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1.
PLoS Pathog ; 18(6): e1010628, 2022 06.
Artigo em Inglês | MEDLINE | ID: mdl-35767594

RESUMO

Helicobacter pylori (H. pylori) is a common gastric pathogen that infects approximately half of the world's population. Infection with H. pylori can lead to diverse pathological conditions, including chronic gastritis, peptic ulcer disease, and cancer. The latter is the most severe consequence of H. pylori infection. According to epidemiological studies, gastric infection with H. pylori is the strongest known risk factor for non-cardia gastric cancer (GC), which remains one of the leading causes of cancer-related deaths worldwide. However, it still remains to be poorly understood how host-microbe interactions result in cancer development in the human stomach. Here we focus on the H. pylori bacterial factors that affect the host ubiquitin proteasome system. We investigated E3 ubiquitin ligases SIVA1 and ULF that regulate p14ARF (p19ARF in mice) tumor suppressor. ARF plays a key role in regulation of the oncogenic stress response and is frequently inhibited during GC progression. Expression of ARF, SIVA1 and ULF proteins were investigated in gastroids, H. pylori-infected mice and human gastric tissues. The role of the H. pylori type IV secretion system was assessed using various H. pylori isogenic mutants. Our studies demonstrated that H. pylori infection results in induction of ULF, decrease in SIVA1 protein levels, and subsequent ubiquitination and degradation of p14ARF tumor suppressor. Bacterial CagA protein was found to sequentially bind to SIVA1 and ULF proteins. This process is regulated by CagA protein phosphorylation at the EPIYA motifs. Downregulation of ARF protein leads to inhibition of cellular apoptosis and oncogenic stress response that may promote gastric carcinogenesis.


Assuntos
Infecções por Helicobacter , Helicobacter pylori , Neoplasias Gástricas , Animais , Antígenos de Bactérias/genética , Antígenos de Bactérias/metabolismo , Apoptose , Proteínas de Bactérias/genética , Proteínas de Bactérias/metabolismo , Carcinogênese/metabolismo , Mucosa Gástrica/microbiologia , Infecções por Helicobacter/microbiologia , Helicobacter pylori/metabolismo , Camundongos , Neoplasias Gástricas/metabolismo , Proteína Supressora de Tumor p14ARF/metabolismo , Ubiquitinas/metabolismo
2.
Curr Top Microbiol Immunol ; 444: 25-52, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-38231214

RESUMO

The human pathogen Helicobacter pylori is the strongest known risk factor for gastric disease and cancer, and gastric cancer remains a leading cause of cancer-related death across the globe. Carcinogenic mechanisms associated with H. pylori are multifactorial and are driven by bacterial virulence constituents, host immune responses, environmental factors such as iron and salt, and the microbiota. Infection with strains that harbor the cytotoxin-associated genes (cag) pathogenicity island, which encodes a type IV secretion system (T4SS) confer increased risk for developing more severe gastric diseases. Other important H. pylori virulence factors that augment disease progression include vacuolating cytotoxin A (VacA), specifically type s1m1 vacA alleles, serine protease HtrA, and the outer-membrane adhesins HopQ, BabA, SabA and OipA. Additional risk factors for gastric cancer include dietary factors such as diets that are high in salt or low in iron, H. pylori-induced perturbations of the gastric microbiome, host genetic polymorphisms, and infection with Epstein-Barr virus. This chapter discusses in detail host factors and how H. pylori virulence factors augment the risk of developing gastric cancer in human patients as well as how the Mongolian gerbil model has been used to define mechanisms of H. pylori-induced inflammation and cancer.


Assuntos
Infecções por Vírus Epstein-Barr , Helicobacter pylori , Neoplasias Gástricas , Humanos , Neoplasias Gástricas/genética , Herpesvirus Humano 4 , Citotoxinas , Helicobacter pylori/genética , Ferro , Fatores de Virulência/genética
3.
Int J Cancer ; 151(10): 1703-1716, 2022 11 15.
Artigo em Inglês | MEDLINE | ID: mdl-35751398

RESUMO

The incidence of esophageal adenocarcinoma (EA) has drastically increased in the United States since 1970s for unclear reasons. We hypothesized that the widespread usage of antibiotics has increased the procarcinogenic potential of the orodigestive microbiota along the sequence of gastroesophageal reflux (GR), Barrett's esophagus (BE) and EA phenotypes. This case control study included normal controls (NC) and three disease phenotypes GR, BE and EA. Microbiota in the mouth, esophagus, and stomach, and rectum were analyzed using 16S rRNA gene sequencing. Overall, we discovered 44 significant pairwise differences in abundance of microbial taxa between the four phenotypes, with 12 differences in the mouth, 21 in the esophagus, two in the stomach, and nine in the rectum. Along the GR→BE→EA sequence, oral and esophageal microbiota were more diversified, the dominant genus Streptococcus was progressively depleted while six other genera Atopobium, Actinomyces, Veillonella, Ralstonia, Burkholderia and Lautropia progressively enriched. In NC, Streptococcus appeared to control populations of other genera in the foregut via numerous negative and positive connections, while in disease states, the rich network was markedly simplified. Inferred gene functional content showed a progressive enrichment through the stages of EA development in genes encoding antibiotic resistance, ligands of Toll-like and NOD-like receptors, nitrate-nitrite-nitric oxide pathway and acetaldehyde metabolism. The orodigestive microbiota is in a progressive dysbiotic state along the GR-BE-EA sequence. The increasing dysbiosis and antibiotic and procarcinogenic genes in the disease states warrants further study to define their roles in EA pathogenesis.


Assuntos
Adenocarcinoma , Esôfago de Barrett , Neoplasias Esofágicas , Refluxo Gastroesofágico , Microbiota , Acetaldeído , Adenocarcinoma/patologia , Antibacterianos/farmacologia , Antibacterianos/uso terapêutico , Esôfago de Barrett/genética , Esôfago de Barrett/patologia , Estudos de Casos e Controles , Disbiose , Neoplasias Esofágicas/epidemiologia , Humanos , Ligantes , Microbiota/genética , Proteínas NLR , Nitratos , Óxido Nítrico , Nitritos , RNA Ribossômico 16S/genética
4.
Gastroenterology ; 161(5): 1443-1459, 2021 11.
Artigo em Inglês | MEDLINE | ID: mdl-34358488

RESUMO

BACKGROUND & AIMS: Helicobacter pylori infects approximately 50% of individuals worldwide. Successful H pylori eradication is associated with reduced risk of gastric cancer and peptic ulcer disease, among other conditions. We hypothesized that host genetic determinants, especially those affecting gastric pH, might contribute to eradication therapy failure, particularly when treatment adherence and antibiotic susceptibility are confirmed. We aimed to conduct a meta-analysis of host genetic variants associated with H pylori eradication failure. METHODS: We searched the literature for studies comparing posttreatment H pylori eradication failure vs success (outcome) according to host genetic polymorphisms (exposure). Reference groups were defined according to genotypes (or corresponding phenotypes) hypothesized to be associated with successful eradication. We pooled estimates using a random-effects model and performed comprehensive sensitivity analyses. RESULTS: We analyzed 57 studies from 11 countries; the vast majority analyzed CYP2C19 polymorphisms. Among individuals prescribed eradication regimens with proton pump inhibitors predominantly CYP2C19 metabolized, enhanced vs poor metabolizer phenotypes were associated with a 2.52-fold significantly higher likelihood of eradication failure and 4.44-fold significantly higher likelihood when treatment adherence and H pylori clarithromycin susceptibility (if relevant) were confirmed. There was no association between CYP2C19 variants and eradication failure if proton pump inhibitors less metabolized by or that bypass CYP2C19 metabolism were used. IL1B polymorphisms that are vs are not associated with less gastric acid suppression were associated with 1.72-fold significantly higher likelihood of eradication failure. There was no association between MDR1 polymorphisms and H pylori eradication failure. The certainty of evidence was moderate. CONCLUSION: Based on meta-analysis, we identified host genetic polymorphisms significantly associated with H pylori eradication failure; host genetics might underlie eradication failure among treatment-adherent individuals with confirmed H pylori antibiotic susceptibility.


Assuntos
Antibacterianos/uso terapêutico , Citocromo P-450 CYP2C19/genética , Infecções por Helicobacter/tratamento farmacológico , Helicobacter pylori/efeitos dos fármacos , Interleucina-1beta/genética , Variantes Farmacogenômicos , Polimorfismo de Nucleotídeo Único , Inibidores da Bomba de Prótons/uso terapêutico , Subfamília B de Transportador de Cassetes de Ligação de ATP/genética , Subfamília B de Transportador de Cassetes de Ligação de ATP/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Antibacterianos/efeitos adversos , Citocromo P-450 CYP2C19/metabolismo , Farmacorresistência Bacteriana/genética , Feminino , Infecções por Helicobacter/diagnóstico , Infecções por Helicobacter/microbiologia , Helicobacter pylori/patogenicidade , Humanos , Interleucina-1beta/metabolismo , Masculino , Pessoa de Meia-Idade , Farmacogenética , Testes Farmacogenômicos , Valor Preditivo dos Testes , Inibidores da Bomba de Prótons/efeitos adversos , Medição de Risco , Fatores de Risco , Falha de Tratamento , Adulto Jovem
5.
Gastroenterology ; 160(4): 1106-1117.e3, 2021 03.
Artigo em Inglês | MEDLINE | ID: mdl-33220252

RESUMO

BACKGROUND & AIMS: Helicobacter pylori eradication and endoscopic surveillance of gastric precancerous lesions are strategies to reduce gastric cancer (GC) risk. To our knowledge, this study is the longest prospective cohort of an H pylori eradication trial in a Hispanic population. METHODS: A total of 800 adults with precancerous lesions were randomized to anti-H pylori treatment or placebo. Gastric biopsy samples taken at baseline and 3, 6, 12, 16, and 20 years were assessed by our Correa histopathology score. A generalized linear mixed model with a participant-level random intercept was used to estimate the effect of H pylori status on the score over time. Logistic regression models were used to estimate progression by baseline diagnosis and to estimate GC risk by intestinal metaplasia (IM) subtype and anatomic location. RESULTS: Overall, 356 individuals completed 20 years of follow-up. Anti-H pylori therapy (intention-to-treat) reduced progression of the Correa score (odds ratio [OR], 0.59; 95% confidence interval [CI], 0.38-0.93). H pylori-negative status had a beneficial effect on the score over time (P = .036). Among individuals with IM (including indefinite for dysplasia) at baseline, incidence rates per 100 person-years were 1.09 (95% CI, 0.85-1.33) for low-grade/high-grade dysplasia and 0.14 (95% CI, 0.06-0.22) for GC. Incomplete-type (vs complete-type) IM at baseline presented higher GC risk (OR, 13.4; 95% CI, 1.8-103.8). Individuals with corpus (vs antrum-restricted) IM showed an OR of 2.1 (95% CI, 0.7-6.6) for GC. CONCLUSIONS: In a high-GC-risk Hispanic population, anti-H pylori therapy had a long-term beneficial effect against histologic progression. Incomplete IM is a strong predictor of GC risk.


Assuntos
Antibacterianos/uso terapêutico , Mucosa Gástrica/patologia , Infecções por Helicobacter/tratamento farmacológico , Lesões Pré-Cancerosas/epidemiologia , Neoplasias Gástricas/prevenção & controle , Adulto , Idoso , Biópsia , Colômbia/epidemiologia , Progressão da Doença , Feminino , Seguimentos , Mucosa Gástrica/diagnóstico por imagem , Mucosa Gástrica/microbiologia , Gastroscopia/estatística & dados numéricos , Infecções por Helicobacter/microbiologia , Infecções por Helicobacter/patologia , Helicobacter pylori/isolamento & purificação , Humanos , Incidência , Masculino , Metaplasia/diagnóstico , Metaplasia/epidemiologia , Metaplasia/microbiologia , Metaplasia/patologia , Pessoa de Meia-Idade , Lesões Pré-Cancerosas/diagnóstico , Lesões Pré-Cancerosas/microbiologia , Lesões Pré-Cancerosas/patologia , Estudos Prospectivos , Fatores de Risco , Neoplasias Gástricas/epidemiologia , Neoplasias Gástricas/microbiologia , Neoplasias Gástricas/patologia , Resultado do Tratamento
6.
PLoS Pathog ; 16(12): e1008686, 2020 12.
Artigo em Inglês | MEDLINE | ID: mdl-33370399

RESUMO

Helicobacter pylori chronically infects the stomach of approximately half of the world's population. Manifestation of clinical diseases associated with H. pylori infection, including cancer, is driven by strain properties and host responses; and as chronic infection persists, both are subject to change. Previous studies have documented frequent and extensive within-host bacterial genetic variation. To define how within-host diversity contributes to phenotypes related to H. pylori pathogenesis, this project leverages a collection of 39 clinical isolates acquired prospectively from a single subject at two time points and from multiple gastric sites. During the six years separating collection of these isolates, this individual, initially harboring a duodenal ulcer, progressed to gastric atrophy and concomitant loss of acid secretion. Whole genome sequence analysis identified 1,767 unique single nucleotide polymorphisms (SNPs) across isolates and a nucleotide substitution rate of 1.3x10-4 substitutions/site/year. Gene ontology analysis identified cell envelope genes among the genes with excess accumulation of nonsynonymous SNPs (nSNPs). A maximum likelihood tree based on genetic similarity clusters isolates from each time point separately. Within time points, there is segregation of subgroups with phenotypic differences in bacterial morphology, ability to induce inflammatory cytokines, and mouse colonization. Higher inflammatory cytokine induction in recent isolates maps to shared polymorphisms in the Cag PAI protein, CagY, while rod morphology in a subgroup of recent isolates mapped to eight mutations in three distinct helical cell shape determining (csd) genes. The presence of subgroups with unique genetic and phenotypic properties suggest complex selective forces and multiple niches within the stomach during chronic infection.


Assuntos
Úlcera Duodenal/microbiologia , Infecções por Helicobacter/complicações , Infecções por Helicobacter/genética , Helicobacter pylori/genética , Gastropatias/microbiologia , Animais , Atrofia/microbiologia , Doença Crônica , Ácido Gástrico , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Pessoa de Meia-Idade , Fenótipo , Polimorfismo de Nucleotídeo Único , Gastropatias/patologia
7.
Dig Dis Sci ; 67(9): 4387-4394, 2022 09.
Artigo em Inglês | MEDLINE | ID: mdl-35034240

RESUMO

BACKGROUND: Helicobacter pylori eradication is associated with reduced gastric cancer and peptic ulcer disease incidence and mortality. Factors influencing patients' experiences surrounding H. pylori diagnosis and management are not well-described. Current patient perceptions can influence adherence to treatment, and also their anxieties related to this potentially carcinogenic condition. The objective of this study was to understand the patient experience surrounding H. pylori management and to qualitatively construct a contextual framework to inform and guide providers who manage patients with H. pylori infection. METHODS: We conducted a qualitative analysis using a focus group and one-on-one telephone interviews. An iterative inductive/deductive approach was applied to recorded transcripts to identify and hierarchically order themes. Patient experience was defined according to major themes within a structured health behavior framework. RESULTS: Theme saturation was achieved with thirteen participants (mean age 50.4 years; 62% female; 38% non-Hispanic white). Qualitative analysis yielded a total of 987 codes that resulted in five major themes related to the patient H. pylori experience: context of decision-making; health beliefs; barriers experienced; cues to action; and impact of new knowledge. These themes aligned with the Health Behavior Model framework. Participants were motivated to treat H. pylori. However, the experience was more often perceived negatively versus positively. The perceived patient-provider interaction contributed most prominently to the negative experience compared to other patient experiences, including treatment-related side effects. Internal cues, including symptoms and fear of cancer, modified participants' perceptions and motivation to accept treatment. CONCLUSIONS: Patient experiences related to H. pylori management are predominantly negative. Increasing providers' awareness about patients' values, beliefs, anxieties, and expectations surrounding H. pylori diagnosis/treatment may improve provider-patient communication and, ideally, related outcomes.


Assuntos
Antiulcerosos , Infecções por Helicobacter , Helicobacter pylori , Neoplasias Gástricas , Antibacterianos/uso terapêutico , Antiulcerosos/uso terapêutico , Feminino , Infecções por Helicobacter/complicações , Infecções por Helicobacter/diagnóstico , Infecções por Helicobacter/tratamento farmacológico , Humanos , Masculino , Pessoa de Meia-Idade , Neoplasias Gástricas/complicações
8.
Dig Dis Sci ; 67(11): 5149-5157, 2022 11.
Artigo em Inglês | MEDLINE | ID: mdl-35119598

RESUMO

BACKGROUND: Mother-to-child transmission of Helicobacter pylori (H. pylori) is the primary source of intrafamilial spread in early childhood in regions of high H. pylori prevalence. However, early-in-life H. pylori colonization and associated protective or risk factors have not been fully evaluated in lower prevalence regions, such as the USA. AIMS: Therefore, from a well-characterized prospective US cohort, we selected women who provided fecal samples during pregnancy and had paired fecal samples from their babies up to 24 months postpartum. We evaluated maternal and baby factors associated with likelihood of H. pylori colonization in the babies. Fecal antigen testing was used to determine H. pylori status. We also evaluated the association between maternal breastmilk cytokines and H. pylori colonization in breastfed babies. RESULTS: Among included mother-baby pairs (n = 66), H. pylori prevalence was 31.8% in mothers and 19.7% in their babies. Dominant breastfeeding (adjusted odds ratio [aOR] 0.17, 95% CI 0.03-0.98) and maternal IBD (aOR 0.05, 95% CI 0.01-0.27) were associated with significantly lower likelihood of H. pylori colonization among babies; no other clinical factors were associated with H. pylori colonization in the babies. Matrix metalloproteinase-10 (MMP-10) and tumor necrosis factor-related activation-induced cytokine expression were significantly higher in breastmilk of mothers with H. pylori positive vs negative babies. CONCLUSIONS: Consistent with data from high H. pylori prevalence regions, our findings suggest dominant breastfeeding may protect against early H. pylori colonization. Downregulation of pro-inflammatory cytokines such as MMP-10 may be relevant in mediating this protection among breastfed babies, but more data are needed.


Assuntos
Infecções por Helicobacter , Helicobacter pylori , Feminino , Humanos , Lactente , Gravidez , Aleitamento Materno , Infecções por Helicobacter/epidemiologia , Transmissão Vertical de Doenças Infecciosas/prevenção & controle , Metaloproteinase 10 da Matriz , Estudos Prospectivos , Ligante RANK
9.
Proc Natl Acad Sci U S A ; 116(39): 19652-19658, 2019 09 24.
Artigo em Inglês | MEDLINE | ID: mdl-31488717

RESUMO

Helicobacter pylori-induced gastritis is the strongest risk factor for gastric adenocarcinoma, a malignancy preceded by a series of well-defined histological stages, including metaplasia. One microbial constituent that augments cancer risk is the cag type 4 secretion system (T4SS), which translocates the oncoprotein CagA into host cells. Aberrant stem cell activation is linked to carcinogenesis, and Lrig1 (leucine-rich repeats and Ig-like domains 1) marks a distinct population of progenitor cells. We investigated whether microbial effectors with carcinogenic potential influence Lrig1 progenitor cells ex vivo and via lineage expansion within H. pylori-infected gastric mucosa. Lineage tracing was induced in Lrig1-CreERT2/+;R26R-YFP/+ (Lrig1/YFP) mice that were uninfected or subsequently infected with cag+H. pylori or an isogenic cagE- mutant (nonfunctional T4SS). In contrast to infection with wild-type (WT) H. pylori for 2 wk, infection for 8 wk resulted in significantly increased inflammation and proliferation in the corpus and antrum compared with uninfected or mice infected with the cagE- mutant. WT H. pylori-infected mice harbored significantly higher numbers of Lrig1/YFP epithelial cells that coexpressed UEA1 (surface cell marker). The number of cells coexpressing intrinsic factor (chief cell marker), YFP (lineage marker), and GSII lectin (spasmolytic polypeptide-expressing metaplasia marker) were increased only by WT H. pylori In human samples, Lrig1 expression was significantly increased in lesions with premalignant potential compared with normal mucosa or nonatrophic gastritis. In conclusion, chronic H. pylori infection stimulates Lrig1-expressing progenitor cells in a cag-dependent manner, and these reprogrammed cells give rise to a full spectrum of differentiated cells.


Assuntos
Helicobacter pylori/metabolismo , Glicoproteínas de Membrana/metabolismo , Proteínas do Tecido Nervoso/metabolismo , Sistemas de Secreção Tipo IV/metabolismo , Adenocarcinoma/metabolismo , Adenocarcinoma/microbiologia , Animais , Carcinogênese/patologia , Modelos Animais de Doenças , Células Epiteliais/metabolismo , Feminino , Mucosa Gástrica/metabolismo , Gastrite/metabolismo , Gastrite/patologia , Infecções por Helicobacter/metabolismo , Infecções por Helicobacter/microbiologia , Infecções por Helicobacter/patologia , Humanos , Masculino , Camundongos , Camundongos Knockout , Lesões Pré-Cancerosas/metabolismo , Lesões Pré-Cancerosas/microbiologia , Lesões Pré-Cancerosas/patologia , Cultura Primária de Células , Fatores de Risco , Células-Tronco/metabolismo , Estômago/microbiologia , Estômago/patologia , Neoplasias Gástricas/metabolismo , Neoplasias Gástricas/microbiologia , Neoplasias Gástricas/patologia
10.
Proc Natl Acad Sci U S A ; 116(11): 5077-5085, 2019 03 12.
Artigo em Inglês | MEDLINE | ID: mdl-30804204

RESUMO

Infection by Helicobacter pylori is the primary cause of gastric adenocarcinoma. The most potent H. pylori virulence factor is cytotoxin-associated gene A (CagA), which is translocated by a type 4 secretion system (T4SS) into gastric epithelial cells and activates oncogenic signaling pathways. The gene cagY encodes for a key component of the T4SS and can undergo gene rearrangements. We have shown that the cancer chemopreventive agent α-difluoromethylornithine (DFMO), known to inhibit the enzyme ornithine decarboxylase, reduces H. pylori-mediated gastric cancer incidence in Mongolian gerbils. In the present study, we questioned whether DFMO might directly affect H. pylori pathogenicity. We show that H. pylori output strains isolated from gerbils treated with DFMO exhibit reduced ability to translocate CagA in gastric epithelial cells. Further, we frequently detected genomic modifications in the middle repeat region of the cagY gene of output strains from DFMO-treated animals, which were associated with alterations in the CagY protein. Gerbils did not develop carcinoma when infected with a DFMO output strain containing rearranged cagY or the parental strain in which the wild-type cagY was replaced by cagY with DFMO-induced rearrangements. Lastly, we demonstrate that in vitro treatment of H. pylori by DFMO induces oxidative DNA damage, expression of the DNA repair enzyme MutS2, and mutations in cagY, demonstrating that DFMO directly affects genomic stability. Deletion of mutS2 abrogated the ability of DFMO to induce cagY rearrangements directly. In conclusion, DFMO-induced oxidative stress in H. pylori leads to genomic alterations and attenuates virulence.


Assuntos
Proteínas de Bactérias/genética , Carcinogênese/genética , Carcinogênese/patologia , Eflornitina/farmacologia , Helicobacter pylori/genética , Mutação/genética , Neoplasias Gástricas/microbiologia , Neoplasias Gástricas/patologia , Animais , Dano ao DNA , Deleção de Genes , Rearranjo Gênico , Gerbillinae , Helicobacter pylori/efeitos dos fármacos , Helicobacter pylori/patogenicidade , Masculino , Estresse Oxidativo/efeitos dos fármacos , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Virulência
11.
J Infect Dis ; 224(2): 360-365, 2021 07 15.
Artigo em Inglês | MEDLINE | ID: mdl-33245103

RESUMO

Helicobacter pylori is the strongest risk factor for gastric adenocarcinoma. The H. pylori cancer-associated cag pathogenicity island (cag-PAI) encodes a type IV secretion system (T4SS), which translocates microbial DNA and activates TLR9; however, most cag-PAI+-infected persons do not develop cancer and cag-PAI-independent regulators of pathogenesis, including strain-specific adhesins, remain understudied. We defined the relationships between H. pylori HopQ adhesin allelic type, gastric injury, and TLR9 activation. Type I hopQ alleles were significantly associated with magnitude of injury, cag-T4SS function, and TLR9 activation. Genetic deletion of hopQ significantly decreased H. pylori-induced TLR9 activation, implicating this adhesin in H. pylori-mediated disease.


Assuntos
Adesinas Bacterianas , Infecções por Helicobacter , Receptor Toll-Like 9/imunologia , Adesinas Bacterianas/genética , Antígenos de Bactérias , Proteínas de Bactérias/genética , Ilhas Genômicas , Infecções por Helicobacter/imunologia , Helicobacter pylori/genética , Humanos , Receptor Toll-Like 9/genética , Sistemas de Secreção Tipo IV/genética , Virulência
12.
Gastroenterology ; 159(5): 1705-1714.e2, 2020 11.
Artigo em Inglês | MEDLINE | ID: mdl-32771406

RESUMO

BACKGROUND & AIMS: There are racial and ethnic differences in the incidence of gastric adenocarcinoma worldwide and in the US. Based on a decision analysis, screening for noncardia gastric adenocarcinoma might be cost-effective for non-White individuals 50 years or older. However, a lack of precise, contemporary information on gastric adenocarcinoma incidence in specific anatomic sites for this age group has impeded prevention and early detection programs in the US. We aimed to estimate the differences in gastric adenocarcinoma incidence in specific anatomic sites among races and ethnicities in individuals 50 years or older. METHODS: We analyzed California Cancer Registry data from 2011 through 2015 to estimate incidences of gastric adenocarcinoma in specific anatomic sites for non-Hispanic White (NHW), non-Hispanic Black, Hispanic, and the 7 largest Asian American populations. We calculated the differential incidence between non-White groups and NHW using incidence rate ratios and 95% confidence intervals (CIs). RESULTS: Compared with NHW subjects, all non-White groups had significantly higher incidences of noncardia gastric adenocarcinoma; the incidence was highest among Korean American men 50 years and older (70 cases per 100,000). Compared with NHW subjects 50 years and older, the risk of noncardia gastric adenocarcinoma was 1.8-fold (95% CI, 1.37-2.31) to 7.3-fold (95% CI, 5.73-9.19) higher in most non-White groups and 12.0-fold (95% CI, 9.96-14.6) to 14.5-fold (95% CI, 12.5-16.9) higher among Korean American men and women 50 years and older, respectively. Compared with NHW men 50 years and older, all non-White men, except Japanese and Korean American men, had a significantly lower risk of cardia gastric adenocarcinoma. CONCLUSIONS: We identified several-fold differences in incidences of gastric adenocarcinoma in specific anatomic sites among racial and ethnic groups, with significant age and sex differences. These findings can be used to develop targeted risk reduction programs for gastric adenocarcinoma.


Assuntos
Adenocarcinoma/etnologia , Asiático , Negro ou Afro-Americano , Disparidades nos Níveis de Saúde , Hispânico ou Latino , Neoplasias Gástricas/etnologia , População Branca , Adenocarcinoma/patologia , Fatores Etários , California/epidemiologia , Feminino , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , Fatores Raciais , Sistema de Registros , Medição de Risco , Fatores de Risco , Fatores Sexuais , Neoplasias Gástricas/patologia , Fatores de Tempo
13.
J Clin Microbiol ; 59(5)2021 04 20.
Artigo em Inglês | MEDLINE | ID: mdl-33692136

RESUMO

Colombia, South America has one of the world's highest burdens of Helicobacter pylori infection and gastric cancer. While multidrug antibiotic regimens can effectively eradicate H. pylori, treatment efficacy is being jeopardized by the emergence of antibiotic-resistant H. pylori strains. Moreover, the spectrum of and genetic mechanisms for antibiotic resistance in Colombia is underreported. In this study, 28 H. pylori strains isolated from gastric biopsy specimens from a high-gastric-cancer-risk (HGCR) population living in the Andes Mountains in Túquerres, Colombia and 31 strains from a low-gastric-cancer-risk (LGCR) population residing on the Pacific coast in Tumaco, Colombia were subjected to antibiotic susceptibility testing for amoxicillin, clarithromycin, levofloxacin, metronidazole, rifampin, and tetracycline. Resistance-associated genes were amplified by PCR for all isolates, and 29 isolates were whole-genome sequenced (WGS). No strains were resistant to amoxicillin, clarithromycin, or rifampin. One strain was resistant to tetracycline and had an A926G mutation in its 16S rRNA gene. Levofloxacin resistance was observed in 12/59 isolates and was significantly associated with N87I/K and/or D91G/Y mutations in gyrA Most isolates were resistant to metronidazole; this resistance was significantly higher in the LGCR (31/31) group compared to the HGCR (24/28) group. Truncations in rdxA and frxA were present in nearly all metronidazole-resistant strains. There was no association between phylogenetic relationship and resistance profiles based on WGS analysis. Our results indicate H. pylori isolates from Colombians exhibit multidrug antibiotic resistance. Continued surveillance of H. pylori antibiotic resistance in Colombia is warranted in order to establish appropriate eradication treatment regimens for this population.


Assuntos
Infecções por Helicobacter , Helicobacter pylori , Neoplasias Gástricas , Antibacterianos/farmacologia , Antibacterianos/uso terapêutico , Claritromicina/farmacologia , Colômbia/epidemiologia , Farmacorresistência Bacteriana/genética , Infecções por Helicobacter/tratamento farmacológico , Infecções por Helicobacter/epidemiologia , Helicobacter pylori/genética , Humanos , Metronidazol/farmacologia , Testes de Sensibilidade Microbiana , Filogenia , RNA Ribossômico 16S/genética , RNA Ribossômico 23S , América do Sul , Neoplasias Gástricas/tratamento farmacológico
14.
PLoS Pathog ; 15(1): e1007468, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30703170

RESUMO

Helicobacter pylori (H. pylori) is the major risk factor for the development of gastric cancer. Our laboratory has reported that the Sonic Hedgehog (Shh) signaling pathway is an early response to infection that is fundamental to the initiation of H. pylori-induced gastritis. H. pylori also induces programmed death ligand 1 (PD-L1) expression on gastric epithelial cells, yet the mechanism is unknown. We hypothesize that H. pylori-induced PD-L1 expression within the gastric epithelium is mediated by the Shh signaling pathway during infection. To identify the role of Shh signaling as a mediator of H. pylori-induced PD-L1 expression, human gastric organoids generated from either induced pluripotent stem cells (HGOs) or tissue (huFGOs) were microinjected with bacteria and treated with Hedgehog/Gli inhibitor GANT61. Gastric epithelial monolayers generated from the huFGOs were also infected with H. pylori and treated with GANT61 to study the role of Hedgehog signaling as a mediator of induced PD-1 expression. A patient-derived organoid/autologous immune cell co-culture system infected with H. pylori and treated with PD-1 inhibitor (PD-1Inh) was developed to study the protective mechanism of PD-L1 in response to bacterial infection. H. pylori significantly increased PD-L1 expression in organoid cultures 48 hours post-infection when compared to uninfected controls. The mechanism was cytotoxic associated gene A (CagA) dependent. This response was blocked by pretreatment with GANT61. Anti-PD-L1 treatment of H. pylori infected huFGOs, co-cultured with autologous patient cytotoxic T lymphocytes and dendritic cells, induced organoid death. H. pylori-induced PD-L1 expression is mediated by the Shh signaling pathway within the gastric epithelium. Cells infected with H. pylori that express PD-L1 may be protected from the immune response, creating premalignant lesions progressing to gastric cancer.


Assuntos
Antígeno B7-H1/metabolismo , Infecções por Helicobacter/imunologia , Adolescente , Antígenos de Bactérias/genética , Antígeno B7-H1/genética , Células Epiteliais/metabolismo , Mucosa Gástrica/microbiologia , Gastrite/microbiologia , Regulação da Expressão Gênica/genética , Proteínas Hedgehog/metabolismo , Infecções por Helicobacter/genética , Helicobacter pylori/metabolismo , Helicobacter pylori/patogenicidade , Humanos , Organoides/microbiologia , Piridinas/farmacologia , Pirimidinas/farmacologia , Transdução de Sinais , Estômago , Adulto Jovem
15.
Mol Cell Proteomics ; 18(2): 352-371, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30455363

RESUMO

Helicobacter pylori is the strongest risk factor for gastric cancer. Initial interactions between H. pylori and its host originate at the microbial-gastric epithelial cell interface, and contact between H. pylori and gastric epithelium activates signaling pathways that drive oncogenesis. One microbial constituent that increases gastric cancer risk is the cag pathogenicity island, which encodes a type IV secretion system that translocates the effector protein, CagA, into host cells. We previously demonstrated that infection of Mongolian gerbils with a carcinogenic cag+H. pylori strain, 7.13, recapitulates many features of H. pylori-induced gastric cancer in humans. Therefore, we sought to define gastric proteomic changes induced by H. pylori that are critical for initiation of the gastric carcinogenic cascade. Gastric cell scrapings were harvested from H. pylori-infected and uninfected gerbils for quantitative proteomic analyses using isobaric tags for relative and absolute quantitation (iTRAQ). Quantitative proteomic analysis of samples from two biological replicate experiments quantified a total of 2764 proteins, 166 of which were significantly altered in abundance by H. pylori infection. Pathway mapping identified significantly altered inflammatory and cancer-signaling pathways that included Rab/Ras signaling proteins. Consistent with the iTRAQ results, RABEP2 and G3BP2 were significantly up-regulated in vitro, ex vivo in primary human gastric monolayers, and in vivo in gerbil gastric epithelium following infection with H. pylori strain 7.13 in a cag-dependent manner. Within human stomachs, RABEP2 and G3BP2 expression in gastric epithelium increased in parallel with the severity of premalignant and malignant lesions and was significantly elevated in intestinal metaplasia and dysplasia, as well as gastric adenocarcinoma, compared with gastritis alone. These results indicate that carcinogenic strains of H. pylori induce dramatic and specific changes within the gastric proteome in vivo and that a subset of altered proteins within pathways with oncogenic potential may facilitate the progression of gastric carcinogenesis in humans.


Assuntos
Proteínas de Transporte/metabolismo , Infecções por Helicobacter/complicações , Helicobacter pylori/patogenicidade , Neoplasias Gástricas/microbiologia , Proteínas de Transporte Vesicular/metabolismo , Proteínas Adaptadoras de Transdução de Sinal , Animais , Linhagem Celular , Modelos Animais de Doenças , Regulação Neoplásica da Expressão Gênica , Gerbillinae , Infecções por Helicobacter/microbiologia , Humanos , Mucosa Intestinal/metabolismo , Mucosa Intestinal/microbiologia , Masculino , Mapas de Interação de Proteínas , Proteômica , Proteínas de Ligação a RNA , Neoplasias Gástricas/metabolismo , Regulação para Cima
16.
Infect Immun ; 88(2)2020 01 22.
Artigo em Inglês | MEDLINE | ID: mdl-31712269

RESUMO

Helicobacter pylori colonizes the stomach in about half of the world's population. H. pylori strains containing the cag pathogenicity island (cag PAI) are associated with a higher risk of gastric adenocarcinoma or peptic ulcer disease than cag PAI-negative strains. The cag PAI encodes a type IV secretion system (T4SS) that mediates delivery of the CagA effector protein as well as nonprotein bacterial constituents into gastric epithelial cells. H. pylori-induced nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) activation and interleukin-8 (IL-8) secretion are attributed to T4SS-dependent delivery of lipopolysaccharide metabolites and peptidoglycan into host cells, and Toll-like receptor 9 (TLR9) activation is attributed to delivery of bacterial DNA. In this study, we analyzed the bacterial energetic requirements associated with these cellular alterations. Mutant strains lacking Cagα, Cagß, or CagE (putative ATPases corresponding to VirB11, VirD4, and VirB4 in prototypical T4SSs) were capable of T4SS core complex assembly but defective in CagA translocation into host cells. Thus, the three Cag ATPases are not functionally redundant. Cagα and CagE were required for H. pylori-induced NF-κB activation, IL-8 secretion, and TLR9 activation, but Cagß was dispensable for these responses. We identified putative ATP-binding motifs (Walker-A and Walker-B) in each of the ATPases and generated mutant strains in which these motifs were altered. Each of the Walker box mutant strains exhibited properties identical to those of the corresponding deletion mutant strains. These data suggest that Cag T4SS-dependent delivery of nonprotein bacterial constituents into host cells occurs through mechanisms different from those used for recruitment and delivery of CagA into host cells.


Assuntos
Antígenos de Bactérias/genética , Antígenos de Bactérias/metabolismo , Proteínas de Bactérias/genética , Proteínas de Bactérias/metabolismo , Células Epiteliais/microbiologia , Helicobacter pylori/genética , Helicobacter pylori/metabolismo , Sistemas de Secreção Tipo IV/genética , Sistemas de Secreção Tipo IV/metabolismo , Transporte Biológico , DNA Bacteriano/metabolismo , Humanos , Interleucina-8/metabolismo , Lipopolissacarídeos/metabolismo , NF-kappa B/metabolismo , Peptidoglicano/metabolismo , Receptor Toll-Like 9/metabolismo , Fatores de Virulência/genética , Fatores de Virulência/metabolismo
17.
Int J Cancer ; 146(11): 2999-3010, 2020 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-31472027

RESUMO

Gastric cancer remains a leading cause of cancer-related mortality. Identifying dietary and other modifiable disease determinants has important implications for risk attenuation in susceptible individuals. Our primary aim was to estimate the association between dietary and supplemental intakes of calcium and magnesium and the risk of incident gastric cancer. We conducted a prospective cohort analysis of the National Institutes of Health-American Association of Retired Persons Diet and Health Study. We used Cox proportional hazard modeling to estimate the association between calcium and magnesium intakes with risk of incident gastric adenocarcinoma (GA) overall and by anatomic location, noncardia GA (NCGA) and cardia GA (CGA). A total of 536,403 respondents (59% males, 41% females) were included for analysis, among whom 1,518 incident GAs (797 NCGA and 721 CGA) occurred. Increasing calcium intake was associated with lower risk of GA overall (p-trend = 0.05), driven primarily by the association with NCGA, where the above median calcium intakes were associated with a 23% reduction in risk compared to the lowest quartile (p-trend = 0.05). This magnitude of NCGA risk reduction was greater among nonwhite ethnic group and Hispanics (hazard ratio [HR] 0.51, 95% confidence interval [CI]: 0.24-1.07, p-trend = 0.04), current/former smokers (HR 0.58, 95% CI: 0.41-0.81), obese individuals (HR 0.54, 95% CI: 0.31-0.96) and those with high NCGA risk scores (HR 0.50, 95% CI: 0.31-0.80). Among men only, increasing magnesium intake was associated with 22-27% reduced risk of NCGA (p-trend = 0.05), while for the cohort, dietary magnesium intake in the highest vs. lowest quartile was associated with a 34% reduced risk of NCGA (HR 0.66, 95% CI: 0.48-0.90). These findings have important implications for risk factor modification. Future investigations are needed not only to confirm our results, but to define mechanisms underlying these associations.


Assuntos
Adenocarcinoma/prevenção & controle , Cálcio da Dieta/farmacologia , Magnésio/farmacologia , Neoplasias Gástricas/prevenção & controle , Adenocarcinoma/epidemiologia , Cárdia/patologia , Estudos de Coortes , Dieta , Suplementos Nutricionais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estado Nutricional/fisiologia , Estudos Prospectivos , Neoplasias Gástricas/dietoterapia , Neoplasias Gástricas/epidemiologia , Inquéritos e Questionários , Estados Unidos/epidemiologia
18.
Br J Cancer ; 122(12): 1857-1864, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32242097

RESUMO

BACKGROUND: Risk reduction through dietary modifications is an adjunct strategy for prevention of oesophageal cancer, a leading cause of cancer-related mortality and morbidity worldwide. We aimed to estimate the association between calcium and magnesium intakes and incident oesophageal cancer (OC). METHODS: We conducted a retrospective analysis of the NIH-AARP Diet and Health Study prospective cohort. We used multivariable Cox proportional hazard modeling to estimate the association between total intakes and incident OC overall and by histology (oesophageal squamous cell carcinoma (OSCC) and adenocarcinoma (OAC)). Sensitivity and stratified analyses were performed. RESULTS: Among 536,359 included respondents, 1414 incident OCs occurred over 6.5 million person-years follow-up time. Increasing dietary calcium intake was associated with an adjusted 32-41% lower risk of OSCC compared to the lowest quartile (p-trend 0.01). There was a positive association between increasing magnesium intake and OAC risk, but only among participants with low calcium:magnesium intake ratios (p-trend 0.04). There was a significant interaction with smoking status. CONCLUSIONS: Based on a retrospective analysis of the NIH-AARP Diet and Health Study prospective cohort, dietary intakes of calcium and magnesium were significantly associated with risk of OSCC and, among certain participants, OAC, respectively. If validated, these findings could inform dietary modifications among at-risk individuals. Mechanistic investigations would provide additional insight.


Assuntos
Cálcio da Dieta , Neoplasias Esofágicas/epidemiologia , Magnésio , Idoso , Dieta , Inquéritos sobre Dietas , Feminino , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Fatores de Risco
19.
Clin Gastroenterol Hepatol ; 18(13): 3026-3039, 2020 12.
Artigo em Inglês | MEDLINE | ID: mdl-32707341

RESUMO

BACKGROUND & AIMS: Endoscopic screening for gastric cancer is routine in some countries with high incidence and is associated with reduced gastric cancer-related mortality. Immigrants from countries of high incidence to low incidence of gastric cancer retain their elevated risk, but no screening recommendations have been made for these groups in the United States. We aimed to determine the cost effectiveness of different endoscopic screening strategies for noncardia gastric cancer, compared with no screening, among Chinese, Filipino, Southeast Asian, Vietnamese, Korean, and Japanese Americans. METHODS: We generated a decision-analytic Markov model to simulate a cohort of asymptomatic 50-year-old Asian Americans. The cost effectiveness of 2 distinct strategies for endoscopic gastric cancer screening was compared with no screening for each group, stratified by sex. Outcome measures were reported in incremental cost-effectiveness ratios (ICERs), with a willingness-to-pay threshold of $100,000/quality-adjusted life-year (QALY). Extensive sensitivity analyses were performed. RESULTS: Compared with performing no endoscopic gastric cancer screening, performing a 1-time upper endoscopy with biopsies, with continued endoscopic surveillance if gastric intestinal metaplasia was identified, was cost effective, whereas performing ongoing biennial endoscopies, even for patients with normal findings from endoscopy and histopathology, was not. The lowest ICERs were observed for Chinese, Japanese, and Korean Americans (all <$73,748/QALY). CONCLUSIONS: Endoscopic screening for gastric cancer with ongoing surveillance of gastric preneoplasia is cost effective for Asian Americans ages 50 years or older in the United States. The lowest ICERs were for Chinese, Japanese, and Korean Americans (all <$73,748/QALY).


Assuntos
Asiático , Neoplasias Gástricas , Análise Custo-Benefício , Detecção Precoce de Câncer , Gastroscopia , Humanos , Programas de Rastreamento , Pessoa de Meia-Idade , Anos de Vida Ajustados por Qualidade de Vida , Neoplasias Gástricas/diagnóstico , Estados Unidos
20.
Gastroenterology ; 156(1): 175-186.e2, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30296434

RESUMO

BACKGROUND & AIMS: Previous studies reported an association of the bacteria Helicobacter pylori, the primary cause of gastric cancer, and risk of colorectal cancer (CRC). However, these findings have been inconsistent, appear to vary with population characteristics, and may be specific for virulence factor VacA. To more thoroughly evaluate the potential association of H pylori antibodies with CRC risk, we assembled a large consortium of cohorts representing diverse populations in the United States. METHODS: We used H pylori multiplex serologic assays to analyze serum samples from 4063 incident cases of CRC, collected before diagnosis, and 4063 matched individuals without CRC (controls) from 10 prospective cohorts for antibody responses to 13 H pylori proteins, including virulence factors VacA and CagA. The association of seropositivity to H pylori proteins, as well as protein-specific antibody level, with odds of CRC was determined by conditional logistic regression. RESULTS: Overall, 40% of controls and 41% of cases were H pylori-seropositive (odds ratio [OR], 1.09; 95% CI, 0.99-1.20). H pylori VacA-specific seropositivity was associated with an 11% increased odds of CRC (OR, 1.11; 95% CI, 1.01-1.22), and this association was particularly strong among African Americans (OR, 1.45; 95% CI, 1.08-1.95). Additionally, odds of CRC increased with level of VacA antibody in the overall cohort (P = .008) and specifically among African Americans (P = .007). CONCLUSIONS: In an analysis of a large consortium of cohorts representing diverse populations, we found serologic responses to H pylori VacA to associate with increased risk of CRC risk, particularly for African Americans. Future studies should seek to understand whether this marker is related to virulent H pylori strains carried in these populations.


Assuntos
Anticorpos Antibacterianos/imunologia , Proteínas de Bactérias/imunologia , Neoplasias Colorretais/microbiologia , Infecções por Helicobacter/microbiologia , Helicobacter pylori/imunologia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Anticorpos Antibacterianos/sangue , Biomarcadores/sangue , Estudos de Casos e Controles , Neoplasias Colorretais/sangue , Neoplasias Colorretais/epidemiologia , Feminino , Infecções por Helicobacter/sangue , Infecções por Helicobacter/epidemiologia , Helicobacter pylori/patogenicidade , Interações Hospedeiro-Patógeno , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Fatores de Risco , Estudos Soroepidemiológicos , Estados Unidos/epidemiologia , Virulência , Adulto Jovem
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