Helicobacter pylori infection, serum pepsinogens as markers of atrophic gastritis, and leukocyte telomere length: a population-based study.
ABSTRACT: BACKGROUND:Persistent infections that induce prolonged inflammation might negatively affect the leukocyte telomere length (LTL); however, the role in LTL of Helicobacter pylori (H. pylori) infection, which persistently colonizes the stomach, remains unknown. The study objective was to examine associations of sero-prevalence of H. pylori immunoglobulin G (IgG) antibody and serum pepsinogens (PGs), as markers of atrophic gastritis, with LTL. A cross-sectional study was performed among 934 Arab residents of East Jerusalem, aged 27-78 years, randomly selected from Israel's national population registry. Sera were tested for H. pylori IgG and PG levels by ELISA. LTL was measured by southern blots. Multiple linear regression models were fitted to adjust for sociodemographic and lifestyle factors. RESULTS:LTL decreased significantly with age (p < 0.001) and was shorter in men than women (p = 0.032). The mean LTL was longer in H. pylori sero-positive persons than negative ones: mean difference 0.13 kb (95% CI 0.02, 0.24), p = 0.016. Participants with atrophic gastritis (PGI < 30 μg/L or a PGI: PGII < 3.0) had shorter LTL than did those without: mean difference - 0.18 (95% CI - 0.32, - 0.04). The difference was of larger magnitude between persons who had past H. pylori infection (sero-negative to H. pylori IgG antibody) and atrophic gastritis, compared to those who were H. pylori sero-negative and did not have atrophic gastritis: mean difference - 0.32 kb (95% CI - 0.55, - 0.10). This association remained significant after adjustment for age, sex, and religiosity: beta coefficient - 0.21 kb (95% CI - 0.41, - 0.001), p = 0.049. The results were similar after further adjustment for lifestyle factors. In bivariate analysis, mean LTL was longer in physically active persons than non-active ones, and shorter in persons with than without obesity; however, these differences were diminished and were not significant in the multivariable model. CONCLUSIONS:H. pylori IgG sero-positivity per se was not related to reduced LTL. However, persons with past H. pylori infection (i.e., lacking H. pylori IgG serum antibody) and with serological evidence of atrophic gastritis, had a significantly shorter LTL than did those without atrophic gastritis.
Project description:Associations observed of Helicobacter pylori infection with haemoglobin levels are inconsistent. We examined associations of H. pylori sero-prevalence and serum pepsinogens (PGs), as non-invasive markers of atrophic gastritis, with haemoglobin levels. A cross-sectional study was undertaken among 654 Jewish and 937 Arab residents of Jerusalem, aged 25-78 years, randomly selected from Israel's national population registry in age-sex and population strata. Sera were tested for H. pylori IgG, cytotoxin-associated gene A (CagA) antigen IgG antibody and PGs levels. Multivariable models were fitted to account for confounders. Participants with atrophic gastritis (PGI?<?30??g/L or a PGI: PGII?<?3.0) had lower haemoglobin levels than those without: beta-coefficient -0.34 (95% CI -0.59, -0.09); in men -0.27 (95% CI -0.67, 0.12), and in women -0.43 (95% CI -0.74, -0.12). Lower haemoglobin levels were noted in persons with CagA antibody than in those H. pylori sero-negative or H. pylori-CagA sero-negative: beta-coefficient -0.14 (95% CI -0.29, 0.01). Anaemia was more common among women and men with than without atrophic gastritis: adjusted OR 2.58 (95% CI 1.48, 4.48) and 1.52 (95% CI 0.59, 3.95), respectively. In conclusion, independent of known correlates, atrophic gastritis and apparently CagA sero-positivity, a marker of H. pylori virulent strains, are associated with lower haemoglobin levels.
Project description:OBJECTIVE:Understanding the correlates of premalignant gastric lesions is essential for gastric cancer prevention. We examined the prevalence and correlates of serological evidence of atrophic gastritis, a premalignant gastric condition, using serum pepsinogens (PGs) in two populations with differing trends in gastric cancer incidence. METHODS:In a cross-sectional study, using ELISA we measured serum PGI and PGII concentrations (Biohit, Finland), Helicobacter pylori serum IgG and cytotoxin-associated gene A (CagA) antigen IgG antibodies in archived sera of 692 Jews and 952 Arabs aged 25-78 years, randomly selected from Israel's population registry in age-sex and population strata. Multivariable logistic regression analyses were performed. RESULTS:Using cut-offs of PGI <30µg/L ?or PGI:PGII <3.0, the prevalence of atrophic gastritis was higher among Arab than Jewish participants: 8.8% (95% CIs 7.2% to 10.8%) vs 5.9% (95% CI 4.4% to 7.9%), increasing with age in both groups (p<0.001 for trend). Among Jewish participants, infection with H. pylori CagA phenotype was positively related to atrophic gastritis: adjusted OR (aOR) 2.16 (95% CI 0.94 to 4.97), but not to non-CagA infections aOR 1.17 (95% CI 0.53 to 2.55). The opposite was found among Arabs: aOR 0.09 (95% CI 0.03 to 0.24) for CagA positive and aOR 0.15 (95% CI 0.06 to 0.41) for Cag A negative phenotypes (p<0.001 for interaction). Women had a higher atrophic gastritis prevalence than men. Obesity and smoking were not significantly related to atrophic gastritis; physical activity tended to be inversely associated in Arabs (p=0.08 for interaction). CONCLUSIONS:The prevalence of atrophic gastritis was higher among Arabs than Jews and was differently associated with the CagA phenotype.
Project description:BACKGROUND: Helicobacter pylori urease is a major target for immune responses among various bacterial components in H pylori infected patients. AIMS: To analyse the relation between systemic and local humoral immune responses to H pylori urease and grades of chronic gastritis. PATIENTS: Seventy five patients with chronic gastritis associated with H pylori infection were classified into three groups (grade I, superficial gastritis; II, atrophic gastritis, quiescent; or III, atrophic gastritis, active). METHODS: Anti-H pylori urease specific antibodies in the serum, gastric juice, and biopsy specimens were determined by ELISA or western blotting analysis. The sites for H pylori urease and its specific antibody producing B lymphocytes were confirmed by immunohistochemical analysis. RESULTS: In the sera of patients with grade I gastritis, weak IgG but relatively strong IgG responses to H pylori urease were observed; dominant strong IgG responses were detected in grade II gastritis. In grade III gastritis, significant IgG and IgA responses were obtained. A similar pattern of IgA and IgG responses was detected in gastric juice and tissue. H pylori urease specific, antibody producing B cells were not found in the gastric mucosa of patients with grade I gastritis despite the presence of such B cells in the duodenal bulb. Specific B cells were observed in the gastric mucosa of patients with grade II and III gastritis with atrophy. CONCLUSIONS: Purified H pylori urease, together with localisation of its specific antibody producing B cells, are useful for serological testing and histopathological analysis for determining the stage of chronic gastritis and studying the pathogenesis of H pylori infection.
Project description:The study aimed to investigate the role of serum EBV-VCA IgG in assessing gastric cancer (GC) risk and prognosis. A total of 1790 Northern Chinese participants with pathologically confirmed disease underwent EBV-VCA IgG serologic testing using enzyme-linked immunosorbent assay (ELISA), including 821 controls, 410 atrophic gastritis (AG) patients, and 559 GC patients. We found that positive EBV-VCA IgG was significantly associated with GC and its precursor, conferring a 1.55- and 1.36-fold increased risk of GC and AG, respectively (P = 0.001, 95% CI = 1.21-1.99; P = 0.011, 95% CI = 1.07-1.72, respectively). The risk effects were more remarkable in younger, female, and Helicobacter pylori-negative individuals than in older, male, and H. pylori-positive individuals. EBV-VCA IgG-positive subjects had a lower PGI/II ratio than EBV-VCA IgG-negative subjects (median 8.0 vs 8.8, P = 0.001), especially those in the H. pylori-positive (median 6.1 vs 6.8, P = 0.027) and GC subgroups (median 6.4 vs 7.9, P = 0.020). In the intestinal GC subgroup, the survival of EBV-VCA IgG-positive patients was worse than that of EBV-VCA IgG-negative patients (P = 0.041, HR = 2.45, 95% CI = 1.04-5.78). Our study suggests that EBV-VCA IgG seropositivity has potential in predicting the risk of GC and its precursor as well as the prognosis of histologically classified GC.
Project description:Several conditions associated with reduced gastric acid secretion confer an altered risk of developing a gastric malignancy. Helicobacter pylori-induced atrophic gastritis predisposes to gastric adenocarcinoma, autoimmune atrophic gastritis is a precursor of type I gastric neuroendocrine tumours, whereas proton pump inhibitor (PPI) use does not affect stomach cancer risk. We hypothesised that each of these conditions was associated with specific alterations in the gastric microbiota and that this influenced subsequent tumour risk. 95 patients (in groups representing normal stomach, PPI treated, H. pylori gastritis, H. pylori-induced atrophic gastritis and autoimmune atrophic gastritis) were selected from a cohort of 1400. RNA extracted from gastric corpus biopsies was analysed using 16S rRNA sequencing (MiSeq). Samples from normal stomachs and patients treated with PPIs demonstrated similarly high microbial diversity. Patients with autoimmune atrophic gastritis also exhibited relatively high microbial diversity, but with samples dominated by Streptococcus. H. pylori colonisation was associated with decreased microbial diversity and reduced complexity of co-occurrence networks. H. pylori-induced atrophic gastritis resulted in lower bacterial abundances and diversity, whereas autoimmune atrophic gastritis resulted in greater bacterial abundance and equally high diversity compared to normal stomachs. Pathway analysis suggested that glucose-6-phospahte1-dehydrogenase and D-lactate dehydrogenase were over represented in H. pylori-induced atrophic gastritis versus autoimmune atrophic gastritis, and that both these groups showed increases in fumarate reductase. Autoimmune and H. pylori-induced atrophic gastritis were associated with different gastric microbial profiles. PPI treated patients showed relatively few alterations in the gastric microbiota compared to healthy subjects.
Project description:<h4>Background</h4>Pepsinogen (PG) II (PGII) is a serological marker used to estimate the risk of gastric cancer but how PGII expression is regulated is largely unknown. It has been suggested that PGII expression, from the <i>PGC</i> (Progastricsin) gene, is regulated by microRNAs (miRNA), but how PGII levels vary with <i>Helicobacter pylori (H. pylori)</i> infection and miRNAs genotype remains unclear.<h4>Methods</h4>Serum levels of PGI and PGII were determined in 80 patients with gastric cancer and persons at risk for gastric cancer (74 first-degree relatives of patients, 62 patients with autoimmune chronic atrophic gastritis, and 2 patients with dysplasia), with and without <i>H. pylori</i> infection. As control from the general population, 52 blood donors were added to the analyses. Associations between PGII levels and genetic variants in <i>PGC</i> and miRNA genes in these groups were explored based on <i>H. pylori</i> seropositivity and the risk for gastric cancer. The two-dimensional difference in gel electrophoresis (2D-DIGE) and the NanoString analysis of messenger RNA (mRNAs) from gastric cancer tissue were used to determine the pathways associated with increased PGII levels.<h4>Results</h4>PGII levels were significantly higher in patients with gastric cancer, and in those with <i>H. pylori</i> infection, than in other patients or controls. A PGI/PGII ratio ? 3 was found better than PGI < 25 ng/mL to identify patients with gastric cancer (15.0% vs. 8.8%). For two genetic variants, namely rs8111742 in miR-Let-7e and rs121224 in miR-365b, there were significant differences in PGII levels between genotype groups among patients with gastric cancer (<i>p</i> = 0.02 and <i>p</i> = 0.01, respectively), but not among other study subjects. Moreover, a strict relation between rs9471643 C-allele with <i>H. pylori</i> infection and gastric cancer was underlined. Fold change in gene expression of mRNA isolated from gastric cancer tissue correlated well with polymorphism, <i>H. pylori</i> infection, increased PGII level, and pathway for bacteria cell entry into the host.<h4>Conclusions</h4>Serum PGII levels depend in part on an interaction between <i>H. pylori</i> and host miRNA genotypes, which may interfere with the cut-off of PGI/PGII ratio used to identify persons at risk of gastric cancer. Results reported new findings regarding the relation among <i>H. pylori</i>, PGII-related host polymorphism, and genes involved in this interaction in the gastric cancer setting.
Project description:BACKGROUND: Gastric carcinogenesis is a multifactorial, multistep process, in which chronic inflammation plays a major role. AIMS: In order to ascertain whether free radical mediated oxidative DNA damage is involved in such a process, concentrations of 8-hydroxydeoxyguanosine (8OHdG), a mutagenic/carcinogenic adduct, and thiobarbituric acid reactive substances (TBARS), as an indirect measure of free radical mediated damage, were determined in biopsy specimens from patients undergoing endoscopy. PATIENTS: Eighty eight patients were divided into histological subgroups as follows: 27 with chronic non-atrophic gastritis, 41 with atrophic gastritis, six with gastric cancer, and 14 unaffected controls. METHODS: Intestinal metaplasia, Helicobacter pylori infection, and disease activity were semiquantitatively scored. 8OHdG concentrations were assessed by HPLC with electrochemical detection, and TBARS concentrations were fluorimetrically assayed. RESULTS: 8OHdG concentrations (mean number of adducts/10(5) dG residues) were significantly higher in chronic atrophic gastritis (p = 0.0009). Significantly higher concentrations were also detected in the presence of severe disease activity (p = 0.02), intestinal metaplasia (p = 0.035), and H pylori infection (p = 0.001). TBARS concentrations were also higher in atrophic gastritis, though not significantly so. In a multiple logistic regression analysis, 8OHdG concentrations correlated best with the presence and severity of H pylori infection (r = 0.53, p = 0.002). CONCLUSION: Chronic gastritis is characterised by the accumulation of oxidative DNA damage with mutagenic and carcinogenic potential. H pylori infection is the major determinant for DNA adduct formation.
Project description:INTRODUCTION:Non-Helicobacter pylori microbiota might account for some cases with unexplained chronic gastritis that may in a minority eventually progress to gastric cancer through the Correa cascade. We characterized gastric microbiota by describing the normal stomach, compared it with early precancerous lesions and other disease states, and assessed whether H. pylori status affects bacterial diversity. METHODS:In a population-based study of those with and without gastrointestinal symptoms, cytology brush samples were collected during endoscopy from 316 individuals. Mucosal status was classified as normal mucosa (171), nonatrophic H. pylori gastritis (33), atrophic gastritis (12), or antral chemical gastritis (61). The 16S rRNA gene sequencing and analysis were performed to characterize the microbiota. RESULTS:Microbiota in atrophic gastritis and nonatrophic H. pylori gastritis stomachs were dysbiotic and differed from those in the normal stomach (P = 0.001). The normal stomach had the highest microbial diversity, followed by antral chemical gastritis. The atrophic gastritis and chronic H. pylori gastritis groups had the lowest diversity, a difference that was statistically significant (P = 0.01). Besides H. pylori, non-H. pylori bacteria accounted for group differences. Microbial network analysis showed that the normal group network was most highly connected, whereas the H. pylori gastritis group had the lowest connection. We found an increasing positive co-occurrence of oral bacteria in the stomach because samples deviated from the normal network, some of which were pathogens. The H. pylori-negative group had the highest microbial diversity (Shannon index) compared with the H. pylori-positive group (P = 0.001). DISCUSSION:In this low-H. pylori prevalence general population, the gastric mucosal microbiota of the normal stomach differed significantly from those with nonatrophic or atrophic gastritis. There was an increasing abundance of pathogenic bacteria from the normal state to early precancerous states.
Project description:Aberrant let-7c microRNA (miRNA) expression has been observed in Helicobacter pylori-related gastric cancer (GC) but fragmentary information is available on the let-7c dysregulation occurring with each phenotypic change involved in gastric carcinogenesis. Let-7c expression was assessed (qRT-PCR) in a series of 175 gastric biopsy samples representative of the whole spectrum of phenotypic changes involved in H. pylori-related gastric oncogenesis including: i) normal gastric mucosa, as obtained from dyspeptic controls (40 biopsy samples); ii) non-atrophic gastritis (40 samples); iii) atrophic-metaplastic gastritis (35 samples); iv) intra-epithelial neoplasia (30 samples); v) GC (30 samples). Let-7c expression was also tested in 20 biopsy samples obtained from 10 patients before and after H. pylori eradication therapy (median follow-up: 10 weeks; range: 7-14). The results obtained were further validated by in situ hybridization on multiple tissue specimens obtained from 5 surgically treated H. pylori-related GCs. The study also included 40 oxyntic biopsy samples obtained from serologically/histologically confirmed autoimmune gastritis (AIG: 20 corpus-restricted, non-atrophic; 20 corpus-restricted, atrophic-metaplastic). Let-7c expression dropped from non-atrophic gastritis to atrophic-metaplastic gastritis, intra-epithelial neoplasia, and invasive GC (p<0.001). It rose again significantly following H. pylori eradication (p=0.009). As in the H. pylori model, AIG also featured a significant let-7c down-regulation (p<0.001). The earliest phases of the two pathways to gastric oncogenesis (H. pylori-environmental and autoimmune host-related) are characterized by similar let-7c dysregulations. In H. pylori infection, let-7c down-regulation regresses after the bacterium's eradication, while it progresses significantly with the increasing severity of the histological lesions.
Project description:MiR-27a rs895819 is a loop-stem structure single nucleotide polymorphism affecting mature miR-27a function. In this study, we performed a comprehensive analysis about the association of rs895819 with gastric cancer risk and prognosis, atrophic gastritis risk, as well as the interactions with environmental factors. A total of 939 gastric cancer patients, 1,067 atrophic gastritis patients and 1,166 healthy controls were screened by direct sequencing and MALDI-TOF-MS. The association of rs895819 with clinical pathological parameters and prognostic survival in 357 gastric cancer patients was also been analyzed. The rs895819 variant genotype increased the risk for atrophic gastritis (1.58-fold) and gastric cancer (1.24-fold). While in stratified analysis, the risk effect was demonstrated more significantly in the female, age >60y, Helicobacter pylori (H. pylori) negative and non-drinker subgroups. Rs895819 and H. pylori showed an interaction effect for atrophic gastritis risk. In the survival analysis, the rs895819 AG heterozygosis was associated with better survival than the AA wild-type in the TNM stage I-II subgroup. In vitro study by overexpressing miR-27a, cells carrying polymorphic-type G allele expressed lower miR-27a than wild-type A allele. In conclusion, miR-27a rs895819 is implicated as a biomarker for gastric cancer and atrophic gastritis risk, and interacts with H. pylori in gastric carcinogenesis.