Variants in autophagy genes affect susceptibility to both Crohn's disease and Helicobacter pylori infection.
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ABSTRACT:
SUBMITTER: Zavros Y
PROVIDER: S-EPMC5013528 | biostudies-literature | 2012 May
REPOSITORIES: biostudies-literature
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Variants in autophagy genes affect susceptibility to both Crohn's disease and Helicobacter pylori infection.
Zavros Yana Y Rogler Gerhard G
Gastroenterology 20120323 5
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Project description:In vitro studies have shown that Helicobacter pylori (H. pylori) infection induces autophagy in gastric epithelial cells. However, prolonged exposure to H. pylori reduces autophagy by preventing maturation of the autolysosome. The alterations of the autophagy-related genes in H. pylori infection are not yet fully understood. We analyzed autophagy-related gene expression in H. pylori-infected gastric mucosa compared with uninfected gastric mucosa obtained from 136 Bhutanese volunteers with mild dyspeptic symptoms. We also studied single nucleotide polymorphisms (SNPs) of autophagy-related gene in 283 Bhutanese participants to identify the influence on susceptibility to H. pylori infection. Microarray analysis of 226 autophagy-related genes showed that 16 genes were upregulated (7%) and nine were downregulated (4%). We used quantitative reverse transcriptase polymerase chain reaction to measure mRNA levels of the downregulated genes (ATG16L1, ATG5, ATG4D, and ATG9A) that were core molecules of autophagy. ATG16L1 and ATG5 mRNA levels in H. pylori-positive specimens (n=86) were significantly less than those in H. pylori-negative specimens (n=50). ATG16L1 mRNA levels were inversely related to H. pylori density. We also compared SNPs of ATG16L1 (rs2241880) among 206 H. pylori-positive and 77 H. pylori-negative subjects. The odds ratio for the presence of H. pylori in the GG genotype was 0.40 (95% CI: 0.18-0.91) relative to the AA/AG genotypes. Autophagy-related gene expression profiling using high-throughput microarray analysis indicated that downregulation of core autophagy machinery genes may depress autophagy functions and possibly provide a better intracellular habit for H. pylori in gastric epithelial cells.
| S-EPMC5422124 | biostudies-literature
Project description:The Helicobacter pylori toxin vacuolating cytotoxin (VacA) promotes gastric colonization, and its presence (VacA(+)) is associated with more-severe disease. The exact mechanisms by which VacA contributes to infection are unclear. We previously found that limited exposure to VacA induces autophagy of gastric cells, which eliminates the toxin; we investigated whether autophagy serves as a defense mechanism against H pylori infection.We investigated the effect of VacA on autophagy in human gastric epithelial cells and primary gastric cells from mice. Expression of p62, a marker of autophagy, was also assessed in gastric tissues from patients infected with toxigenic (VacA(+)) or nontoxigenic strains. We analyzed the effect of VacA on autophagy in peripheral blood monocytes obtained from subjects with different genotypes of ATG16L1, which regulates autophagy. We performed genotyping for ATG16L1 in 2 cohorts of infected and uninfected subjects.Prolonged exposure of human gastric epithelial cells and mouse gastric cells to VacA disrupted induction of autophagy in response to the toxin, because the cells lacked cathepsin D in autophagosomes. Loss of autophagy resulted in the accumulation of p62 and reactive oxygen species. Gastric biopsy samples from patients infected with VacA(+), but not nontoxigenic strains of H pylori, had increased levels of p62. Peripheral blood monocytes isolated from individuals with polymorphisms in ATG16L1 that increase susceptibility to Crohn's disease had reduced induction of autophagy in response to VacA(+) compared to cells from individuals that did not have these polymorphisms. The presence of the ATG16L1 Crohn's disease risk variant increased susceptibility to H pylori infection in 2 separate cohorts.Autophagy protects against infection with H pylori; the toxin VacA disrupts autophagy to promote infection, which could contribute to inflammation and eventual carcinogenesis.
| S-EPMC3336037 | biostudies-literature
Project description:In this review, we discuss the problem of antibiotic resistance, heteroresistance, the utility of cultures and antibiotic susceptibility tests in Helicobacter pylori (Hp) eradication, as well as the updated treatment strategies for this infection. The prevalence of antibiotic resistance is increasing all over the world, especially for metronidazole and clarithromycin, because of their heavy use in some geographical areas. Heteroresistance (simultaneous presence of both susceptible and resistant strains in different sites of a single stomach) is another important issue, as an isolate could be mistakenly considered susceptible if a single biopsy is used for antimicrobial tests. We also examined literature data regarding eradication success rates of culture-guided and empiric therapies. The empiric therapy and the one based on susceptibility testing, in Hp eradication, may depend on several factors such as concomitant diseases, the number of previous antibiotic treatments, differences in bacterial virulence in individuals with positive or negative cultures, together with local antibiotic resistance patterns in real-world settings. Updated treatment strategies in Hp infection presented in the guidelines of the Toronto Consensus Group (2016) are reported. These suggest to prolong eradication therapy up to 14 days, replacing the old triple therapy with a quadruple therapy based on proton pump inhibitor (PPI), bismuth, metronidazole, and tetracycline for most of the patients, or as an alternative quadruple therapy without bismuth, based on the use of PPI, amoxicillin, metronidazole, and clarithromycin. The new drug vonoprazan, a first-in-class potassium-competitive acid blocker recently approved in Japan, is also considered to be a promising solution for Hp eradication, even for clarithromycin-resistant strains. Furthermore, there is growing interest in finding new therapeutic strategies, such as the development of vaccines or the use of natural resources, including probiotics, plants, or nutraceuticals.
| S-EPMC5546184 | biostudies-other
Project description:BackgroundSusceptibility-guided therapies (SGTs) have been proposed as preferable to empirical rescue treatments after two treatment failures. The aim of this study was to perform a systematic review and meta-analysis evaluating the effectiveness and efficacy of SGT as third-line therapy.MethodsA systematic search was performed in multiple databases. Studies reporting cure rates of Helicobacter pylori with SGT in third-line therapy were selected. A qualitative analysis describing the current evidence and a pooled mean analysis summarizing the cure rates of SGT in third-line therapy was performed.ResultsNo randomized controlled trials or comparative studies were found. Four observational studies reported cure rates with SGT in third-line treatment, and three studies which mixed patients with second- and third-line treatment also reported cure rates with SGT. The majority of the studies included the patients when culture had been already obtained, and so the effectiveness of SGT and empirical therapy has never been compared. A pooled mean analysis including four observational studies (283 patients) showed intention-to-treat and per-protocol eradication rates with SGT of 72% (95% confidence interval 56-87%; I(2) : 92%) and 80% (95% confidence interval 71-90%; I(2) : 80%), respectively.ConclusionsSGT may be an acceptable option as rescue treatment. However, cure rates are, at best, moderate and this approach has never been compared with a well-devised empirical therapy. The evidence in favor of SGT as rescue therapy is currently insufficient to recommend its use.
| S-EPMC4913327 | biostudies-literature
Project description:BackgroundEmpirical therapy of Helicobacter pylori frequently results in treatment failure due to unrecognized antimicrobial resistance. The aim of this study was to investigate the effectiveness of susceptibility-guided therapy for rescue treatment of H. pylori infection in China.MethodsThis was a prospective study of consecutive 200 patients infected with H. pylori with one or more treatment failures. The therapy chosen was susceptibility based using the most effective, best-tolerated regimens first and a locally proven, reliably effective regimen for multidrug-resistant infections. All patients received 14-day triple therapy, i.e. esomeprazole 20 mg and amoxicillin 1 g twice a day plus clarithromycin 500 mg twice a day, metronidazole 400 mg twice a day, or levofloxacin 500 mg daily, or, for multidrug-resistant infections, amoxicillin-containing bismuth quadruple therapy with esomeprazole 20 mg twice a day, bismuth 220 mg twice a day, amoxicillin 1 g three times a day, and metronidazole 400 mg four times a day. Antibiotic resistance was determined by agar dilution.ResultsThe eradication rate of susceptibility-guided therapy overall was 94.5% (189/200, 95% confidence interval: 90.4-97.2%). Around 28% (56/200) of patients carried strains susceptible to one of the tested antibiotics and were prescribed the triple therapy. A total of 144 multidrug-resistant patients received bismuth quadruple therapy. The eradication rates were all greater than 90%, i.e. 91.7% (11/12), 92.3% (12/13), and 93.5% (29/31) in those who received clarithromycin, metronidazole, and levofloxacin-containing triple therapy and 95.1% (137/144) for the bismuth quadruple therapy. There were no differences in eradication rates between the subgroups.ConclusionsAlthough susceptibility-guided therapy proved high efficacious despite the high proportion of multidrug-resistant strains, the strategy suggested the best approach for this population would be empirical amoxicillin-containing bismuth quadruple therapy. ClinicalTrials.gov identifier: NCT03413020.
| S-EPMC6734621 | biostudies-literature
Project description:Background:Gastric cancer (GC) ranks the second leading cause of cancer-related mortality worldwide. We aimed to clarify the relevance of genetic variants of IL-11, a hub of various carcinogenic pathways, as well as their interactions with Helicobacter pylori (H. pylori) infection in the development of GC. Methods:A case-control study with 880 GC cases and 900 healthy controls was conducted in a Chinese population. Six tagSNPs were detected by Taqman Allelic Discrimination assay, while H. pylori status was detected by Typing Detection Kit for Antibody to H. pylori and serum IL-11 level was measured using ELISA method. Results:We found that rs1126760 (C vs T: OR=1.39, 95% CIs=1.13-1.70, P=0.002) and rs1126757 (C vs T: OR=0.82, 95% CIs=0.72-0.93, P=0.002) were significantly associated with susceptibility of GC. Even adjusted for Bonferroni correction, the results were still significant (P=0.002×6=0.012). IL-11 rs1126760 was significantly associated with higher serum and expression level of IL-11, while rs1126757 was significantly associated with lower serum IL-11 level (P<0.001). Significant interaction with H. pylori infection was identified for rs1126760 (P for interaction =0.005). Higher expression of the IL-11 gene was significant with development and poor prognosis of GC. Conclusion:Our study provides strong evidence that genetic variants of the IL-11 gene may interact with H. pylori infection and contribute to the development of GC. Further studies with larger sample size and functional experiments are needed to validate our findings.
| S-EPMC6751226 | biostudies-literature
Project description:Helicobacter pylori, a bacterial pathogen that can infect human stomach causing gastritis, ulcers and cancer, is known to have a high degree of genome/epigenome diversity as the result of mutation and recombination. The bacteria often infect in childhood and persist for the life of the host. One of the reasons of the rapid evolution of H. pylori is that it changes its genome drastically for adaptation to a new host. To investigate microevolution and adaptation of the H. pylori genome, we undertook whole genome sequencing of the same or very similar sequence type in multi-locus sequence typing (MLST) with seven genes in members of the same family consisting of parents and children in Japan. Detection of nucleotide substitutions revealed likely transmission pathways involving children. Nonsynonymous (amino acid changing) mutations were found in virulence-related genes (cag genes, vacA, hcpDX, tnfα, ggt, htrA and the collagenase gene), outer membrane protein (OMP) genes and other cell surface-related protein genes, signal transduction genes and restriction-modification genes. We reconstructed various pathways by which H. pylori can adapt to a new human host, and our results raised the possibility that the mutational changes in virulence-related genes have a role in adaptation to a child host. Changes in restriction-modification genes might remodel the methylome and transcriptome to help adaptation. This study has provided insights into H. pylori transmission and virulence and has implications for basic research as well as clinical practice.
| S-EPMC4433339 | biostudies-literature
Project description:We used 10X 5' single cell RNA sequencing (scRNAseq) technology to examine the transcriptional profiles of distinct gastric metaplastic cell types within the gastric corpus of mice chronically infected with Helicobacter pylori or chronically inflamed with autoimmune gastritis and humans with autoimmune gastritis.
2024-09-25 | GSE271866 | GEO
Project description:Infection with Helicobacter pylori (H. pylori) is necessary but not sufficient for the development of gastric cancer, the third leading cause of cancer death globally. H. pylori infection affects over half of people globally; however, it does not affect populations uniformly. H. pylori infection rates are declining in western industrialized countries but are plateauing in developing and newly industrialized countries where gastric cancer is most prevalent. Despite H. pylori infection being the primary causative agent for gastric cancer, H. pylori infection can also cause other effects, detrimental or beneficial, throughout an individual's life, with the beneficial effects often being seen in childhood and the deleterious effects in adulthood. H. pylori is an ancient bacterium and its likelihood of affecting disease or health is dependent on both human and bacterial genetics that have co-evolved over millennia. In this review, we focus on the impact of infection and its genetic bases in different populations and diseases throughout an individual's lifespan, highlighting the benefits of individualized treatment and argue that universal eradication of H. pylori in its host may cause more harm than good for those infected with H. pylori.
| S-EPMC8390445 | biostudies-literature
Project description:Helicobacter pylori infection affects more than half of the world population and it occurs generally in childhood. It is associated with gastroduodenal ulcer, gastric atrophy, intestinal metaplasia, gastric adenocarcinoma and lymphoid tissue-associated lymphoma. It is difficult to eradicate this bacterium due to its high antimicrobial resistance. In children, the infection is asymptomatic in the majority of cases and complications are less common. Probable inverse relationships with allergic diseases and inflammatory bowel diseases are being studied. These reasons mean that the decision to diagnose and treat the infection in children is only considered in specific circumstances in which it provides true benefits. This review focuses on some current considerations regarding epidemiology, diagnosis and treatment of childhood infection, emphasising outcomes and treatment schemes in children.
| S-EPMC7402006 | biostudies-literature