Regional variations in Helicobacter pylori infection, gastric atrophy and gastric cancer risk: The ENIGMA study in Chile.

BACKGROUND: Regional variations in gastric cancer incidence are not explained by prevalence of Helicobacter pylori, the main cause of the disease, with several areas presenting high H. pylori prevalence but low gastric cancer incidence. The IARC worldwide H. pylori prevalence surveys (ENIGMA) aim at systematically describing age and sex-specific prevalence of H. pylori infection around the world and generating hypotheses to explain regional variations in gastric cancer risk. METHODS: We selected age- and sex-stratified population samples in two areas with different gastric cancer incidence and mortality in Chile: Antofagasta (lower rate) and Valdivia (higher rate). Participants were 1-69 years old and provided interviews and blood for anti-H. pylori antibodies (IgG, VacA, CagA, others) and atrophy biomarkers (pepsinogens). RESULTS: H. pylori seroprevalence (Age-standardized to world population) and antibodies against CagA and VacA were similar in both sites. H. pylori seroprevalence was 20% among children <10 years old, 40% among 10-19 year olds, 60% in the 20-29 year olds and close to or above 80% in those 30+ years. The comparison of the prevalence of known and potential H. pylori cofactors in gastric carcinogenesis between the high and the low risk area showed that consumption of chili products was significantly higher in Valdivia and daily non-green vegetable consumption was more common in Antofagasta. Pepsinogen levels suggestive of gastric atrophy were significantly more common and occurred at earlier ages in Valdivia, the higher risk area. In a multivariate model combining both study sites, age, chili consumption and CagA were the main risk factors for gastric atrophy. CONCLUSIONS: The prevalence of H. pylori infection and its virulence factors was similar in the high and the low risk area, but atrophy was more common and occurred at younger ages in the higher risk area. Dietary factors could partly explain higher rates of atrophy and gastric cancer in Valdivia. IMPACT: The ENIGMA study in Chile contributes to better understanding regional variations in gastric cancer incidence and provides essential information for public health interventions.

The Hippo Kinase LATS2 Controls Helicobacter pylori-Induced Epithelial-Mesenchymal Transition and Intestinal Metaplasia in Gastric Mucosa.

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

Distinct Campylobacter fetus lineages adapted as livestock pathogens and human pathobionts in the intestinal microbiota.

Campylobacter fetus is a venereal pathogen of cattle and sheep, and an opportunistic human pathogen. It is often assumed that C. fetus infection occurs in humans as a zoonosis through food chain transmission. Here we show that mammalian C. fetus consists of distinct evolutionary lineages, primarily associated with either human or bovine hosts. We use whole-genome phylogenetics on 182 strains from 17 countries to provide evidence that C. fetus may have originated in humans around 10,500 years ago and may have "jumped" into cattle during the livestock domestication period. We detect C. fetus genomes in 8% of healthy human fecal metagenomes, where the human-associated lineages are the dominant type (78%). Thus, our work suggests that C. fetus is an unappreciated human intestinal pathobiont likely spread by human to human transmission. This genome-based evolutionary framework will facilitate C. fetus epidemiology research and the development of improved molecular diagnostics and prevention schemes for this neglected pathogen.

Helicobacter pylori cagA and vacA genotypes in Cuban and Venezuelan populations.

The aim of this study was to determine the presence of Helicobacter pylori cytotoxin-associated gene (cagA)/vacuolating cytotoxin gene (vacA) among patients with chronic gastritis in Cuba and Venezuela. Gastric antrum biopsies were taken for culture, DNA extraction and PCR analysis. Amplification of vacA and cagA segments was performed using two regions of cagA: 349 bp were amplified with the F1/B1 primers and the remaining 335 bp were amplified with the B7629/B7628 primers. The VA1-F/VA1-R set of primers was used to amplify the 259-bp (s1) or 286-bp (s2) product and the VAG-R/VAG-F set of primers was used to amplify the 567-bp (m1) or 642-bp (m2) regions of vacA. cagA was detected in 87% of the antral samples from Cuban patients and 80.3% of those from Venezuelan patients. All possible combinations of vacA regions were found, with the exception of s2/m1. The predominant combination found in both countries was s1/m1. The percentage of cagA+ strains was increased by the use of a second set of primers and a greater number of strains was amplified with the B7629/B7628 primers in the Cuban patients (p = 0.0001). There was no significant difference between the presence of the allelic variants of vacA and cagA in both populations. The predominant genotype was cagA+/s1m1 in both countries. The results support the necessary investigation of isolates circulating among the human population in each region.

Helicobacter pylori cagA and vacA genotypes in Cuban and Venezuelan populations

The aim of this study was to determine the presence of Helicobacter pylori cytotoxin-associated gene (cagA)/vacuolating cytotoxin gene (vacA) among patients with chronic gastritis in Cuba and Venezuela. Gastric antrum biopsies were taken for culture, DNA extraction and PCR analysis. Amplification of vacA and cagA segments was performed using two regions of cagA: 349 bp were amplified with the F1/B1 primers and the remaining 335 bp were amplified with the B7629/B7628 primers. The VA1-F/VA1-R set of primers was used to amplify the 259-bp (s1) or 286-bp (s2) product and the VAG-R/VAG-F set of primers was used to amplify the 567-bp (m1) or 642-bp (m2) regions of vacA. cagA was detected in 87 percent of the antral samples from Cuban patients and 80.3 percent of those from Venezuelan patients. All possible combinations of vacA regions were found, with the exception of s2/m1. The predominant combination found in both countries was s1/m1. The percentage of cagA+ strains was increased by the use of a second set of primers and a greater number of strains was amplified with the B7629/B7628 primers in the Cuban patients (p = 0.0001). There was no significant difference between the presence of the allelic variants of vacA and cagA in both populations. The predominant genotype was cagA+/s1m1 in both countries. The results support the necessary investigation of isolates circulating among the human population in each region.

Relation of atrophic gastritis with Helicobacter pylori-CagA(+) and interleukin-1 gene polymorphisms.

AIM: To determine the association of Helicobacter pylori (H pylori) CagA(+) infection and pro-inflammatory polymorphisms of the genes interleukin (IL)-1RN and IL-1B with the risk of gastric atrophy and peptic ulcers in a dyspeptic population in Costa Rica, a country with high incidence and mortality of gastric cancer. METHODS: Seven biopsy specimens, a fasting blood sample and a questionnaire concerning nutritional and sociodemographic factors were obtained from 501 consecutive patients who had undergone endoscopy for dyspeptic symptoms. A histopathological diagnosis was made. Pepsinogen concentrations were analyzed by enzyme linked immunosorbent assay (ELISA). Infection with H pylori CagA(+) was determined by serology and polymerase chain reaction (PCR). IL-1B and IL-1RN polymorphisms genotyping was performed by PCR-restriction fragment length polymorphism (PCR-RFLP) and PCR respectively. RESULTS: In this dyspeptic population, 86% were H pylori positive and of these, 67.8% were positive for CagA. Atrophic antral gastritis (AAG) was associated with CagA(+) status [odd ratio (OR) = 4.1; P < 0.000] and fruit consumption (OR = 0.3; P < 0.00). Atrophic body gastritis (ABG) was associated with pepsinogen PGI/PGII < 3.4 (OR = 4.9; P < 0.04) and alcohol consumption (OR = 7.3; P < 0.02). Duodenal ulcer was associated with CagA(+) (OR = 2.9; P < 0.04) and smoking (OR = 2.4; P < 0.04). PGI < 60 microg/L as well as PGI/PGII < 3.4 were associated with CagA(+). CONCLUSION: In a dyspeptic population in Costa Rica, H pylori CagA(+) is not associated with ABG, but it is a risk factor for AAG. The pro-inflammatory cytokine polymorphisms IL-1B + 3945 and IL-1RN are not associated with the atrophic lesions of this dyspeptic population.

Seroprevalencia de la infección por Helicobacter pylori en pacientes con Gastritis Crónica, Úlcera Duodenal y Gástrica: primer estudio de corte retrospectivo / Seroprevalence of Helicobacter pylori infection in chronic gastritis patients, duodenal and gastric ulcer patients

Objectivo. El objetivo de este estudio fue analizar la seroprevalencia de la población en tres centros hospitalarios, correspondientes a tres países; Venezuela, Cuba y República Dominicana. Métodos. El total de pacientes estudiados fueron 300, Se emplearon las técnicas Microwell ELISA de Diagnostic Automation INC (U.S.A.) y Pyloriset EIA-IIIG de Orion Diagnostic (Finland), para determinar la seroprevalencia de H. pylori (IgG) en los sueros obtenidos. La causa de las endoscopías en el 100 por ciento fue epigastralgias. El promedio de edad fue 46 años, con 127/300 (42 por ciento) hombres y 173/300 (58 por ciento) mujeres. Resultados. De acuerdo al diagnóstico endoscópico se obtuvieron los siguientes resultados: úlcera duodenal: 31/300 (10 por ciento); úlcera gástrica: 27/300 (9 por ciento); dispepsia no ulcerosa, incluyendo gastritis: 242/300 (81 por ciento). Del total de los 300 sueros testados, el 100 por ciento de estos fueron positivos para cada país, para anticuerpos IgG anti H. pylori. Conclusiones. Existe poca información acerca de la infección por Helicobacter pylori en los países de la región del Caribe y Latinoamérica, por lo que se requieren más estudios para completar la epidemiología de la infección a H.pylori en la región(AU)

Objective. Our aim was to determine the (Hp)-seroprevalence of the infection in a group of 300 consecutive adult subjects population submitted to upper digestive tract endoscopy clinics in three countries, Venezuela, Cuba and República Dominicana. Methods. The total patients (300). Serology (IgG) was performed using Microwell ELISA from Diagnostic Automation INC (U.S.A.) and Pyloriset E IA-IIIG de Orion Diagnostic (Finland). Patients had the following endoscopic Diagnosis: duodenal ulcer 31/300 (10 percent); gastric ulcer: 27/300 (9 percent); non ulcer dyspepsia, including chronic gastritis: 242/300 (81 percent). The mean age was 46 years with 127/300 (42 percent) men and 173/300 (58 percent) women. Results. Among the 300 serums tested, 100 percent were positive in Venezuela, Cuba and Dominican Republic. The (Hp)-seroprevalence of H. pylori infection in the symptomatic population of La Havana-Cuba, Caracas-Venezuela and Santo Domingo- República Dominicana. Conclusions. There is a great paucity of information about Helicobacter pylori infection in the countries of the Caribbean basin. These results indicate the importance for further studies to identify factors influencing the high prevalence of the infection with H. pylori in the region(AU)

Seroprevalencia de la infección por Helicobacter pylori en pacientes con Gastritis Crónica, Úlcera Duodenal y Gástrica: primer estudio de corte retrospectivo / Seroprevalence of Helicobacter pylori infection in chronic gastritis patients, duodenal and gastric ulcer patients

Objectivo. El objetivo de este estudio fue analizar la seroprevalencia de la población en tres centros hospitalarios, correspondientes a tres países; Venezuela, Cuba y República Dominicana. Métodos. El total de pacientes estudiados fueron 300, Se emplearon las técnicas Microwell ELISA de Diagnostic Automation INC (U.S.A.) y Pyloriset EIA-IIIG de Orion Diagnostic (Finland), para determinar la seroprevalencia de H. pylori (IgG) en los sueros obtenidos. La causa de las endoscopías en el 100 por ciento fue epigastralgias. El promedio de edad fue 46 años, con 127/300 (42 por ciento) hombres y 173/300 (58 por ciento) mujeres. Resultados. De acuerdo al diagnóstico endoscópico se obtuvieron los siguientes resultados: úlcera duodenal: 31/300 (10 por ciento); úlcera gástrica: 27/300 (9 por ciento); dispepsia no ulcerosa, incluyendo gastritis: 242/300 (81 por ciento). Del total de los 300 sueros testados, el 100 por ciento de estos fueron positivos para cada país, para anticuerpos IgG anti H. pylori. Conclusiones. Existe poca información acerca de la infección por Helicobacter pylori en los países de la región del Caribe y Latinoamérica, por lo que se requieren más estudios para completar la epidemiología de la infección a H.pylori en la región.

Objective. Our aim was to determine the (Hp)-seroprevalence of the infection in a group of 300 consecutive adult subjects population submitted to upper digestive tract endoscopy clinics in three countries, Venezuela, Cuba and República Dominicana. Methods. The total patients (300). Serology (IgG) was performed using Microwell ELISA from Diagnostic Automation INC (U.S.A.) and Pyloriset E IA-IIIG de Orion Diagnostic (Finland). Patients had the following endoscopic Diagnosis: duodenal ulcer 31/300 (10 percent); gastric ulcer: 27/300 (9 percent); non ulcer dyspepsia, including chronic gastritis: 242/300 (81 percent). The mean age was 46 years with 127/300 (42 percent) men and 173/300 (58 percent) women. Results. Among the 300 serums tested, 100 percent were positive in Venezuela, Cuba and Dominican Republic. The (Hp)-seroprevalence of H. pylori infection in the symptomatic population of La Havana-Cuba, Caracas-Venezuela and Santo Domingo- República Dominicana. Conclusions. There is a great paucity of information about Helicobacter pylori infection in the countries of the Caribbean basin. These results indicate the importance for further studies to identify factors influencing the high prevalence of the infection with H. pylori in the region.

Helicobacter pylori infection in Havana, Cuba: prevalenceand cagA status of the strains

There is a great paucity of information about Helicobacter pylori infection in the countries of the Caribbean basin. Almost no studies have been performed to determine the prevalence, antibiotic resistance or virulence factors of the bacterium. To measure the prevalence of H. pylori infection among patients attending endoscopy in three clinics in Havana, Cuba, toevaluate clarithromycin resistance, and to determine the cagA status of the strains obtained. Endoscopy was performed and biopsies were obtained from 117 successive patients attending the Institute of Oncology, the Institute of Gastroenterology, and the Calixto Garcia Hospital in Havana, Cuba. Biopsies were maintained at –70 ºC before being cultured on three different media (two selective and one non-selective) and incubated for 7 days at 37 °C under a microaerobic atmosphere. The presence of H. pylori was identified by oxidase, catalase and urease activities. DNA was extracted, and PCR was performed with primers H2761676 which amplify a 397 bp fragment of the cagA gene. Clarithromycin susceptibility was measured bythe gel diffusion method. The diagnoses of patients were: 1 gastric carcinoma; 19 duodenal ulcers; 8 gastric ulcers; and 89 non-ulcer dyspepsia, including (62) gastritis, (9) hiatalhernia,(2) biliary reflux, (1) gastric polyps, and (15) no abnormality. Among the 117 biopsies tested, 83 were H. pylori positive (70.9percent). The cagA status determined for 35 cases gave a positive result in 31 cases (88.5percent). Only 3por ciento of the strains were resistant to clarithromycin.The prevalence of Helicobacter pylori infection in the symptomatic population of La Habana is the same as reported for other developing countries. Most strains were cagA positive and are likely harbour the cag pathogenicity island. The low resistance to clarithromycin in the strains studied probably reflects the low degree of use of the antibiotic in this population(AU)

Comparison of non-invasive tests to detect Helicobacter pylori infection in children and adolescents: results of a multicenter European study.

OBJECTIVE: To compare the current non-invasive tests for Helicobacter pylori infection in children and adolescents. STUDY DESIGN: This multicenter, multinational study investigated the sensitivity, specificity, and positive and negative predictive values of four non-invasive tests: urea breath test (UBT), stool antigen test, and antibody detection in serum and urine, in comparison with biopsy-based tests. RESULTS: Of 503 patients included pre-treatment, 473 fulfilled the definition of H pylori status and among those 316 had results available for the four non-invasive tests (including 133 H pylori -positive patients). The specificity was excellent for all tests. The UBT had the best sensitivity in all age groups, followed by serology, stool test, and antibody detection in urine. A trend for better sensitivity with an increase in age was observed except for the stool test. The receiver operating characteristics (ROC) curves showed that sensitivity of serology, stool test, and urinelisa could be improved by changing the cutoff value. An inadequate storage of the specimens may explain the poor results of the stool test. CONCLUSION: The UBT appears to be an excellent test for diagnosis of H pylori infection for children and adolescents.

The cag pathogenicity island of Helicobacter pylori is disrupted in the majority of patient isolates from different human populations.

The cag pathogenicity island (cag-PAI) is one of the major virulence determinants of Helicobacter pylori. The chromosomal integrity of this island or the lack thereof is speculated to play an important role in the progress of the gastroduodenal pathology caused by H. pylori. We determined the integrity of the cag-PAI by using specific flanking and internally anchored PCR primers to know the biogeographical distribution of strains carrying fully integral cag-PAI with proinflammatory behavior in vivo. Genotypes based on eight selected loci were studied in 335 isolates obtained from eight different geographic regions. The cag-PAI appeared to be disrupted in the majority of patient isolates throughout the world. Conservation of cag-PAI was highest in Japanese isolates (57.1%). However, only 18.6% of the Peruvian and 12% of the Indian isolates carried an intact cag-PAI. The integrity of cag-PAI in European and African strains was minimal. All 10 strains from Costa Rica had rearrangements. Overall, a majority of the strains of East Asian ancestry were found to have intact cag-PAI compared to strains of other descent. We also found that the cagE and cagT genes were less often rearranged (18%) than the cagA gene (27%). We attempted to relate cag-PAI rearrangement patterns to disease outcome. Deletion frequencies of cagA, cagE, and cagT genes were higher in benign cases than in isolates from severe ulcers and gastric cancer. Conversely, the cagA promoter and the left end of the cag-PAI were frequently rearranged or deleted in isolates linked to severe pathology. Analysis of the cag-PAI genotypes with a different biogeoclimatic history will contribute to our understanding of the pathogen-host interaction in health and disease.