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1.
Sci Rep ; 14(1): 14185, 2024 06 20.
Article in English | MEDLINE | ID: mdl-38902391

ABSTRACT

Helicobacter pylori (H. pylori), together with its CagA, has been implicated in causing DNA damage, cell cycle arrest, apoptosis, and the development of gastric cancer. Although lncRNA H19 is abundantly expressed in gastric cancer and functions as a pro-oncogene, it remains unclear whether lncRNA H19 contributes to the oncogenic process of H. pylori CagA. This study investigates the role of H19 in the DNA damage response and malignancy induced by H. pylori. It was observed that cells infected with CagA+ H. pylori strain (GZ7/cagA) showed significantly higher H19 expression, resulting in increased γH2A.X and p-ATM expression and decreased p53 and Rad51 expression. Faster cell migration and invasion was also observed, which was reversed by H19 knockdown in H. pylori. YWHAZ was identified as an H19 target protein, and its expression was increased in H19 knockdown cells. GZ7/cagA infection responded to the increased YWHAZ expression induced by H19 knockdown. In addition, H19 knockdown stimulated cells to enter the G2-phase and attenuated the effect of GZ7/cagA infection on the cellular S-phase barrier. The results suggest that H. pylori CagA can upregulate H19 expression, participate in the DNA damage response and promote cell migration and invasion, and possibly affect cell cycle arrest via regulation of YWHAZ.


Subject(s)
Antigens, Bacterial , Bacterial Proteins , Cell Movement , DNA Damage , Helicobacter pylori , RNA, Long Noncoding , Stomach Neoplasms , Humans , Antigens, Bacterial/metabolism , Antigens, Bacterial/genetics , RNA, Long Noncoding/genetics , RNA, Long Noncoding/metabolism , Bacterial Proteins/genetics , Bacterial Proteins/metabolism , Helicobacter pylori/genetics , Stomach Neoplasms/microbiology , Stomach Neoplasms/genetics , Stomach Neoplasms/pathology , Stomach Neoplasms/metabolism , Cell Movement/genetics , Cell Line, Tumor , Helicobacter Infections/microbiology , Helicobacter Infections/genetics , Helicobacter Infections/metabolism , Rad51 Recombinase/metabolism , Rad51 Recombinase/genetics , Tumor Suppressor Protein p53/metabolism , Tumor Suppressor Protein p53/genetics , Histones/metabolism
2.
Helicobacter ; 29(3): e13100, 2024.
Article in English | MEDLINE | ID: mdl-38873839

ABSTRACT

BACKGROUND: The formation of gallstones is often accompanied by chronic inflammation, and the mechanisms underlying inflammation and stone formation are not fully understood. Our aim is to utilize single-cell transcriptomics, bulk transcriptomics, and microbiome data to explore key pathogenic bacteria that may contribute to chronic inflammation and gallstone formation, as well as their associated mechanisms. METHODS: scRNA-seq data from a gallstone mouse model were extracted from the Gene Expression Omnibus (GEO) database and analyzed using the FindCluster() package for cell clustering analysis. Bulk transcriptomics data from patients with gallstone were also extracted from the GEO database, and intergroup functional differences were assessed using GO and KEGG enrichment analysis. Additionally, 16S rRNA sequencing was performed on gallbladder mucosal samples from asymptomatic patients with gallstone (n = 6) and liver transplant donor gallbladder mucosal samples (n = 6) to identify key bacteria associated with stone formation and chronic inflammation. Animal models were constructed to investigate the mechanisms by which these key pathogenic bacterial genera promote gallstone formation. RESULTS: Analysis of scRNA-seq data from the gallstone mouse model (GSE179524) revealed seven distinct cell clusters, with a significant increase in neutrophil numbers in the gallstone group. Analysis of bulk transcriptomics data from patients with gallstone (GSE202479) identified chronic inflammation in the gallbladder, potentially associated with dysbiosis of the gallbladder microbiota. 16S rRNA sequencing identified Helicobacter pylori as a key bacterium associated with gallbladder chronic inflammation and stone formation. CONCLUSIONS: Dysbiosis of the gallbladder mucosal microbiota is implicated in gallstone disease and leads to chronic inflammation. This study identified H. pylori as a potential key mucosal resident bacterium contributing to gallstone formation and discovered its key pathogenic factor CagA, which causes damage to the gallbladder mucosal barrier. These findings provide important clues for the prevention and treatment of gallstones.


Subject(s)
Antigens, Bacterial , Bacterial Proteins , Epithelial Cells , Gallbladder , Gallstones , Helicobacter pylori , Animals , Gallstones/microbiology , Gallstones/pathology , Epithelial Cells/microbiology , Mice , Humans , Gallbladder/microbiology , Gallbladder/pathology , Bacterial Proteins/genetics , Bacterial Proteins/metabolism , Antigens, Bacterial/genetics , Antigens, Bacterial/metabolism , Helicobacter pylori/genetics , Helicobacter pylori/pathogenicity , Helicobacter pylori/physiology , RNA, Ribosomal, 16S/genetics , Disease Models, Animal , Permeability , Helicobacter Infections/microbiology , Helicobacter Infections/pathology , Female , Male , Mice, Inbred C57BL
3.
Int J Med Microbiol ; 315: 151622, 2024 Jun.
Article in English | MEDLINE | ID: mdl-38776570

ABSTRACT

BACKGROUND: The increasing prevalence of antibiotic-resistant Helicobacter pylori strains poses a significant threat to children's health. This study investigated antibiotic resistance rates in Helicobacter pylori strains isolated from children in Shanghai and analyzed the presence of virulence genes in these strains. METHODS: We obtained 201 Helicobacter pylori strains from pediatric patients with upper gastrointestinal symptoms who underwent gastrointestinal endoscopy between 2019 and 2022. Subsequently, we performed antibiotic susceptibility tests and virulence gene PCR assays on these strains. RESULTS: Helicobacter pylori resistance rates of 45.8%, 15.4%, 1.0%, and 2.5% were detected for metronidazole, clarithromycin, amoxicillin, and levofloxacin, respectively. Among all isolates, 64.7% exhibited resistance to at least one antibiotic. Resistance to metronidazole and clarithromycin increased from 2019 to 2022. The predominant vacA gene subtype was vacA s1a/m2. The prevalence of vacA m2 and dupA exhibited an upward trend, while oipA presented a decreasing trend from 2019 to 2022. The prevalence of dupA was significantly higher in gastritis than peptic ulcer disease, and in non-treatment compared to treatment groups. CONCLUSIONS: Helicobacter pylori antibiotic resistance remains high in children and has risen in recent years. Therefore, the increasing use of metronidazole and clarithromycin requires increased monitoring in children. No association was observed between antibiotic resistance and virulence gene phenotypes.


Subject(s)
Anti-Bacterial Agents , Bacterial Proteins , Clarithromycin , Drug Resistance, Bacterial , Helicobacter Infections , Helicobacter pylori , Microbial Sensitivity Tests , Virulence Factors , Humans , Helicobacter pylori/genetics , Helicobacter pylori/drug effects , Helicobacter pylori/pathogenicity , Helicobacter pylori/isolation & purification , China/epidemiology , Child , Helicobacter Infections/microbiology , Helicobacter Infections/epidemiology , Anti-Bacterial Agents/pharmacology , Female , Male , Bacterial Proteins/genetics , Virulence Factors/genetics , Drug Resistance, Bacterial/genetics , Adolescent , Child, Preschool , Clarithromycin/pharmacology , Metronidazole/pharmacology , Virulence/genetics , Gastritis/microbiology , Gastritis/epidemiology , Prevalence , Peptic Ulcer/microbiology , Infant , Amoxicillin/pharmacology , Bacterial Outer Membrane Proteins
4.
mBio ; 15(6): e0044024, 2024 Jun 12.
Article in English | MEDLINE | ID: mdl-38700325

ABSTRACT

Motility promotes biofilm initiation during the early steps of this process: microbial surface association and attachment. Motility is controlled in part by chemotaxis signaling, so it seems reasonable that chemotaxis may also affect biofilm formation. There is a gap, however, in our understanding of the interactions between chemotaxis and biofilm formation, partly because most studies analyzed the phenotype of only a single chemotaxis signaling mutant, e.g., cheA. Here, we addressed the role of chemotaxis in biofilm formation using a full set of chemotaxis signaling mutants in Helicobacter pylori, a class I carcinogen that infects more than half the world's population and forms biofilms. Using mutants that lack each chemotaxis signaling protein, we found that chemotaxis signaling affected the biofilm initiation stage, but not mature biofilm formation. Surprisingly, some chemotaxis mutants elevated biofilm initiation, while others inhibited it in a manner that was not tied to chemotaxis ability or ligand input. Instead, the biofilm phenotype correlated with flagellar rotational bias. Specifically, mutants with a counterclockwise bias promoted biofilm initiation, e.g., ∆cheA, ∆cheW, or ∆cheV1; in contrast, those with a clockwise bias inhibited it, e.g., ∆cheZ, ∆chePep, or ∆cheV3. We tested this correlation using a counterclockwise bias-locked flagellum, which induced biofilm formation independent of the chemotaxis system. These CCW flagella, however, were not sufficient to induce biofilm formation, suggesting there are downstream players. Overall, our work highlights the new finding that flagellar rotational direction promotes biofilm initiation, with the chemotaxis signaling system operating as one mechanism to control flagellar rotation. IMPORTANCE: Chemotaxis signaling systems have been reported to contribute to biofilm formation in many bacteria; however, how they regulate biofilm formation remains largely unknown. Chemotaxis systems are composed of many distinct kinds of proteins, but most previous work analyzed the biofilm effect of loss of only a few. Here, we explored chemotaxis' role during biofilm formation in the human-associated pathogenic bacterium Helicobacter pylori. We found that chemotaxis proteins are involved in biofilm initiation in a manner that correlated with how they affected flagellar rotation. Biofilm initiation was high in mutants with counterclockwise (CCW) flagellar bias and low in those with clockwise bias. We supported the idea that a major driver of biofilm formation is flagellar rotational direction using a CCW-locked flagellar mutant, which stays CCW independent of chemotaxis input and showed elevated biofilm initiation. Our data suggest that CCW-rotating flagella, independent of chemotaxis inputs, are a biofilm-promoting signal.


Subject(s)
Bacterial Proteins , Biofilms , Chemotaxis , Flagella , Helicobacter pylori , Biofilms/growth & development , Helicobacter pylori/physiology , Helicobacter pylori/genetics , Flagella/physiology , Flagella/genetics , Bacterial Proteins/genetics , Bacterial Proteins/metabolism , Signal Transduction , Mutation , Rotation
5.
Helicobacter ; 29(3): e13084, 2024.
Article in English | MEDLINE | ID: mdl-38717034

ABSTRACT

BACKGROUND: Recently, a simple tailored therapy based on clarithromycin resistance has been implemented as Helicobacter pylori (H. pylori) eradication therapy. Nonetheless, despite the tailored therapy and frequent adverse events, studies on treatment period are lacking. This study aimed to compare the H. pylori eradication rates of 7-day and 14-day tailored therapy regimens according to clarithromycin resistance. MATERIALS AND METHODS: This multicenter, prospective, randomized, noninferiority trial enrolled H. pylori-positive patients who were randomly assigned to 7-day and 14-day regimen groups, depending on the presence or absence of clarithromycin resistance by 23S rRNA gene point mutations. Standard triple therapy (STT) (20 mg rabeprazole, 1 g amoxicillin, and 500 mg clarithromycin twice daily) or bismuth quadruple therapy (BQT) (20 mg rabeprazole twice daily, 500 mg metronidazole thrice daily, 120 mg bismuth four times daily, and 500 mg tetracycline four times daily) was assigned by clarithromycin resistance. Eradication rates and adverse events were evaluated. RESULTS: A total of 314 and 278 patients were included in the intention-to-treat (ITT) and per-protocol (PP) analyses, respectively; however, 31 patients were lost to follow-up, whereas five patients violated the protocol. Both the 7-day and 14-day regimens showed similar eradication rates in the ITT (7-day vs. 14-day: 78.3% vs. 78.3%, p > 0.99) and PP (87.9% vs. 89.1%, p = 0.851) analyses. Non-inferiority was confirmed (p < 0.025). A subgroup analysis according to clarithromycin resistance (clarithromycin resistance rate: 28.7%) revealed no significant difference in eradication rates between the 7-day and 14-day STT (90.0% vs. 90.1%, p > 0.99) and BQT (82.5% vs. 86.5%, p = 0.757). Furthermore, adverse events did not significantly differ between the two groups. CONCLUSIONS: The 7-day triple and quadruple therapy according to clarithromycin resistance showed similar eradication rates, as compared to the 14-day therapy.


Subject(s)
Anti-Bacterial Agents , Clarithromycin , Drug Resistance, Bacterial , Helicobacter Infections , Helicobacter pylori , Humans , Helicobacter Infections/drug therapy , Helicobacter Infections/microbiology , Clarithromycin/therapeutic use , Clarithromycin/pharmacology , Helicobacter pylori/drug effects , Helicobacter pylori/genetics , Male , Female , Anti-Bacterial Agents/therapeutic use , Anti-Bacterial Agents/administration & dosage , Anti-Bacterial Agents/adverse effects , Anti-Bacterial Agents/pharmacology , Middle Aged , Adult , Prospective Studies , Drug Therapy, Combination , Aged , Treatment Outcome , Rabeprazole/therapeutic use , Rabeprazole/administration & dosage , Bismuth/therapeutic use , Bismuth/administration & dosage , RNA, Ribosomal, 23S/genetics
6.
Arq Gastroenterol ; 61: e23139, 2024.
Article in English | MEDLINE | ID: mdl-38775582

ABSTRACT

BACKGROUND: Helicobacter pylori (H. pylori) is a gram-negative bacterium associated with the etiology of several gastrointestinal tract pathologies, and cagA-positive (cagA+) strains are found in populations with gastric ulcers and precancerous lesions, inducing pro-inflammatory responses. The development of neoplasms is related to microRNA (miRNA) dysregulation, indicating highly expressed miRNA-629. The article aims to correlate the expression level of miRNA-629 with the presence of H. pylori and the pathogenicity marker cagA. METHODS: 203 gastric biopsy samples were evaluated from individuals with normal gastric tissue (n=60), gastritis (n=96), and gastric cancer (n=47) of both genders and over 18 years old. The samples were subdivided according to the presence or absence of H. pylori, detected by polymerase chain reaction (PCR). RNA was extracted using a commercial kit and quantified. Complementary DNA (cDNA) was synthesized using commercial kits, and the relative expression was calculated using the 2-ΔΔCt method. RESULTS: Individuals infected with H. pylori are nine times more likely to develop gastric cancer. Cancer patients appeared to have decreased expression of miRNA-629; however, the presence of the bacterium would not influence this reduction. Individuals in the cancer group showed lower miRNA-629 expression when cagA+; however, in the control group, the expression was higher when cagA+. CONCLUSION: H. pylori is a factor involved in the etiology and progression of gastric diseases. Reduction in miRNA-629 expression in cancer patients occurs independent of the presence of the bacterium, but when the cagA pathogenicity marker is present, it induces changes in the gene expression of the respective miRNA.


Subject(s)
Antigens, Bacterial , Bacterial Proteins , Helicobacter Infections , Helicobacter pylori , MicroRNAs , Stomach Neoplasms , Humans , Helicobacter pylori/genetics , Helicobacter pylori/pathogenicity , Stomach Neoplasms/microbiology , Stomach Neoplasms/genetics , Antigens, Bacterial/genetics , Bacterial Proteins/genetics , MicroRNAs/genetics , MicroRNAs/analysis , Female , Male , Helicobacter Infections/microbiology , Middle Aged , Adult , Aged , Gastritis/microbiology
7.
BMC Biol ; 22(1): 125, 2024 May 29.
Article in English | MEDLINE | ID: mdl-38807090

ABSTRACT

BACKGROUND: Bacterial epigenetics is a rapidly expanding research field. DNA methylation by diverse bacterial methyltransferases (MTases) contributes to genomic integrity and replication, and many recent studies extended MTase function also to global transcript regulation and phenotypic variation. Helicobacter pylori is currently one of those bacterial species which possess the highest number and the most variably expressed set of DNA MTases. Next-generation sequencing technologies can directly detect DNA base methylation. However, they still have limitations in their quantitative and qualitative performance, in particular for cytosine methylation. RESULTS: As a complementing approach, we used enzymatic methyl sequencing (EM-Seq), a technology recently established that has not yet been fully evaluated for bacteria. Thereby, we assessed quantitatively, at single-base resolution, whole genome cytosine methylation for all methylated cytosine motifs in two different H. pylori strains and isogenic MTase mutants. EM-Seq reliably detected both m5C and m4C methylation. We demonstrated that three different active cytosine MTases in H. pylori provide considerably different levels of average genome-wide single-base methylation, in contrast to isogenic mutants which completely lost specific motif methylation. We found that strain identity and changed environmental conditions, such as growth phase and interference with methyl donor homeostasis, significantly influenced quantitative global and local genome-wide methylation in H. pylori at specific motifs. We also identified significantly hyper- or hypo-methylated cytosines, partially linked to overlapping MTase target motifs. Notably, we revealed differentially methylated cytosines in genome-wide coding regions under conditions of methionine depletion, which can be linked to transcript regulation. CONCLUSIONS: This study offers new knowledge on H. pylori global and local genome-wide methylation and establishes EM-Seq for quantitative single-site resolution analyses of bacterial cytosine methylation.


Subject(s)
DNA Methylation , Genome, Bacterial , Helicobacter pylori , Helicobacter pylori/genetics , Genome, Bacterial/genetics , Homeostasis , Cytosine/metabolism , Sequence Analysis, DNA/methods , High-Throughput Nucleotide Sequencing/methods
8.
BMC Genomics ; 25(1): 466, 2024 May 13.
Article in English | MEDLINE | ID: mdl-38741045

ABSTRACT

BACKGROUND: Protein-protein interactions (PPIs) hold significant importance in biology, with precise PPI prediction as a pivotal factor in comprehending cellular processes and facilitating drug design. However, experimental determination of PPIs is laborious, time-consuming, and often constrained by technical limitations. METHODS: We introduce a new node representation method based on initial information fusion, called FFANE, which amalgamates PPI networks and protein sequence data to enhance the precision of PPIs' prediction. A Gaussian kernel similarity matrix is initially established by leveraging protein structural resemblances. Concurrently, protein sequence similarities are gauged using the Levenshtein distance, enabling the capture of diverse protein attributes. Subsequently, to construct an initial information matrix, these two feature matrices are merged by employing weighted fusion to achieve an organic amalgamation of structural and sequence details. To gain a more profound understanding of the amalgamated features, a Stacked Autoencoder (SAE) is employed for encoding learning, thereby yielding more representative feature representations. Ultimately, classification models are trained to predict PPIs by using the well-learned fusion feature. RESULTS: When employing 5-fold cross-validation experiments on SVM, our proposed method achieved average accuracies of 94.28%, 97.69%, and 84.05% in terms of Saccharomyces cerevisiae, Homo sapiens, and Helicobacter pylori datasets, respectively. CONCLUSION: Experimental findings across various authentic datasets validate the efficacy and superiority of this fusion feature representation approach, underscoring its potential value in bioinformatics.


Subject(s)
Computational Biology , Protein Interaction Mapping , Protein Interaction Mapping/methods , Computational Biology/methods , Algorithms , Helicobacter pylori/metabolism , Helicobacter pylori/genetics , Support Vector Machine , Proteins/metabolism , Proteins/chemistry , Humans , Protein Interaction Maps , Databases, Protein
9.
Helicobacter ; 29(3): e13093, 2024.
Article in English | MEDLINE | ID: mdl-38757432

ABSTRACT

BACKGROUND: The purpose of this analysis is to evaluate the antimicrobial susceptibility of eight drugs effective against Helicobacter pylori (H. pylori) strains and the genetic diversity of H. pylori virulence genes to foresee clinical outcomes in North India. MATERIALS AND METHODS: Fifty-eight H. pylori strains isolated from patients suffering from various gastrointestinal (GI) diseases were included in the study. MICs of various antibiotics were determined by the agar dilution method. The chi-squared test and Fisher exact test were used to determine the p-value, which was considered significant at p-value ≤ 0.05. RStudio 4.0 was used to for the data visualization. RESULTS: The prevalence of drug resistance was found to be: cefixime (CFM) (41.3%), furazolidone (FZD) (34.4%), amoxicillin (AMX) (20.7%), levofloxacin (LVFX) (70.7%), metronidazole (MTZ) (39.6%), tetracycline (TET) (20.7%), clarithromycin (CLA) (17.2%), and rifabutin (RIF) (17.2%). Out of 58 H. pylori strains, 3 were pan susceptible. There were H. pylori strains with single-drug resistance (21.8%, 12/55), dual resistance (30.9%, 17/55), triple resistance (20%, 11/55), and multidrug resistance (27.3%, 15/55). The resistance rate in MTZ, CLA and RIF were found to be significantly higher in females as compared to males (p = 0.005, p = 0.002, and p = 0.02), respectively. The resistance to TET exhibited significantly higher levels in gastritis compared to GERD, DU, and other disease groups (p = 0.04) respectively. CONCLUSION: TET, AMX, CLA, and RIF were found to be more effective antibiotics against H. pylori infections, whereas more studies are required to provide evidence on increasing resistance rate of LVFX.


Subject(s)
Anti-Bacterial Agents , Helicobacter Infections , Helicobacter pylori , Microbial Sensitivity Tests , Helicobacter pylori/drug effects , Helicobacter pylori/genetics , Helicobacter pylori/isolation & purification , Humans , Anti-Bacterial Agents/pharmacology , India/epidemiology , Female , Male , Helicobacter Infections/microbiology , Helicobacter Infections/drug therapy , Adult , Middle Aged , Young Adult , Aged , Adolescent , Drug Resistance, Bacterial
10.
Helicobacter ; 29(3): e13091, 2024.
Article in English | MEDLINE | ID: mdl-38780150

ABSTRACT

BACKGROUND: Helicobacter pylori eradication failure influences its antibiotic resistance. AIMS: This study aimed to evaluate the effect of previous treatment failures on it, including the changes in the antibiotic resistance rates, minimal inhibitory concentration (MIC) distributions, and resistance patterns. MATERIALS AND METHODS: This single-center retrospective study included 860 primary isolates and 247 secondary isolates. Antibiotic susceptibility testing was performed for amoxicillin, metronidazole, clarithromycin, levofloxacin, furazolidone, tetracycline, and rifampicin. The demographic data and detailed regimens were collected. RESULTS: The primary resistance rates to amoxicillin, metronidazole, clarithromycin, levofloxacin, tetracycline, rifampin, and furazolidone were 5.93%, 83.84%, 28.82%, 26.28%, 0.35%, 1.16%, and 0%, while secondary were 25.10%, 92.31%, 79.76%, 63.16%, 1.06%, 3.19%, and 0%, respectively. The resistance rates to amoxicillin, metronidazole, clarithromycin, and levofloxacin increased significantly with the number of treatment failures accumulated, and showed a linear trend. The proportion of primary and secondary multidrug-resistant (MDR) isolates were 17.79% and 63.16%, respectively. The MIC values of amoxicillin, clarithromycin, and levofloxacin were elevated significantly with medication courses increased. CONCLUSION: The prevalence of amoxicillin, clarithromycin, levofloxacin, and metronidazole resistance would increase rapidly following first-line treatment failure, as well as the MIC values of them. Clinicians should pay great attention to the first-line treatment to cure H. pylori infection successfully.


Subject(s)
Anti-Bacterial Agents , Helicobacter Infections , Helicobacter pylori , Microbial Sensitivity Tests , Treatment Failure , Humans , Helicobacter pylori/drug effects , Helicobacter pylori/genetics , Helicobacter pylori/isolation & purification , Helicobacter Infections/drug therapy , Helicobacter Infections/microbiology , Anti-Bacterial Agents/pharmacology , Anti-Bacterial Agents/therapeutic use , Retrospective Studies , Female , Male , Middle Aged , Adult , Aged , Drug Resistance, Bacterial , Young Adult , Adolescent , Aged, 80 and over
11.
Sci Rep ; 14(1): 12066, 2024 05 27.
Article in English | MEDLINE | ID: mdl-38802465

ABSTRACT

Heterogeneity of Helicobacter pylori communities contributes to its pathogenicity and diverse clinical outcomes. We conducted drug-susceptibility tests using four antibiotics, clarithromycin (CLR), amoxicillin (AMX), metronidazole and sitafloxacin, to examine H. pylori population diversity. We also analyzed genes associated with resistance to CLR and AMX. We examined multiple isolates from 42 Japanese patients, including 28 patients in whom primary eradication with CLR and AMX had failed, and 14 treatment-naïve patients. We identified some patients with coexistence of drug resistant- and sensitive-isolates (drug-heteroR/S-patients). More than 60% of patients were drug-heteroR/S to all four drugs, indicating extensive heterogeneity. For the four drugs except AMX, the rates of drug-heteroR/S-patients were higher in treatment-naïve patients than in primary eradication-failure patients. In primary eradication-failure patients, isolates multi-resistant to all four drugs existed among other isolates. In primary eradication-failure drug-heteroR/S-patients, CLR- and AMX-resistant isolates were preferentially distributed to the corpus and antrum with different minimum inhibitory concentrations, respectively. We found two mutations in PBP1A, G591K and A480V, and analyzed these in recombinants to directly demonstrate their association with AMX resistance. Assessment of multiple isolates from different stomach regions will improve accurate assessment of H. pylori colonization status in the stomach.


Subject(s)
Amoxicillin , Anti-Bacterial Agents , Drug Resistance, Bacterial , Helicobacter Infections , Helicobacter pylori , Microbial Sensitivity Tests , Mutation , Humans , Helicobacter pylori/genetics , Helicobacter pylori/drug effects , Helicobacter pylori/isolation & purification , Helicobacter Infections/microbiology , Helicobacter Infections/drug therapy , Anti-Bacterial Agents/pharmacology , Anti-Bacterial Agents/therapeutic use , Drug Resistance, Bacterial/genetics , Amoxicillin/pharmacology , Amoxicillin/therapeutic use , Male , Female , Metronidazole/pharmacology , Stomach/microbiology , Clarithromycin/pharmacology , Middle Aged , Aged , Adult , Bacterial Proteins/genetics , Penicillin-Binding Proteins/genetics , Fluoroquinolones/pharmacology , Fluoroquinolones/therapeutic use
12.
Gene ; 920: 148526, 2024 Aug 20.
Article in English | MEDLINE | ID: mdl-38703866

ABSTRACT

INTRODUCTION: Outer membrane protein (OMP) of Helicobacter pylori (H. pylori) i.e., blood group antigen binding adhesin (babA) is responsible for the attachment of H. pylori in the gastric epithelium. Its adherence is causative for gastric pathology such as gastritis, peptic ulcer disease (PUD), or digestive tract disorders like erosive reflux disease (ERD) and (NERD) non-erosive reflux disease and together called Gastroesophageal reflux disease (GERD). BabA manifests rapid and varied selection via substitution of amino acid in its Leb-carbohydrate binding domain (CBD) which enables better binding preferences for distinct human populations and ABO blood group phenotypes. The positive evolutionary selection of the pathogenic factor of this genetically diverse bacterium has enabled it to adapt to the host gastric environment. Analyzing the association of virulent genes (cagA, vacA) and babA will help us better understand bacteria's pathogenicity. METHOD: 109 H. pylori strains from patients with distinct gastrointestinal diseases were genotyped using Polymerase Chain Reaction(PCR) for cagA, vacA, and babA followed by Sanger sequencing and phylogenetic analysis. RESULT: In the babA + ve genotype, a statistically significant association with p = 0.04 and < 0.0001 is seen in gastritis and ERD respectively. A significant association of genotype vacAs1m2 (p = 0.0002) was seen in gastritis, vacAs1m1 (p = 0.02) in NERD, vacAs1m1 (p < 0.0001) and vacAs1m2 (p = 0.002) in ERD. This relationship helps to detect gastritis or ERD where BabA gene can be used as an independent marker for detecting their presence. CONCLUSION: The appearance of variants within distinct disease categories is due to local genetic variation.


Subject(s)
Adhesins, Bacterial , Helicobacter Infections , Helicobacter pylori , Phylogeny , Humans , Helicobacter pylori/genetics , Helicobacter pylori/pathogenicity , Helicobacter pylori/isolation & purification , Adhesins, Bacterial/genetics , Helicobacter Infections/microbiology , India , Male , Gastritis/microbiology , Female , Gastrointestinal Diseases/microbiology , Gastrointestinal Diseases/genetics , Antigens, Bacterial/genetics , Genotype , Adult , Middle Aged , Bacterial Proteins/genetics
13.
J Med Microbiol ; 73(5)2024 May.
Article in English | MEDLINE | ID: mdl-38712922

ABSTRACT

Introduction. Resistance towards amoxicillin in Helicobacter pylori causes significant therapeutic impasse in healthcare settings worldwide. In Malaysia, the standard H. pylori treatment regimen includes a 14-day course of high-dose proton-pump inhibitor (rabeprazole, 20 mg) with amoxicillin (1000 mg) dual therapy.Hypothesis/Gap Statement. The high eradication rate with amoxicillin-based treatment could be attributed to the primary resistance rates of amoxicillin being relatively low at 0%, however, a low rate of secondary resistance has been documented in Malaysia recently.Aim. This study aims to investigate the amino acid mutations and related genetic variants in PBP1A of H. pylori, correlating with amoxicillin resistance in the Malaysian population.Methodology. The full-length pbp1A gene was amplified via PCR from 50 genomic DNA extracted from gastric biopsy samples of H. pylori-positive treatment-naïve Malaysian patients. The sequences were then compared with reference H. pylori strain ATCC 26695 for mutation and variant detection. A phylogenetic analysis of 50 sequences along with 43 additional sequences from the NCBI database was performed. These additional sequences included both amoxicillin-resistant strains (n=20) and amoxicillin-sensitive strains (n=23).Results. There was a total of 21 variants of amino acids, with three of them located in or near the PBP-motif (SKN402-404). The percentages of these three variants are as follows: K403X, 2%; S405I, 2% and E406K, 16%. Based on the genetic markers identified, the resistance rate for amoxicillin in our sample remained at 0%. The phylogenetic examination suggested that H. pylori might exhibit unique conserved pbp1A sequences within the Malaysian context.Conclusions. Overall, the molecular analysis of PBP1A supported the therapeutic superiority of amoxicillin-based regimens. Therefore, it is crucial to continue monitoring the amoxicillin resistance background of H. pylori with a larger sample size to ensure the sustained effectiveness of amoxicillin-based treatments in Malaysia.


Subject(s)
Amoxicillin , Anti-Bacterial Agents , Genetic Variation , Helicobacter Infections , Helicobacter pylori , Penicillin-Binding Proteins , Adult , Female , Humans , Male , Middle Aged , Amoxicillin/pharmacology , Amoxicillin/therapeutic use , Anti-Bacterial Agents/pharmacology , Anti-Bacterial Agents/therapeutic use , Bacterial Proteins/genetics , Drug Resistance, Bacterial/genetics , Drug Therapy, Combination , Helicobacter Infections/drug therapy , Helicobacter Infections/microbiology , Helicobacter pylori/genetics , Helicobacter pylori/drug effects , Malaysia , Microbial Sensitivity Tests , Mutation , Penicillin-Binding Proteins/genetics , Phylogeny , Proton Pump Inhibitors/therapeutic use
14.
Cell Commun Signal ; 22(1): 250, 2024 May 02.
Article in English | MEDLINE | ID: mdl-38698410

ABSTRACT

Single nucleotide polymorphisms (SNPs) account for significant genomic variability in microbes, including the highly diverse gastric pathogen Helicobacter pylori. However, data on the effects of specific SNPs in pathogen-host interactions are scarce. Recent functional studies unravelled how a serine/leucine polymorphism in serine protease HtrA affects the formation of proteolytically active trimers and modulates cleavage of host cell-to-cell junction proteins during infection. A similar serine/leucine mutation in the carbohydrate binding domain of the adhesin BabA controls binding of ABO blood group antigens, enabling binding of either only the short Lewis b/H antigens of blood group O or also the larger antigens of blood groups A and B. Here we summarize the functional importance of these two remarkable bacterial SNPs and their effect on the outcome of pathogen-host interactions.


Subject(s)
Adhesins, Bacterial , Helicobacter pylori , Leucine , Serine , Helicobacter pylori/genetics , Adhesins, Bacterial/genetics , Adhesins, Bacterial/metabolism , Humans , Serine/genetics , Serine/metabolism , Leucine/genetics , Leucine/metabolism , Polymorphism, Single Nucleotide/genetics , Serine Endopeptidases/genetics , Serine Endopeptidases/metabolism , Helicobacter Infections/microbiology , Helicobacter Infections/genetics , Animals
15.
Arab J Gastroenterol ; 25(2): 194-204, 2024 May.
Article in English | MEDLINE | ID: mdl-38705811

ABSTRACT

BACKGROUND AND STUDY AIMS: Immunotherapy has emerged as a hot topic in cancer treatment in recent years and has also shown potential in the treatment of Helicobacter pylori-associated gastric cancer. However, there is still a need to identify potential immunotherapy targets. MATERIAL AND METHODS: We used the GSE116312 dataset of Helicobacter pylori-associated gastric cancer to identify differentially expressed genes, which were then overlapped with immune genes from the ImmPort database. The identified immune genes were used to classify gastric cancer samples and evaluate the relationship between classification and tumor mutations, as well as immune infiltration. An immune gene-based prognostic model was constructed, and the expression levels of the genes involved in constructing the model were explored in the tumor immune microenvironment. RESULTS: We successfully identified 60 immune genes and classified gastric cancer samples into two subtypes, which showed differences in prognosis, tumor mutations, immune checkpoint expression, and immune cell infiltration. Subsequently, we constructed an immune prognostic model consisting of THBS1 and PDGFD, which showed significant associations with macrophages and fibroblasts. CONCLUSION: We identified abnormal expression of THBS1 and PDGFD in cancer-associated fibroblasts (CAFs) within the tumor immune microenvironment, suggesting their potential as therapeutic targets.


Subject(s)
Helicobacter Infections , Helicobacter pylori , Platelet-Derived Growth Factor , Stomach Neoplasms , Thrombospondin 1 , Tumor Microenvironment , Stomach Neoplasms/microbiology , Stomach Neoplasms/immunology , Stomach Neoplasms/genetics , Stomach Neoplasms/pathology , Humans , Tumor Microenvironment/immunology , Tumor Microenvironment/genetics , Helicobacter pylori/immunology , Helicobacter pylori/genetics , Helicobacter Infections/immunology , Helicobacter Infections/complications , Thrombospondin 1/genetics , Prognosis , Platelet-Derived Growth Factor/genetics , Platelet-Derived Growth Factor/metabolism , Cancer-Associated Fibroblasts/immunology , Cancer-Associated Fibroblasts/metabolism , Mutation , Lymphokines
16.
BMC Infect Dis ; 24(1): 540, 2024 May 29.
Article in English | MEDLINE | ID: mdl-38811871

ABSTRACT

BACKGROUND: Eradication of oral Helicobacter pylori (H. pylori) not only reduces the infection rate from the transmission route but also improves the success rate of intragastric eradication. MAXPOWER Biological Bacteriostatic Liquid, developed in our previous work, is a composite biological preparation with strong antibacterial ability and unique antibacterial mechanism. The present study evaluated the efficacy of the MAXPOWER biocontrol solution on H. pylori and its success rate in eradicating oral H. pylori in clinical patients. METHODS: Live-dead cell staining and hemolysis test were used to evaluate the cellular safety of MAXPOWER biocontrol solution; plate spreading, live-dead bacterial staining, and scanning electron microscopy methods were used to evaluate its antimicrobial effect against H. pylori. Transcriptomics was used to analyze the changes in H. pylori genes before and after treatment. After seven days of gavage treatment, H&E staining and mice feces were collected for 16SrDNA sequencing to evaluate the animals' safety. Oral H. pylori-positive patients were randomized to be given a placebo and MAXPOWER Bio-Bacteriostatic Liquid gargle for seven days to evaluate the effect on oral H. pylori eradication. RESULTS: In vitro tests demonstrated that this product has excellent biocompatibility and hemocompatibility and can effectively eradicate oral H. pylori. In vivo tests further showed that it has good biosafety and virtually no adverse effect on intestinal microflora. Transcriptomics analysis revealed that it kills H. pylori cells mainly by disrupting their cell membranes and metabolism. Additionally, the results of randomized controlled trials on humans disclosed that the oral H. pylori eradication rates achieved by MAXPOWER Biological Antibacterial Liquid were 71.4% and 78.9% according to the intention-to-treat and the per-protocol analysis, respectively. CONCLUSION: MAXPOWER Biological Antibacterial Liquid is both safe and efficacious in the eradication of oral H. pylori. TRIAL REGISTRATION: This study was retrospectively registered in the ClinicalTrials.gov Trial Registry on 21/09/2023 (NCT06045832).


Subject(s)
Anti-Bacterial Agents , Helicobacter Infections , Helicobacter pylori , Helicobacter pylori/drug effects , Helicobacter pylori/genetics , Humans , Helicobacter Infections/drug therapy , Helicobacter Infections/microbiology , Anti-Bacterial Agents/pharmacology , Animals , Mice , Male , Female , Middle Aged , Adult , Microbial Sensitivity Tests
17.
Lett Appl Microbiol ; 77(6)2024 Jun 03.
Article in English | MEDLINE | ID: mdl-38794899

ABSTRACT

Non-antibiotic adjuncts may improve Helicobacter pylori infection control. Our aim was to emphasize curcumin benefits in controlling H. pylori infection. We discussed publications in English mostly published since 2020 using keyword search. Curcumin is the main bioactive substance in turmeric. Curcumin inhibited H. pylori growth, urease activity, three cag genes, and biofilms through dose- and strain-dependent activities. Curcumin also displayed numerous anticancer activities such as apoptosis induction, anti-inflammatory and anti-angiogenic effects, caspase-3 upregulation, Bax protein enhancement, p53 gene activation, and chemosensitization. Supplementing triple regimens, the agent increased H. pylori eradication success in three Iranian studies. Bioavailability was improved by liposomal preparations, lipid conjugates, electrospray-encapsulation, and nano-complexation with proteins. The agent was safe at doses of 0.5->4 g daily, the most common (in 16% of the users) adverse effect being gastrointestinal upset. Notably, curcumin favorably influences the intestinal microbiota and inhibits Clostridioides difficile. Previous reports showed the inhibitory effect of curcumin on H pylori growth. Curcumin may become an additive in the therapy of H. pylori infection, an adjunct for gastric cancer control, and an agent beneficial to the intestinal microbiota. Further examination is necessary to determine its optimal dosage, synergy with antibiotics, supplementation to various eradication regimens, and prophylactic potential.


Subject(s)
Anti-Bacterial Agents , Curcuma , Curcumin , Helicobacter Infections , Helicobacter pylori , Curcumin/pharmacology , Helicobacter Infections/drug therapy , Helicobacter Infections/microbiology , Helicobacter pylori/drug effects , Helicobacter pylori/genetics , Humans , Anti-Bacterial Agents/pharmacology , Gastrointestinal Microbiome/drug effects
18.
Sci Rep ; 14(1): 9998, 2024 05 01.
Article in English | MEDLINE | ID: mdl-38693196

ABSTRACT

It is estimated that more than half of the world population has been infected with Helicobacter pylori. Most newly acquired H. pylori infections occur in children before 10 years of age. We hypothesized that early life H. pylori infection could influence the composition of the microbiome at mucosal sites distant to the stomach. To test this hypothesis, we utilized the infant rhesus macaque monkey as an animal model of natural H. pylori colonization to determine the impact of infection on the lung and oral microbiome during a window of postnatal development. From a cohort of 4-7 month-old monkeys, gastric biopsy cultures identified 44% of animals infected by H. pylori. 16S ribosomal RNA gene sequencing of lung washes and buccal swabs from animals showed distinct profiles for the lung and oral microbiome, independent of H. pylori infection. In order of relative abundance, the lung microbiome was dominated by the phyla Proteobacteria, Firmicutes, Bacteroidota, Fusobacteriota, Campilobacterota and Actinobacteriota while the oral microbiome was dominated by Proteobacteria, Firmicutes, Bacteroidota, and Fusobacteriota. In comparison to the oral cavity, the lung was composed of more genera and species that significantly differed by H. pylori status, with a total of 6 genera and species that were increased in H. pylori negative infant monkey lungs. Lung, but not plasma IL-8 concentration was also associated with gastric H. pylori load and lung microbial composition. We found the infant rhesus macaque monkey lung harbors a microbiome signature that is distinct from that of the oral cavity during postnatal development. Gastric H. pylori colonization and IL-8 protein were linked to the composition of microbial communities in the lung and oral cavity. Collectively, these findings provide insight into how H. pylori infection might contribute to the gut-lung axis during early childhood and modulate future respiratory health.


Subject(s)
Helicobacter Infections , Helicobacter pylori , Lung , Macaca mulatta , Microbiota , Mouth , RNA, Ribosomal, 16S , Animals , Macaca mulatta/microbiology , Lung/microbiology , Helicobacter Infections/microbiology , Helicobacter pylori/genetics , Mouth/microbiology , RNA, Ribosomal, 16S/genetics , Male , Disease Models, Animal
19.
Braz J Microbiol ; 55(2): 1393-1404, 2024 Jun.
Article in English | MEDLINE | ID: mdl-38676790

ABSTRACT

Helicobacter pylori is the most common cause of gastroduodenal diseases. The concept that cagA-positive H. pylori is a risk factor for gastric cancer appears to be true only for H. pylori strains from Western countries. Other virulent genes may have a synergistic interaction with cagA during pathogenesis. This study aims to investigate H. pylori cagA, vacA, and iceA prevalence, genotypes, and their association to clinical outcomes in Vietnamese patients. The cagA status and vacA and iceA genotypes were determined using the PCR technique on DNA extracted from gastric biopsies of 141 patients with gastroduodenal diseases. After performing molecular analysis for cagA, vacA, and iceA genes, samples with mixed H. pylori strains, positivity, or negativity for both cagA and cagPAI-empty site, or unidentified genotypes were excluded. Finally, 107 samples were examined. The presence of the cagA, vacA, and iceA genes were detected in 77.6%, 100%, and 80.4% of cases, respectively. Notably, cagA( +) with EPIYA-ABD, vacA s1i1m1, vacA s1i1m2, iceA1, and iceA2 accounted for 73.8%, 44.9%, 33.6%, 48.6%, and 31.8% of cases, respectively. Four iceA2 subtypes (24-aa, 59-aa, 94-aa, and 129-aa variants) were found, with the 59-aa variant the most prevalent (70.6%). The cagA( +)/vacAs1i1m1/iceA1 and cagA( +)/vacAs1i1m2/iceA1 combinations were found in 26.2% and 25.1% of cases, respectively. A multivariable logistic regression analysis was performed, after adjusting for age and gender, with the gastritis group was used as a reference control. Statistically significant associations were found between the vacA s1i1m2 genotype, the iceA1 variant, and the cagA( +)/vacAs1i1m2/iceA1 combination and gastric cancer; the adjusted ORs were estimated as 18.02 (95% CI: 3.39-95.81), 4.09 (95% CI: 1.1-15.08), and 16.19 (95% CI: 3.42-76.66), respectively. Interestingly, for the first time, our study found that vacA s1i1m2, but not vacA s1i1m1, was a risk factor for gastric cancer. This study illustrates the genetic diversity of the H. pylori cagA, vacA, and iceA genes across geographical regions and contributes to understanding the importance of these genotypes for clinical outcomes.


Subject(s)
Antigens, Bacterial , Bacterial Proteins , Genotype , Helicobacter Infections , Helicobacter pylori , Humans , Bacterial Proteins/genetics , Helicobacter pylori/genetics , Helicobacter pylori/isolation & purification , Helicobacter pylori/classification , Helicobacter pylori/pathogenicity , Vietnam/epidemiology , Antigens, Bacterial/genetics , Helicobacter Infections/microbiology , Helicobacter Infections/epidemiology , Cross-Sectional Studies , Male , Female , Middle Aged , Adult , Bacterial Outer Membrane Proteins/genetics , Aged , Young Adult , Prevalence , Virulence Factors/genetics
20.
Microbiol Spectr ; 12(5): e0355423, 2024 May 02.
Article in English | MEDLINE | ID: mdl-38619276

ABSTRACT

There has been a suggestion of a potential protective effect of Helicobacter pylori (H. pylori) in the development of ulcerative colitis (UC). Virulence factor is an important factor in H. pylori, but little is known about the clinical characteristics of ulcerative colitis. In this retrospective study, a total of 322 patients with UC were analyzed. They were divided into three groups based on H. pylori antibody typing classification: type I H. pylori infection group, type II H. pylori infection group, and H. pylori-negative group. The study aimed to analyze the clinical characteristics of different types of H. pylori infection groups. The proportions of disease course, nationality, clinical type, and disease severity among UC patients in different types of H. pylori infection groups exhibited statistically significant differences (P < 0.05). However, no significant differences were observed in terms of sex, age, smoking status, alcohol consumption, body mass index (BMI), or lesion range (P > 0.05). Among the extraintestinal manifestations, the incidence of joint lesions in the type I H. pylori infection group was significantly lower compared with H. pylori-negative group (P < 0.05). The levels of red blood cell, hemoglobin, packed cell volume, albumin, A/G, and alanine aminotransferase were significantly higher in the type I H. pylori infection group compared with both the type II H. pylori infection group and H. pylori-negative group in the hematology index. Conversely, the levels of D-Dimer, C-reactive protein, and erythrocyte sedimentation rate were significantly lower in the type II H. pylori infection group (P < 0.05). In patients with UC, infections with the highly virulent type I H. pylori exhibit a negative correlation with both the severity of the disease and extraintestinal manifestations. While infections with the less virulent type II H. pylori are negatively correlated only with the disease severity. Therefore, the virulence factors of H. pylori play an important role in the regulation of UC. IMPORTANCE: The number of patients with ulcerative colitis (UC) has increased dramatically worldwide, posing a global public health challenge, There has been a suggestion of a potential protective effect of Helicobacter pylori in the development of UC. Virulence factor is an important factor in H. pylori, but high-quality clinical evidence is lacking. This study comprehensively analyzed the clinical characteristics of UC patients with different types of H. pylori infection. Infections with the highly virulent type I H. pylori are found to be negatively correlated with the severity of the disease as well as extraintestinal manifestations, whereas infections with the less virulent type II H. pylori demonstrate a negative correlation solely with disease severity. These results suggest that the virulence factors of H. pylori play a pivotal role in UC. Consequently, virulence factors should be taken into consideration when targeting H. pylori eradication in clinical practice, particularly in UC patients. It is crucial to evaluate the individual benefits to optimize personalized eradication therapies.


Subject(s)
Colitis, Ulcerative , Helicobacter Infections , Helicobacter pylori , Humans , Colitis, Ulcerative/microbiology , Colitis, Ulcerative/pathology , Helicobacter Infections/microbiology , Helicobacter Infections/complications , Helicobacter Infections/pathology , Male , Helicobacter pylori/genetics , Helicobacter pylori/pathogenicity , Female , Retrospective Studies , Middle Aged , Adult , Aged , Young Adult , Adolescent
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