylori/isolamento & purificação , Helicobacter pylori/patogenicidade , Humanos , Pessoa de Meia-Idade , Filogenia , Polimorfismo Genético
5.
BMC Complement Altern Med ; 19(1): 91, 2019 Apr 29.
Artigo em Inglês | MEDLINE | ID: mdl-31035975

RESUMO

BACKGROUND: The extract of Celastrus orbiculatus (COE) have been studied for anti-Helicobacter pylori (H. pylori) activity and anti-cancer effects in vitro and in vivo. However, the molecular mechanism by which COE inhibits H. pylori-induced inflammatory response has not been fully elucidated so far. METHODS: The effects of COE on viability, morphological changes, inflammatory cytokine secretion, protein and mRNA expression were analyzed by MTT assay, enzyme-linked immunosorbent assay (ELISA), immunofluorescence, western blot and real-time PCR (RT-PCR), respectively. The methylation level of programmed cell death 4 (PDCD4) promoter was investigated by methylation-specific PCR. (MSP) . RESULTS: COE effectively inhibited the H.pylori-induced inflammatory response by regulating epithelial-mesenchymal transition (EMT). The methylation level of PDCD4 promoter was suppressed by COE, which increased the expression ofPDCD4. Moreover, COE could inhibit microRNA-21 (miR-21) expression, as shown by an enhancement of its target gene PDCD4. Furthermore, both miR-21 over-expression and PDCD4 silencing attenuated the anti-inflammatory effect. of COE. CONCLUSIONS: COE inhibits H. pylori induced inflammatory response through regulating EMT, correlating with inhibition of miR-21/PDCD4 signal pathways in gastric epithelial cells.


Assuntos
Proteínas Reguladoras de Apoptose/metabolismo , Celastrus/química , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Helicobacter pylori , MicroRNAs/metabolismo , Extratos Vegetais/farmacologia , Proteínas de Ligação a RNA/metabolismo , Anti-Inflamatórios/farmacologia , Proteínas Reguladoras de Apoptose/genética , Linhagem Celular , Citocinas/análise , Citocinas/metabolismo , Células Epiteliais/citologia , Células Epiteliais/efeitos dos fármacos , Transição Epitelial-Mesenquimal/genética , Mucosa Gástrica/citologia , Mucosa Gástrica/efeitos dos fármacos , Mucosa Gástrica/microbiologia , Infecções por Helicobacter/imunologia , Infecções por Helicobacter/metabolismo , Infecções por Helicobacter/microbiologia , Helicobacter pylori/imunologia , Helicobacter pylori/patogenicidade , Humanos , MicroRNAs/genética , Proteínas de Ligação a RNA/genética , Transdução de Sinais/efeitos dos fármacos
6.
Curr Top Microbiol Immunol ; 421: 1-19, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31123883

RESUMO

It has been over 30 years since a link was established between H. pylori infection of the gastric mucosa and the development of chronic gastric diseases. Research in rodent models supported by data from human tissue demonstrated that the host immune response to H. pylori is limited by host regulatory T cells. Immunization has been shown to induce a potent Th1- and Th17-mediated immune response capable of eradicating or at least significantly reducing the bacterial load of H. pylori in the stomach in small animal models. These results have not translated well to humans. Clinical trials employing many of the strategies used in rodents for oral immunization including the use of a mucosal adjuvant such as Escherichia coli LT or delivery by attenuated enteric bacteria have failed to limit H. pylori infection and have highlighted the potential toxicity of exotoxin-based mucosal adjuvants. A recent study, however, utilizing a recombinant fusion protein of H. pylori urease and the subunit B of E. coli LT, was performed on over 4000 children. Efficacy of over 70% was demonstrated against naturally acquired infection compared to control volunteers one year post-immunization. Efficacy was reduced, but still above 50% at three years. This study provided new insight into the strategies for developing an improved vaccine for widespread use in countries with high infection rates and where gastric cancer (GC) remains one of the most common causes of death due to cancer.


Assuntos
Vacinas Bacterianas/imunologia , Mucosa Gástrica/microbiologia , Infecções por Helicobacter/imunologia , Infecções por Helicobacter/patologia , Helicobacter pylori/imunologia , Helicobacter pylori/patogenicidade , Animais , Anticorpos Antibacterianos/imunologia , Vacinas Bacterianas/química , Escherichia coli/imunologia , Mucosa Gástrica/imunologia , Mucosa Gástrica/patologia , Infecções por Helicobacter/microbiologia , Infecções por Helicobacter/prevenção & controle , Humanos , Inflamação/imunologia , Inflamação/microbiologia , Inflamação/patologia
7.
Curr Top Microbiol Immunol ; 421: 21-52, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31123884

RESUMO

Helicobacter pylori chronically infects nearly half the world's population, yet most of those infected remain asymptomatic throughout their lifetime. The outcome of infection-peptic ulcer disease or gastric cancer versus asymptomatic colonization-is a product of host genetics, environmental influences, and differences in bacterial virulence factors. Here, we review the current understanding of the cag pathogenicity island (cagPAI), the vacuolating cytotoxin (VacA), and a large family of outer membrane proteins (OMPs), which are among the best understood H. pylori virulence determinants that contribute to disease. Each of these virulence factors is characterized by allelic and phenotypic diversity that is apparent within and across individuals, as well as over time, and modulates inflammation. From the bacterial perspective, inflammation is probably a necessary evil because it promotes nutrient acquisition, but at the cost of reduction in bacterial load and therefore decreases the chance of transmission to a new host. The general picture that emerges is one of a chronic bacterial infection that is dependent on both inducing and carefully regulating the host inflammatory response. A better understanding of these regulatory mechanisms may have implications for the control of chronic inflammatory diseases that are increasingly common causes of human morbidity and mortality.


Assuntos
Infecções por Helicobacter/imunologia , Infecções por Helicobacter/patologia , Helicobacter pylori/imunologia , Helicobacter pylori/patogenicidade , Estômago/microbiologia , Estômago/patologia , Fatores de Virulência , Proteínas de Bactérias , Infecções por Helicobacter/microbiologia , Humanos , Úlcera Péptica/microbiologia , Úlcera Péptica/patologia , Neoplasias Gástricas/microbiologia , Neoplasias Gástricas/patologia
8.
Curr Top Microbiol Immunol ; 421: 53-76, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31123885

RESUMO

Helicobacter pylori infection is associated with the development of a chronic inflammatory response, which may induce peptic ulcers, gastric cancer (GC), and mucosa-associated lymphoid tissue (MALT) lymphoma. Chronic H. pylori infection promotes the genetic instability of gastric epithelial cells and interferes with the DNA repair systems in host cells. Colonization of the stomach with H. pylori is an important cause of non-cardia GC and gastric MALT lymphoma. The reduction of GC development in patients who underwent anti-H. pylori eradication schemes has also been well described. Individual susceptibility to GC development depends on the host's genetic predisposition, H. pylori virulence factors, environmental conditions, and geographical determinants. Biological determinants are urgently sought to predict the clinical course of infection in individuals with confirmed H. pylori infection. Possible candidates for such biomarkers include genetic aberrations such as single-nucleotide polymorphisms (SNPs) found in various cytokines/growth factors (e.g., IL-1ß, IL-2, IL-6, IL-8, IL-10, IL-13, IL-17A/B, IFN-γ, TNF, TGF-ß) and their receptors (IL-RN, TGFR), innate immunity receptors (TLR2, TLR4, CD14, NOD1, NOD2), enzymes involved in signal transduction cascades (PLCE1, PKLR, PRKAA1) as well as glycoproteins (MUC1, PSCA), and DNA repair enzymes (ERCC2, XRCC1, XRCC3). Bacterial determinants related to GC development include infection with CagA-positive (particularly with a high number of EPIYA-C phosphorylation motifs) and VacA-positive isolates (in particular s1/m1 allele strains). The combined genotyping of bacterial and host determinants suggests that the accumulation of polymorphisms favoring host and bacterial features increases the risk for precancerous and cancerous lesions in patients.


Assuntos
Predisposição Genética para Doença , Helicobacter pylori/genética , Helicobacter pylori/patogenicidade , Mediadores da Inflamação , Polimorfismo de Nucleotídeo Único , Neoplasias Gástricas/genética , Neoplasias Gástricas/patologia , Infecções por Helicobacter/genética , Infecções por Helicobacter/imunologia , Infecções por Helicobacter/microbiologia , Infecções por Helicobacter/patologia , Helicobacter pylori/imunologia , Humanos , Neoplasias Gástricas/imunologia , Neoplasias Gástricas/microbiologia , Fatores de Virulência
9.
Curr Top Microbiol Immunol ; 421: 77-106, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31123886

RESUMO

Mucosa-associated lymphoid tissue (MALT) lymphoma, or extranodal marginal zone lymphoma of MALT, is an indolent B-cell non-Hodgkin lymphoma linked with preexisting chronic inflammation. The stomach is the most commonly affected organ and the MALT lymphoma pathogenesis is clearly associated with Helicobacter pylori gastroduodenitis. Inflammation induces the lymphoid infiltrates in extranodal sites, where the lymphoma then subsequently develops. Genetic aberrations arise through the release of reactive oxygen species (ROS), H. pylori-induced endonucleases, and other effects. The involvement of nuclear factor kappa B (NF-κB) pathway activation, a critical regulator of pro-inflammatory responses, further highlights the role of inflammation in gastric MALT lymphoma. The NF-κB pathway regulates key elements of normal lymphocyte function, including the transcription of proliferation-promoting and anti-apoptotic genes. Aberrant constitutive activation of NF-κB signaling can lead to autoimmunity and malignancy. NF-κB pathway activation can happen through both the canonical and non-canonical pathways and can be caused by multiple genetic aberrations such as t(11;18)(q12;q21), t(1;14)(p22;q32), and t(14;18)(q32;q21) translocations, chronic inflammation and even directly by H. pylori-associated mechanisms. Gastric MALT lymphoma is considered one of the best models of how inflammation initiates genetic events that lead to oncogenesis, determines tumor biology, dictates clinical behavior and leads to viable therapeutic targets. The purpose of this review is to present gastric MALT lymphoma as an outstanding example of the close pathogenetic link between chronic inflammation and tumor development and to describe how this information can be integrated into daily clinical practice.


Assuntos
Inflamação/patologia , Linfoma de Zona Marginal Tipo Células B/patologia , Neoplasias Gástricas/patologia , Infecções por Helicobacter/microbiologia , Infecções por Helicobacter/patologia , Helicobacter pylori/patogenicidade , Humanos , Inflamação/tratamento farmacológico , Inflamação/imunologia , Linfoma de Zona Marginal Tipo Células B/tratamento farmacológico , Linfoma de Zona Marginal Tipo Células B/imunologia , Linfoma de Zona Marginal Tipo Células B/microbiologia , NF-kappa B/metabolismo , Neoplasias Gástricas/tratamento farmacológico , Neoplasias Gástricas/microbiologia
10.
Curr Top Microbiol Immunol ; 421: 107-137, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31123887

RESUMO

Over the last years, intensive investigations in molecular biology and cell physiology extended tremendously the knowledge about the association of inflammation and cancer. In frame of this paradigm, the human pathogen Helicobacter pylori triggers gastritis and gastric ulcer disease, and contributes to the development of gastric cancer. Mechanisms, by which the bacteria-induced inflammation in gastric mucosa leads to intestinal metaplasia and carcinoma, are represented in this review. An altered cell-signaling response and increased production of free radicals by epithelial and immune cells account for the accumulation of DNA damage in gastric mucosa, if infection stays untreated. Host genetics and environmental factors, especially diet, can accelerate the process, which offers the opportunity of intervention based on a balanced nutrition. It is supposed that inflammation might influence stem- or progenitor cells in gastric tissue predisposing for metaplasia or tumor relapse. Herein, DNA is strongly mutated and labile, which restricts therapy options. Thus, the understanding of the mechanisms that underlie gastric carcinogenesis will be of preeminent importance for the development of strategies for screening and early detection. As most gastric cancer patients face late-stage disease with a poor overall survival, the development of multi-targeted therapeutic intervention strategies is a major challenge for the future.


Assuntos
Carcinogênese , Dano ao DNA , Mucosa Gástrica/patologia , Inflamação/patologia , Neoplasias Gástricas/patologia , Mucosa Gástrica/microbiologia , Infecções por Helicobacter/genética , Infecções por Helicobacter/microbiologia , Infecções por Helicobacter/patologia , Helicobacter pylori/patogenicidade , Humanos , Inflamação/genética , Inflamação/microbiologia , Recidiva Local de Neoplasia , Neoplasias Gástricas/genética , Neoplasias Gástricas/microbiologia
11.
Curr Top Microbiol Immunol ; 421: 139-158, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31123888

RESUMO

Infectious diseases have been paramount among the threats to human health and survival throughout evolutionary history. Bacterial cell-surface molecules are key factors in the microorganism-host crosstalk, as they can interact with host pattern-recognition receptors (PRRs) of the gastrointestinal mucosa. The best-studied PRRs are toll-like receptors (TLRs). Because TLRs play an important key role in host defense, they have received increasing interest in the evolutionary and population genetics literature, and their variation represents a potential target of adaptive evolution. Helicobacter pylori is one of the commensal bacteria in our body and can have pathogenic properties in a subset of infected people. The history of H. pylori research indicated that humans and bacteria co-evolved during evolution. A genome-wide association study (GWAS) has opened the way for investigating the genomic evolution of bacterial pathogens during the colonization and infection of humans. Recent GWAS research emphasized the importance of TLRs, especially TLR10 during pathogenesis in H. pylori infection. We demonstrated that TLR10, whose ligand was unknown for a long time, can recognize H. pylori LPS. Our results of H. pylori research suggest that TLR10 might play an important role to also recognize other commensal bacteria. In this review, we discuss the importance of TLRs in pro-inflammatory and anti-inflammatory responses by H. pylori infection. Especially, we highlight the TLR10 interaction with H. pylori infection, providing new insights about TLR10 signaling.


Assuntos
Anti-Inflamatórios/imunologia , Infecções por Helicobacter/imunologia , Helicobacter pylori/imunologia , Helicobacter pylori/patogenicidade , Mediadores da Inflamação/imunologia , Receptores Toll-Like/imunologia , Evolução Molecular , Estudo de Associação Genômica Ampla , Infecções por Helicobacter/genética , Humanos , Receptores Toll-Like/genética
12.
Curr Top Microbiol Immunol ; 421: 209-227, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31123891

RESUMO

The ability of Helicobacter pylori to persist lifelong in the human gastric mucosa is a striking phenomenon. It is even more surprising since infection is typically associated with a vivid inflammatory response. Recent studies revealed the mechanism by which this pathogen inhibits the epithelial responses to IFN-γ and other central inflammatory cytokines in order to abolish an effective antimicrobial defense. The mechanism is based on the modification and depletion of cholesterol by the pathogen's cholesterol-α-glucosyltransferase. It abrogates the assembly of numerous cytokine receptors due to the reduction of lipid rafts. Particularly, the receptors for IFN-γ, IL-22, and IL-6 then fail to assemble properly and to activate JAK/STAT signaling. Consequently, cholesterol depletion prevents the release of antimicrobial peptides, including the highly effective ß-defensin-3. Intriguingly, the inhibition is spatially restricted to heavily infected cells, while the surrounding epithelium continues to respond normally to cytokine stimulation, thus providing a platform of the intense inflammation typically observed in H. pylori infections. It appears that pathogen and host establish a homeostatic balance between tightly colonized and rather inflamed sites. This homeostasis is influenced by the levels of available cholesterol, which potentially exacerbate H. pylori-induced inflammation. The observed blockage of epithelial effector mechanisms by H. pylori constitutes a convincing explanation for the previous failures of T-cell-based vaccination against H. pylori, since infected epithelial cells remain inert upon stimulation by effector cytokines. Moreover, the mechanism provides a rationale for the carcinogenic action of this pathogen in that persistent infection and chronic inflammation represent a pro-carcinogenic environment. Thus, cholesterol-α-glucosyltransferase has been revealed as a central pathogenesis determinant of H. pylori.


Assuntos
Colesterol/deficiência , Infecções por Helicobacter/sangue , Infecções por Helicobacter/microbiologia , Helicobacter pylori/patogenicidade , Colesterol/metabolismo , Células Epiteliais/microbiologia , Mucosa Gástrica/microbiologia , Glucosiltransferases/metabolismo , Infecções por Helicobacter/metabolismo , Helicobacter pylori/enzimologia , Humanos
13.
Curr Top Microbiol Immunol ; 421: 267-302, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31123893

RESUMO

Inflammasome-controlled transcription and subsequent cleavage-mediated activation of mature IL-1ß and IL-18 cytokines exemplify a crucial innate immune mechanism to combat intruding pathogens. Helicobacter pylori represents a predominant persistent infection in humans, affecting approximately half of the population worldwide, and is associated with the development of chronic gastritis, peptic ulcer disease, and gastric cancer. Studies in knockout mice have demonstrated that the pro-inflammatory cytokine IL-1ß plays a central role in gastric tumorigenesis. Infection by H. pylori was recently reported to stimulate the inflammasome both in cells of the mouse and human immune systems. Using mouse models and in vitro cultured cell systems, the bacterial pathogenicity factors and molecular mechanisms of inflammasome activation have been analyzed. On the one hand, it appears that H. pylori-stimulated IL-1ß production is triggered by engagement of the immune receptors TLR2 and NLRP3, and caspase-1. On the other hand, microRNA hsa-miR-223-3p is induced by the bacteria, which controls the expression of NLRP3. This regulating effect by H. pylori on microRNA expression was also described for more than 60 additionally identified microRNAs, indicating a prominent role for inflammatory and other responses. Besides TLR2, TLR9 becomes activated by H. pylori DNA and further TLR10 stimulated by the bacteria induce the secretion of IL-8 and TNF, respectively. Interestingly, TLR-dependent pathways can accelerate both pro- and anti-inflammatory responses during H. pylori infection. Balancing from a pro-inflammation to anti-inflammation phenotype results in a reduction in immune attack, allowing H. pylori to persistently colonize and to survive in the gastric niche. In this chapter, we will pinpoint the role of H. pylori in TLR- and NLRP3 inflammasome-dependent signaling together with the differential functions of pro- and anti-inflammatory cytokines. Moreover, the impact of microRNAs on H. pylori-host interaction will be discussed, and its role in resolution of infection versus chronic infection, as well as in gastric disease development.


Assuntos
Infecções por Helicobacter/genética , Infecções por Helicobacter/imunologia , Helicobacter pylori/imunologia , Inflamassomos/metabolismo , Inflamação/microbiologia , MicroRNAs/biossíntese , Animais , Caspase 1/metabolismo , Infecções por Helicobacter/microbiologia , Helicobacter pylori/patogenicidade , Humanos , Camundongos , Proteína 3 que Contém Domínio de Pirina da Família NLR/imunologia , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Receptor 2 Toll-Like/imunologia , Receptor 2 Toll-Like/metabolismo
14.
Curr Top Microbiol Immunol ; 421: 303-318, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31123894

RESUMO

Microbes within the gastrointestinal tract communicate with each other and with the host, which has profound effects on health and disease development. Only now, it is becoming apparent that how and when we acquire our own unique collection of "gut microbes" and also how we choose to maintain them is fundamental to our health. Helicobacter pylori is the most common bacterial infection worldwide, colonizing around half of the world's population, and is the major risk factor for gastric adenocarcinoma. More recently, it has also been shown to have some beneficial effects in terms of protecting against the development of other diseases. Here, we review the current knowledge on how H. pylori has shaped gastrointestinal microbiota colonization and the host immune system with specific focus on the impact of H. pylori on the various microbiome niches of the gastrointestinal tract. We discuss how the presence of H. pylori influences the physiology of three major regions within the gastrointestinal tract-specifically the oesophagus, stomach and colon. We pay particular attention to the role of H. pylori under chronic inflammatory conditions including the development of cancer. With increased incidence of diseases such as eosinophilic oesophagitis, oesophageal adenocarcinoma and squamous cell carcinoma being attributed to the decline in H. pylori, their disease pathogenesis in light of changing H. pylori colonization is also discussed.


Assuntos
Microbioma Gastrointestinal/imunologia , Microbioma Gastrointestinal/fisiologia , Infecções por Helicobacter/imunologia , Infecções por Helicobacter/microbiologia , Helicobacter pylori/imunologia , Helicobacter pylori/patogenicidade , Sistema Imunitário/imunologia , Sistema Imunitário/microbiologia , Colo/imunologia , Colo/microbiologia , Esôfago/imunologia , Esôfago/microbiologia , Helicobacter pylori/fisiologia , Humanos , Estômago/imunologia , Estômago/microbiologia
15.
Curr Top Microbiol Immunol ; 421: 319-359, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31123895

RESUMO

The connection between inflammation and cancer was initially recognized by Rudolf Virchow in the nineteenth century. During the last decades, a large body of evidence has provided support to his hypothesis, and now inflammation is recognized as one of the hallmarks of cancer, both in etiopathogenesis and ongoing tumor growth. Infection with the pathogen Helicobacter pylori is the primary causal factor in 90% of gastric cancer (GC) cases. As we increase our understanding of how chronic inflammation develops in the stomach and contributes to carcinogenesis, there is increasing interest in targeting cancer-promoting inflammation as a strategy to treat GC. Moreover, once cancer develops and anti-cancer immune responses are suppressed, there is evidence of a substantial shift in the microenvironment and new targets for immune therapy emerge. In this chapter, we provide insight into inflammation-related factors, including T lymphocytes, macrophages, pro-inflammatory chemokines, and cytokines, which promote H. pylori-associated GC initiation and growth. While intervening with chronic inflammation is not a new practice in rheumatology or gastroenterology, this approach has not been fully explored for its potential to prevent carcinogenesis or to contribute to the treatment of GC. This review highlights current and possible strategies for therapeutic intervention including (i) targeting pro-inflammatory mediators, (ii) targeting growth factors and pathways involved in angiogenesis in the gastric tumor microenvironment, and (iii) enhancing anti-tumor immunity. In addition, we highlight a significant number of clinical trials and discuss the importance of individual tumor characterization toward offering personalized immune-related therapy.


Assuntos
Inflamação/imunologia , Inflamação/terapia , Neoplasias Gástricas/patologia , Neoplasias Gástricas/terapia , Citocinas/imunologia , Mucosa Gástrica/imunologia , Mucosa Gástrica/microbiologia , Mucosa Gástrica/patologia , Infecções por Helicobacter/imunologia , Infecções por Helicobacter/microbiologia , Infecções por Helicobacter/patologia , Infecções por Helicobacter/terapia , Helicobacter pylori/patogenicidade , Humanos , Inflamação/microbiologia , Inflamação/patologia , Neoplasias Gástricas/imunologia , Neoplasias Gástricas/microbiologia , Microambiente Tumoral
16.
Int J Mol Sci ; 20(8)2019 Apr 18.
Artigo em Inglês | MEDLINE | ID: mdl-31003453

RESUMO

BACKGROUND: Helicobacter pylori (H. pylori) eradication therapy may improve gastric atrophy and intestinal metaplasia, but the results of previous studies have not always been consistent. The aim of this study was to compare the histological changes of intestinal metaplasia and gastric atrophy among the use of acid-suppressing drugs after H. pylori eradication. METHODS: A cohort of 242 patients who underwent successful eradication therapy for H. pylori gastritis and surveillance endoscopy examination from 1996 to 2015 was analyzed. Changes in the histological scores of intestinal metaplasia and atrophy according to drug use (proton-pump inhibitors (PPIs), H2 receptor antagonists (H2RAs), and non-acid suppressant use) were evaluated in biopsies of the antrum and corpus using a generalized linear mixed model in all patients. RESULTS: The mean follow-up period and number of biopsies were 5.48 ± 4.69 years and 2.62 ± 1.67 times, respectively. Improvement in the atrophy scores of both the antrum (p = 0.042) and corpus (p = 0.020) were significantly superior in patients with non-acid suppressant drug use compared with those of PPI and H2RA use. Metaplasia scores in both the antrum and corpus did not improve in all groups, and no significant differences were observed among groups in the antrum (p = 0.271) and corpus (p = 0.077). CONCLUSIONS: Prolonged acid suppression by PPIs or H2RAs may limit the recovery of gastric atrophy following H. pylori eradication.


Assuntos
Atrofia/tratamento farmacológico , Infecções por Helicobacter/tratamento farmacológico , Helicobacter pylori/efeitos dos fármacos , Inibidores da Bomba de Prótons/administração & dosagem , Adulto , Idoso , Idoso de 80 Anos ou mais , Atrofia/microbiologia , Atrofia/fisiopatologia , Atrofia/prevenção & controle , Endoscopia , Feminino , Ácido Gástrico/metabolismo , Mucosa Gástrica/efeitos dos fármacos , Mucosa Gástrica/microbiologia , Mucosa Gástrica/fisiopatologia , Gastrite/tratamento farmacológico , Gastrite/microbiologia , Gastrite/fisiopatologia , Infecções por Helicobacter/microbiologia , Infecções por Helicobacter/fisiopatologia , Helicobacter pylori/metabolismo , Helicobacter pylori/patogenicidade , Humanos , Intestinos/efeitos dos fármacos , Intestinos/microbiologia , Intestinos/fisiopatologia , Masculino , Metaplasia/tratamento farmacológico , Metaplasia/microbiologia , Metaplasia/fisiopatologia , Pessoa de Meia-Idade
17.
Eur J Gastroenterol Hepatol ; 31(5): 593-598, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30839435

RESUMO

BACKGROUND: Helicobacter pylori (H. pylori) infection is more frequent among men, though the magnitude of the association might be inaccurate due to potential misclassification of lifetime infection and publication bias. Moreover, infection is common, and most studies are cross-sectional. Thus, prevalence ratios (PRs) may be easier to interpret than odds ratios (ORs). AIM: The aim of this study was to quantify the association between sex and H. pylori infection using controls from 14 studies from the Stomach Cancer Pooling (StoP) Project. PARTICIPANTS AND METHODS: H. pylori infection was defined based on IgG serum antibody titers or multiplex serology. Participants were also classified as infected if gastric atrophy was present, based on histological examination or serum pepsinogen (PG) levels (PG I≤70 and PG I/II ratio≤3). Summary ORs and PRs, adjusted for age, social class and smoking, and corresponding 95% confidence intervals (CIs), were estimated through random-effects meta-analysis. RESULTS: Men had significantly higher OR (OR: 1.33, 95% CI: 1.04-1.70) and PR (PR: 1.05, 95% CI: 1.00-1.10) of infection, with stronger associations among hospital-based or older controls. Results were similar when considering the presence of gastric atrophy to define infection status, particularly among participants older than 65 years. CONCLUSION: This collaborative pooled-analysis supports an independent effect of sex on the prevalence of H. pylori infection, while minimizing misclassification of lifetime infection status and publication bias.


Assuntos
Infecções por Helicobacter/epidemiologia , Infecções por Helicobacter/microbiologia , Helicobacter pylori/patogenicidade , Idoso , Anticorpos Antibacterianos/sangue , Anticorpos Antibacterianos/imunologia , Atrofia , Feminino , Gastrite Atrófica/diagnóstico , Gastrite Atrófica/epidemiologia , Gastrite Atrófica/microbiologia , Infecções por Helicobacter/diagnóstico , Helicobacter pylori/imunologia , Humanos , Imunoglobulina G/sangue , Imunoglobulina G/imunologia , Masculino , Pessoa de Meia-Idade , Prevalência , Medição de Risco , Fatores de Risco , Testes Sorológicos , Fatores Sexuais , Estômago/microbiologia , Estômago/patologia
18.
Inflammopharmacology ; 27(2): 203-211, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30820719

RESUMO

The magnitude of gastric mucosal inflammatory response to H. pylori relies primarily on the extent of its key endotoxin, LPS, engagement of Toll-like receptor-4 (TLR4) and the initiation of signal transduction events converging on mitogen-activated protein kinase (MAPK) and IκB complex (IKK) cascades. These cascades, in turn, exert their control over the assembly of transcription factors, NFκB and AP1, implicated in the induction of the expression of iNOS and COX-2 proinflammatory genes. The LPS-induced TLR4 activation and the ensuing phosphorylation of its intracellular tyrosine domain by Src-family kinases not only leads to recruitment to the cytoplasmic domain of TLR4 of adaptor molecules directly involved in propagation of the signaling cascades converging on MAPK and IKK, but also provides a propitious docking site for a non-receptor tyrosine kinase, spleen tyrosine kinase (Syk), the activation of which apparently leads to upregulation in the expression of proinflammatory genes. Here, we review the pathways engaged by H. pylori in the recruitment and interaction of Syk with TLR4 in gastric mucosa, and discuss the cascades involved in Syk-mediated amplification in proinflammatory signaling. We focus, moreover, on the potential role of drugs targeting Syk and TLR4 in the treatment of H. pylori-related gastric disease.


Assuntos
Mucosa Gástrica/metabolismo , Mucosa Gástrica/microbiologia , Infecções por Helicobacter/metabolismo , Helicobacter pylori/patogenicidade , Inflamação/metabolismo , Quinase Syk/metabolismo , Animais , Infecções por Helicobacter/microbiologia , Humanos , Inflamação/microbiologia , Transdução de Sinais/fisiologia , Receptor 4 Toll-Like/metabolismo
19.
J Gastrointestin Liver Dis ; 28(1): 11-14, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30851166

RESUMO

BACKGROUND AND AIM: Standard 10-day sequential therapy is advised as first-line therapy for Helicobacter pylori (H. pylori) eradication by current Italian guidelines. Some data suggested that a 14-day regimen may achieve higher eradication rates. This study compared the efficacy of sequential therapy administered for either 10- or 14-days. METHODS: This prospective, multicenter, open-label study enrolled patients with H. pylori infection without previous treatment. Patients were receiving a sequential therapy for either 10 or 14 days with esomeprazole 40 mg and amoxicillin 1 g (5 or 7 days) followed by esomeprazole 40 mg, clarithromycin 500 mg and tinidazole 500 mg (5 or 7 days), all given twice daily. Bacterial eradication was checked using 13C-urea breath test. Eradication cure rates were calculated at both Intention-to-treat (ITT) and per-protocol (PP) analyses. RESULTS: A total of 291 patients were enrolled, including 146 patients in 10-day and 145 in the 14-day regimen. The eradication rates were 87% (95% CI = 81.5-92.4) and 90.3% (95% CI = 85.5-95.1) at ITT analysis with the 10- and 14-day regimen, respectively, and 92.7% (95% CI = 88.3-97) and 97% (95% CI = 94.2-99.9) at PP analysis (p =0.37). Among patients, who earlier had interrupted therapy, bacterial eradication was achieved in 8 out of 9 who completed the first therapy phase and performed at least >/=3 days of triple therapy in the second phase. CONCLUSION: This study found that both 10- and 14-day sequential therapies achieved a high eradication rate for first-line H. pylori therapy in clinical practice.


Assuntos
Amoxicilina/administração & dosagem , Antibacterianos/administração & dosagem , Claritromicina/administração & dosagem , Esomeprazol/administração & dosagem , Infecções por Helicobacter/tratamento farmacológico , Helicobacter pylori/efeitos dos fármacos , Inibidores da Bomba de Prótons/administração & dosagem , Tinidazol/administração & dosagem , Adulto , Amoxicilina/efeitos adversos , Antibacterianos/efeitos adversos , Carga Bacteriana , Claritromicina/efeitos adversos , Esquema de Medicação , Quimioterapia Combinada , Esomeprazol/efeitos adversos , Feminino , Infecções por Helicobacter/diagnóstico , Infecções por Helicobacter/microbiologia , Helicobacter pylori/patogenicidade , Humanos , Itália , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Inibidores da Bomba de Prótons/efeitos adversos , Fatores de Tempo , Tinidazol/efeitos adversos , Resultado do Tratamento
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