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The growing resistance to amoxicillin (AMX)-one of the main antibiotics used in Helicobacter pylori eradication therapy-is an increasing health concern. Several mutations of penicillin-binding protein 1A (PBP1A) are suspected of causing AMX resistance; however, only a limited set of these mutations have been experimentally explored. This study aimed to investigate four PBP1A mutations (i.e., T558S, N562H, T593A, and G595S) carried by strain KIN76, a high-level AMX-resistant clinical H. pylori isolate with an AMX minimal inhibition concentration (MIC) of 2 µg/mL. We transformed a recipient strain 26695 with the DNA containing one to four mutation allele combinations of the pbp1 gene from strain KIN76. Transformants were subjected to genomic exploration and antimicrobial susceptibility testing. The resistance was transformable, and the presence of two to four PBP1A mutations (T558S and N562H, or T593A and G595S), rather than separate single mutations, was necessary to synergistically increase the AMX MIC up to 16-fold compared with the wild-type (WT) strain 26695. An AMX binding assay of PBP1A was performed using these strains, and binding was visualized by chasing Bocillin, a fluorescent penicillin analog. This revealed that all four-mutation allele-transformed strains exhibited decreased affinity to AMX on PBP1A than the WT. Protein structure modeling indicated that functional modifications occur as a result of these amino acid substitutions. This study highlights a new synergistic AMX resistance mechanism and establishes new markers of AMX resistance in H. pylori.IMPORTANCEThe development of resistance to antibiotics, including amoxicillin, is hampering the eradication of Helicobacter pylori infection. The identification of mechanisms driving this resistance is crucial for the development of new therapeutic strategies. We have demonstrated in vitro the synergistic role of novel mutations in the pbp1 gene of H. pylori that is suspected to drive amoxicillin resistance. Also deepening our understanding of amoxicillin resistance mechanisms, this study establishes new molecular markers of amoxicillin resistance that may be useful in molecular-based antibiotic susceptibility testing approaches for clinical practice or epidemiologic investigations.
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Patients receiving hemodialysis (HD) often develop gastrointestinal diseases. Recently, although in general population, clinical guidelines for Helicobacter pylori have strongly recommended its eradication in patients to prevent gastric cancer, optimal eradication regimen and optimal dosage of drugs for patients receiving HD have not been established, due to possible incidence of adverse events. Some antimicrobial agents used in eradication therapy, particularly amoxicillin, can exacerbate renal dysfunction. Given the delayed pharmacokinetics of drugs in patients receiving HD compared with those in healthy individuals, drug regimen and dosage should be considered to minimize adverse effects. Although previous studies have investigated the benefits of eradication therapy for patients receiving HD, because most studies were small in terms of the number of enrolled patients, it is hard to show evidence. The numbers of eradication in HD patients have recently increased, and it is important to provide an optimal regimen. The consideration of eradication in patients undergoing HD with a reduction in the drug dose by 1/2-1/3 may prevent adverse events. Additionally, another important consideration is whether adverse events can be prevented while maintaining a similar eradication rate with reduced drug dosages. Recent meta-analysis findings indicate comparable eradication rates in patients receiving HD and healthy individuals, both with the same dosage regimen and at a reduced dosage regimen, with no significant differences (relative risk [RR] for successful eradication: 0.85 [95% confidence interval (CI): 0.48-1.50]). Unlike with the same dosage regimen (RR for adverse events: 3.15 [95% CI: 1.93-5.13]), the adverse events in the dosage reduction regimen were similar to those in healthy individuals (RR: 1.26 [95% CI: 0.23-6.99]). From a pharmacological perspective, the eradication regimen in patients receiving HD should consider the dosage (1/2-1/3 dosage), dosing number (bid), dosing timing of drugs (after HD), and susceptibility to antimicrobial agents.
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Antibacterianos , Infecciones por Helicobacter , Helicobacter pylori , Diálisis Renal , Humanos , Infecciones por Helicobacter/tratamiento farmacológico , Diálisis Renal/efectos adversos , Antibacterianos/efectos adversos , Antibacterianos/administración & dosificación , Antibacterianos/uso terapéutico , Antibacterianos/farmacocinética , Helicobacter pylori/efectos de los fármacosRESUMEN
Potassium-competitive acid blockers (P-CABs) provide potent acid inhibition, yet studies on P-CAB-based quadruple therapy for H. pylori eradication are limited. We theorized that integrating bismuth subsalicylate into a quadruple therapy regimen could enhance eradication rates. However, data on the efficacy of vonoprazan bismuth quadruple therapy are notably scarce. Therefore, the aim of this study was to evaluate the efficacy of vonoprazan-based bismuth quadruple therapy in areas with high clarithromycin and levofloxacin resistance. This was a prospective, single-center, randomized trial conducted to compare the efficacy of 7-day and 14-day vonoprazan-based bismuth quadruple therapy for H. pylori eradication between June 1, 2021, and March 31, 2022. Qualified patients were randomly assigned to the 7-day or 14-day regimen (1:1 ratio by computer-generated randomized list as follows: 51 patients for the 7-day regimen and 50 patients for the 14-day regimen). The regimens consisted of vonoprazan (20 mg) twice daily, bismuth subsalicylate (1024 mg) twice daily, metronidazole (400 mg) three times daily, and tetracycline (500 mg) four times daily. CYP3A4/5 genotyping and antibiotic susceptibility tests were also performed. Successful eradication was defined as 13negative C-UBTs 4 weeks after treatment. The primary endpoint was to compare the efficacy of 7-day and 14-day regimens as first-line treatments, which were assessed by intention-to-treat (ITT) and per-protocol (PP) analyses. The secondary endpoints included adverse effects. A total of 337 dyspeptic patients who underwent gastroscopy were included; 105 patients (31.1%) were diagnosed with H. pylori infection, and 101 patients were randomly assigned to each regimen. No dropouts were detected. The antibiotic resistance rate was 33.3% for clarithromycin, 29.4% for metronidazole, and 27.7% for levofloxacin. The CYP3A4 genotype was associated with 100% rapid metabolism. The H. pylori eradication rates for the 7-day and 14-day regimens were 84.4%, 95% CI 74.3-94.2 and 94%, 95% CI 87.4-100, respectively (RR difference 0.25, 95% CI 0.03-0.53, p value = 0.11). Interestingly, the 14-day regimen led to 100% eradication in the clarithromycin-resistant group. Among the patients in the 7-day regimen group, only two exhibited resistance to clarithromycin; unfortunately, neither of them achieved a cure from H. pylori infection. The incidence of adverse events was similar in both treatment groups, occurring in 29.4% (15/51) and 28% (14/50) of patients in the 7-day and 14-day regimens, respectively. No serious adverse reactions were reported. In conclusion, 14 days of vonoprazan-based bismuth quadruple therapy is highly effective for H. pylori eradication in areas with high levels of dual clarithromycin and levofloxacin resistance.
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Infecciones por Helicobacter , Helicobacter pylori , Compuestos Organometálicos , Pirroles , Salicilatos , Sulfonamidas , Humanos , Antibacterianos/uso terapéutico , Bismuto/uso terapéutico , Claritromicina/farmacología , Citocromo P-450 CYP3A , Quimioterapia Combinada , Infecciones por Helicobacter/genética , Levofloxacino/farmacología , Metronidazol/uso terapéutico , Compuestos Organometálicos/uso terapéutico , Estudios Prospectivos , Pirroles/uso terapéutico , Salicilatos/uso terapéutico , Sulfonamidas/uso terapéutico , Resultado del TratamientoRESUMEN
Helicobacter pylori infection is a major global health concern, and its management has witnessed a revolutionary shift with the emergence of antibiotic resistance. In this review, I explore the mechanisms of H. pylori antibiotic resistance and highlight the critical need for susceptibility-based eradication treatments. The increasing prevalence of antibiotic-resistant strains requires innovative approaches to combat this resilient pathogen. I also delve into the importance of mass screening as a preventive strategy for early detection and intervention, describing my experience in Bhutan. Additionally, I explore promising alternatives, such as vaccination. The aim of this review is to provide insight into the evolving landscape of H. pylori treatment and highlight the need for a paradigm shift in the approach to combating this persistent bacterial infection.
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Antibacterianos , Farmacorresistencia Bacteriana , Infecciones por Helicobacter , Helicobacter pylori , Infecciones por Helicobacter/tratamiento farmacológico , Helicobacter pylori/efectos de los fármacos , Humanos , Antibacterianos/uso terapéutico , Tamizaje Masivo/métodos , Bután/epidemiología , Vacunas Bacterianas , Quimioterapia CombinadaRESUMEN
[This corrects the article DOI: 10.1017/jns.2021.104.].
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BACKGROUND: Helicobacter pylori (H. pylori) is associated with gastric cancer. Early and accurate diagnosis of H. pylori infection can reduce risk of gastric cancer. Conventional white light imaging (WLI) and image-enhanced endoscopic (IEE) techniques such as narrow-band imaging (NBI), linked color imaging (LCI) and blue laser imaging (BLI) plays pivotal role in H. pylori diagnosis. This study aimed to determine diagnostic performance of real-time endoscopy between WLI and other IEE techniques for diagnosis of H. pylori infection. METHODS: This prospective study compared endoscopic images by gastroscopy using WLI and IEE techniques (LCI, Magnifying-BLI, and Magnifying-NBI) at Thammasat University Hospital, Thailand between January 2020, and July 2021. All participants underwent gastroscopy. Three biopsies at gastric antrum and two biopsies at body were obtained for H.pylori diagnosis. H. pylori infection was defined as a positive test of either one of the following tests: rapid urease test, histopathology, H. pylori culture. RESULTS: Of 167 dyspeptic patients undergoing gastroscopy, 100 were enrolled in this study. Overall H. pylori infection was 40%. Patients had the mean age of 59.1 years and 53% were males. Enlarged gastric folds and antral nodularity can predict H. pylori infection with 100% PPV, while fundic gland polyps and red streak provided 100% PPV for exclusion of H. pylori infection on WLI. Sensitivity, specificity, PPV, NPV and accuracy for diagnosis of H. pylori infection for WLI were 80%, 71.7%, 65.3%, 84.3% and 75% respectively, while those for LCI were 90%, 70%, 66.7%, 91.3% and 78% respectively. M-NBI and M-BLI endoscopy demonstrated elongated pits in H. pylori-positive patients. Sensitivity, specificity, PPV, NPV and accuracy for M-BLI were 95%, 80%, 76%, 96% and 86% respectively, whereas those for M-NBI were 92.5%, 86.7%, 82.2%, 94.6% and 89% respectively. Sensitivity of M-BLI was better than WLI, while sensitivities of LCI and M-NBI were also numerically higher than WLI without statistical difference (M-BLI 95%vs.WLI 80%, p = 0.03; M-NBI 92.5%vs.WLI 80%, p = 0.13; LCI 90%vs.WLI 80%, p = 0.22). Sensitivities of all IEE modes were not different from one another (LCI 90%vs.M-BLI 95%, p = 0.50; LCI 90%vs.M-NBI 92.5%, p = 1.00, M-BLI 95%vs.M-NBI 92.5%, p = 1.00). CONCLUSIONS: M-BLI significantly improved sensitivity of real-time endoscopic diagnosis of H. pylori infection compared with WLI. Enlarged gastric folds and antral nodularity could be reliable predictors for H. pylori infection, while fundic gland polyps and red streak could be important endoscopic findings for H. pylori-negative mucosa.
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Pólipos Adenomatosos , Infecciones por Helicobacter , Helicobacter pylori , Pólipos , Neoplasias Gástricas , Masculino , Humanos , Persona de Mediana Edad , Femenino , Neoplasias Gástricas/diagnóstico por imagen , Neoplasias Gástricas/patología , Infecciones por Helicobacter/diagnóstico , Estudios Prospectivos , Endoscopía GastrointestinalRESUMEN
Neoadjuvant chemotherapy (NAC) followed by surgery is a standard approach for management of locally advanced esophageal squamous cell carcinoma (ESCC). Patients who do not respond well to NAC have a poor prognosis. Despite extensive research, the mechanisms of chemoresistance in ESCC remain largely unknown. Here, we established paired tumor organoids-designated as PreNAC-O and PostNAC-O-from one ESCC patient before and after NAC, respectively. Although the two organoids did not exhibit significant differences in proliferation, morphology or drug sensitivity in vitro, the tumorigenicity of PostNAC-O in vivo was significantly higher than that of PreNAC-O. Xenografts from PreNAC-O tended to exhibit keratinization, while those from PostNAC-O displayed conspicuous necrotic areas. The tumorigenicity of PostNAC-O xenografts during the chemotherapy was comparable to that of PreNAC-O without treatment. Furthermore, the gene expression profiles of the xenografts suggested that expression of genes involved in the EMT and/or hypoxia response might be related to the tumorigenicity of PostNAC-O. Our data suggested that the tumorigenicity of residual cancer had been enhanced, outweighing the effects of chemotherapy, rather than being attributable to intrinsic chemoresistance. Further studies are required to clarify the extent to which residual cancers share a common mechanism similar to that revealed here.
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Neoplasias Esofágicas , Carcinoma de Células Escamosas de Esófago , Humanos , Carcinoma de Células Escamosas de Esófago/tratamiento farmacológico , Carcinoma de Células Escamosas de Esófago/genética , Carcinoma de Células Escamosas de Esófago/patología , Neoplasias Esofágicas/tratamiento farmacológico , Neoplasias Esofágicas/genética , Neoplasias Esofágicas/metabolismo , Neoplasia Residual , Terapia Neoadyuvante , Organoides/patologíaRESUMEN
Background/Aims: : A latex agglutination turbidity (LA) assay to test for serum antibodies has been approved in Japan and Korea for mass screening of Helicobacter pylori infection. In this study, we evaluated the LA assay for diagnosing H. pylori infection and predicting gastric mucosal changes in a Mongolian population. Methods: : In total, 484 individuals were classified into H. pylori-positive (n=356) and H. pylori-negative (n=128) groups, as determined by histology and H. pylori culture. Results: : The best cutoff, sensitivity, and specificity values for the LA assay were 18.35 U/mL, 74.2%, and 65.6%, respectively. The LA values in the atrophic gastritis group were statistically higher than those in the other groups (healthy, chronic gastritis, intestinal metaplasia, and gastric cancer, p<0.0001). The cutoff value to distinguish the atrophic gastritis group from the other four groups was 32.0 U/mL, and its area under the curve was 0.673, which was the highest among the E-plate, pepsinogen (PG) I, PG II, and PG I/II ratio tests in our data. The odds ratios for atrophic gastritis determined by the LA assay and PG I test in multiple logistic regression were 2.5 and 1.9, respectively, which were significantly higher than for the other tests. Conclusions: : The LA assay can determine the risk of atrophic gastritis, which in turn is a considerable risk factor for gastric cancer. We propose using this assay in combination with the PG I/II ratio to avoid missing gastric cancer patients who have a low LA value (less than 32.0 U/mL).
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Gastritis Atrófica , Infecciones por Helicobacter , Helicobacter pylori , Neoplasias Gástricas , Humanos , Gastritis Atrófica/complicaciones , Neoplasias Gástricas/patología , Infecciones por Helicobacter/diagnóstico , Infecciones por Helicobacter/complicaciones , Pruebas de Fijación de Látex , Pepsinógeno A , Pepsinógeno CRESUMEN
BACKGROUND: We previously showed rising primary antibiotic resistance of Helicobacter pylori during 1990-2015 in the Asia-Pacific region. However, whether primary antibiotic resistance continues to rise is unknown. Therefore, we aimed to assess the latest prevalence of H pylori antibiotic resistance in this region. METHODS: We did an updated systematic review and meta-analysis of observational studies and randomised controlled trials published in PubMed, Embase, and Cochrane Library between Jan 1, 1990, and July 12, 2023. Studies investigating primary H pylori resistance to clarithromycin, metronidazole, levofloxacin, amoxicillin, or tetracycline in individuals naive to eradication therapy in the Asia-Pacific region (as defined by the UN geoscheme) were eligible for inclusion. There were no language restrictions. Studies that focused on specific subpopulations (eg, children) were excluded. Using a standardised extraction form, two authors independently reviewed and extracted summary data from all eligible articles. The updated prevalence of antibiotic resistance was generated by meta-analysis under a random-effects model and subgroup analyses were done by countries and periods of study. Between-study variability was assessed by use of I2. The study is registered in PROSPERO, CRD42022339956. FINDINGS: A total of 351 studies, including 175 new studies and 176 studies from our previous analysis, were included in this meta-analysis. The overall prevalence of primary antibiotic resistance of H pylori between 1990 and 2022 was 22% (95% CI 20-23; I2=96%) for clarithromycin, 52% (49-55; I2=99%) for metronidazole, 26% (24-29; I2=96%) for levofloxacin, 4% (3-5; I2=95%) for tetracycline, and 4% (3-5; I2=95%) for amoxicillin. Prevalence varied considerably between countries and across study periods. From 1990 to 2022, the prevalence of primary resistance increased for clarithromycin, metronidazole, and levofloxacin but remained stable for amoxicillin and tetracycline. The latest primary resistance prevalences were 30% (95% CI 28-33; I2=93%) for clarithromycin, 61% (55-66; I2=99%) for metronidazole, 35% (31-39; I2=95%) for levofloxacin, 4% (2-6; I2=96%) for tetracycline, and 6% (4-8; I2=96%) for amoxicillin in the Asia-Pacific region. INTERPRETATION: Treatment guidelines should be adapted in response to the rising primary resistance of key antibiotics for H pylori eradication. A global policy to control and monitor the antibiotic resistance of H pylori is urgently needed. FUNDING: Ministry of Health and Welfare of Taiwan, National Science and Technology Council of Taiwan, and National Taiwan University. TRANSLATION: For the Chinese translation of the abstract see Supplementary Materials section.
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Infecciones por Helicobacter , Helicobacter pylori , Niño , Humanos , Claritromicina/farmacología , Claritromicina/uso terapéutico , Metronidazol/farmacología , Metronidazol/uso terapéutico , Levofloxacino/farmacología , Levofloxacino/uso terapéutico , Infecciones por Helicobacter/tratamiento farmacológico , Infecciones por Helicobacter/epidemiología , Antibacterianos/farmacología , Antibacterianos/uso terapéutico , Amoxicilina/farmacología , Amoxicilina/uso terapéutico , Tetraciclina , Farmacorresistencia Microbiana , Asia/epidemiologíaRESUMEN
Approximately half of the world's population is estimated to be infected with Helicobacter pylori [...].
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Helicobacter pylori is a pathogen related to severe diseases such as gastric cancer; because of rising antimicrobial-resistant strains, failure to eradicate H. pylori with antibiotics has increased worldwide. Multidrug-resistant H. pylori and gastric cancer is common in Mongolia; therefore, we aimed to explore alternative antimicrobial treatments and the genomes of resistant strains in this country. A total of 361 H. pylori strains isolated from patients in Mongolia were considered. Minimal inhibitory concentrations for two fluoroquinolones (ciprofloxacin and moxifloxacin), rifabutin, and furazolidone were determined via two-fold agar dilution. Genomic mutations in antibiotic-resistant strains were identified by next-generation sequencing using the Illumina Miseq platform and compared with genes from a reference H. pylori strain (26695). The resistance rate of H. pylori strains to quinolones was high (44% to ciprofloxacin and 42% to moxifloxacin), and resistance to rifabutin was low (0.5%); none were resistant to furazolidone. Most quinolone-resistant strains possessed gyrA gene mutations causing amino acid changes (e.g., N87K, A88P, and D91G/Y/N). While one rifabutin-resistant strain had amino acid-substituting mutations in rpoB (D530N and R701C), the other had three novel rpoB mutations; both rifabutin-resistant strains were sensitive to furazolidone. Overall, our findings suggest that rifabutin and/or furazolidone may be an alternative, effective H. pylori treatment in patients who have failed to respond to other treatment regimens.
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BACKGROUND: Helicobacter pylori treatment failure remains a challenging problem. This study aimed to identify predictive factors for successful eradication in patients following treatment failures. METHODS: This was a retrospective cohort study. This study included 1,050 dyspeptic patients diagnosed with H. pylori infection at tertiary care center in Thailand between March 2014 and October 2021. Patients' demographic data, endoscopic findings, H. pylori culture, antimicrobial susceptibility testing (AST), treatment regimens and outcomes were analysed. RESULTS: Of 1,050 patients with H. pylori infections, 302 (28.7%) experienced treatment failure (mean age 58.4 years; 44.7% males). AST was performed in 192. Resistance was observed for metronidazole (43.2%), levofloxacin (33.9%), clarithromycin (24%), and amoxicillin (2.1%). There was no tetracycline resistance. Multidrug-resistance (MDR) was significantly more common following treatment failure (45.5% vs. 15.7%, p<0.001). Baseline characteristics were similar between treatment successes and failures. Eradication rates after first-line and second-line regimens were 71.2% and 54.5%, respectively. Medication nonadherence [OR 36.6 (95%CI 8.65-155.03, p<0.001)] and MDR [OR 4.49 (95%CI 2.29-8.81, p<0.001)] were associated with treatment failure. Over time, resistance increased for metronidazole, levofloxacin, and clarithromycin, while eradication rates with triple therapy declined. Tailored antibiotic therapy [OR 4.92 (95%CI 1.61-14.99, p = 0.005)] and a regimen including 4-times-daily dosing of amoxicillin (2 grams/day) [OR 3.05 (95%CI 1.10-8.41, p = 0.032)] were significantly associated with treatment success after first-line failure. Eradication rates when using tailored therapy and 4-times-daily dosing of amoxicillin (2 grams/day) were 91.1% and 89.4%, respectively. Performing AST before first-line therapy resulted in the highest cure rates. AST performed after multiple treatment failures was also associated with higher eradication rates compared with the group without AST (94.4% vs. 50%,p = 0.008). CONCLUSIONS: AST either before or after treatment failure correlated with a higher proportion of successful eradication. Nonadherence and the MDR infections predicted treatment failure. Tailored therapy and 4-times-daily dosing of amoxicillin after treatment failure were likely to be successful.
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Infecciones por Helicobacter , Helicobacter pylori , Femenino , Humanos , Masculino , Persona de Mediana Edad , Amoxicilina/uso terapéutico , Antibacterianos/uso terapéutico , Claritromicina/uso terapéutico , Quimioterapia Combinada , Infecciones por Helicobacter/tratamiento farmacológico , Infecciones por Helicobacter/diagnóstico , Levofloxacino/uso terapéutico , Metronidazol/uso terapéutico , Estudios Retrospectivos , Insuficiencia del TratamientoRESUMEN
Helicobacter pylori, linked to gastric diseases, is targeted for probiotic treatment through bacteriocin production. Bacteriocins have gained recognition for their non-toxic effects on host cells and their ability to combat a wide range of pathogens. This study aimed to taxonomically characterize and evaluate the safety and probiotic properties of the novel species of Lactococcus sp. NH2-7C isolated from fermented pork, as well as its bacteriocin NH2-7C, both in vitro and in silico. Comparative genotypic analysis revealed an average nucleotide identity of 94.96%, an average amino acid identity of 94.29%, and a digital DNA-DNA hybridization value of 63.80% when compared to Lactococcus lactis subsp. lactis JCM 5805T. These findings suggest that strain NH2-7C represents a novel species within the genus Lactococcus. In silico assessments confirmed the non-pathogenic nature of strain NH2-7C and the absence of genes associated with virulence and biogenic amine formation. Whole-genome analysis revealed the presence of the nisA gene responsible for nisin A production, indicating its potential as a beneficial compound with anti-Helicobacter pylori activity and non-toxic characteristics. Probiotic assessments indicated bile salt hydrolase and cholesterol assimilation activities, along with the modulation of interleukin-6 and tumour necrosis factor-α secretion. Strain NH2-7C demonstrated gastrointestinal tolerance and the ability to adhere to Caco-2 cells, affirming its safety and probiotic potential. Additionally, its ability to produce bacteriocins supports its suitability as a functional probiotic strain with therapeutic potential. However, further in vitro and in vivo investigations are crucial to ensure its safety and explore potential applications for Lactococcus sp. NH2-7C as a probiotic agent.
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Bacteriocinas , Helicobacter pylori , Lactococcus lactis , Carne de Cerdo , Animales , Bacteriocinas/metabolismo , Células CACO-2 , ADN/metabolismo , Lactococcus lactis/genética , Carne de Cerdo/microbiología , PorcinosRESUMEN
BACKGROUND: The prevalence of gastric cancer in Mongolia, in East Asia, remains the highest in the world. However, most Helicobacter pylori strains in Mongolia have a less virulent Western-type CagA. We aimed to determine how H. pylori genomic variation affected gastric diseases, especially gastric cancer, based on comprehensive genome analysis. METHODS: We identified a set of 274 virulence-associated genes in H. pylori, including virulence factor and outer membrane protein (OMP) genes, the type four secretion system gene cluster, and 13 well-known virulence gene genotypes in 223 H. pylori strains and their associations with gastric cancer and other gastric diseases. We conducted a genome-wide association study on 158 H. pylori strains (15 gastric cancer and 143 non-gastric cancer strains). RESULTS: Out of 274 genes, we found 13 genes were variable depending on disease outcome, especially iron regulating OMP genes. H. pylori strains from Mongolia were divided into two main subgroups: subgroup (Sg1) with high risk and Sg2 with low risk for gastric cancer. The general characteristics of Sg1 strains are that they possess more virulence genotype genes. We found nine non-synonymous single nucleotide polymorphisms in seven genes that are linked with gastric cancer strains. CONCLUSIONS: Highly virulent H. pylori strains may adapt through host-influenced genomic variations, potentially impacting gastric carcinogenesis.
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BACKGROUND: Gastric cancer remains the fourth leading cause of cancer-related death worldwide. Significant number of gastric cancer patients presented with bleeding. OBJECTIVE: This study aimed to identify risk factors and overall survival rates of bleeding gastric cancer patients. METHODS: This retrospective cohort study was conducted between 2007-2022 at tertiary care center in Thailand. Clinical information, endoscopic findings and histological type were extensively reviewed and were compared between bleeders and non-bleeders. Patients were monitored for at least 5 years. RESULTS: There were 20,981 patients who underwent upper gastrointestinal endoscopy during study period. Total of 201 gastric cancer patients were included in this study, 21 were excluded due to incomplete medical records. 180 gastric cancer patients were included with mean age of 60.5±14.3 years. There were 65 (36.1%) patients with gastrointestinal bleeding. Hypertension and chronic kidney disease were significantly more common in bleeders than non-bleeders (43.1% vs 23.5%, OR2.51, 95%CI 1.14.-5.52, p = 0.022; and 16.9% vs 5.2%, OR2.00, 95%CI 1.56-6.63, p = 0.025, respectively). current H. pylori infection was also significantly more common in bleeders than non-bleeders (84.6% vs. 55.7%, OR 4.39, 95%CI 1.90-10.12, p<0.001). Median overall survival of bleeders was significantly lower than non-bleeders (7±0.93 vs 10±2.10 months, p = 0.001). CONCLUSIONS: Bleeding gastric cancer was not an uncommon condition. Majority of patients presented at advanced stage with grave prognosis. Male gender, hypertension, chronic kidney disease, and current H. pylori infection were reliable predictors for bleeding. Early diagnosis and prompt treatment are the key to improve clinical outcome.
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Hipertensión , Insuficiencia Renal Crónica , Neoplasias Gástricas , Humanos , Masculino , Persona de Mediana Edad , Anciano , Estudios Retrospectivos , Hemorragia Gastrointestinal/epidemiología , Hemorragia Gastrointestinal/etiología , Pronóstico , Neoplasias Gástricas/complicacionesRESUMEN
We conducted a global-scale study to identify H. pylori antimicrobial-resistant genes (ARG), address their global distribution, and understand their effect on the antimicrobial resistance (AMR) phenotypes of the clinical isolates. We identified ARG using several well-known tools against extensive bacterial ARG databases, then analyzed their correlation with clinical antibiogram data from dozens of patients across countries. This revealed that combining multiple tools and databases, followed by manual selection of ARG from the annotation results, produces more conclusive results than using a single tool or database alone. After curation, the results showed that H. pylori has 42 ARG against 11 different antibiotic classes (16 genes related to single antibiotic class resistance and 26 genes related to multidrug resistance). Further analysis revealed that H. pylori naturally harbors ARG in the core genome, called the 'Set of ARG commonly found in the Core Genome of H. pylori (ARG-CORE)', while ARG-ACC-the ARG in the accessory genome-are exclusive to particular strains. In addition, we detected 29 genes of potential efflux pump-related AMR that were mostly categorized as ARG-CORE. The ARG distribution appears to be almost similar either by geographical or H. pylori populations perspective; however, some ARG had a unique distribution since they tend to be found only in a particular region or population. Finally, we demonstrated that the presence of ARG may not directly correlate with the sensitive/resistance phenotype of clinical patient isolates but may influence the minimum inhibitory concentration phenotype.
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Single-nucleotide polymorphisms (SNPs) in various human genes are key factors in carcinogenesis. However, whether SNPs in bacterial pathogens are similarly crucial in cancer development is unknown. Here, we analyzed 1,043 genomes of the stomach pathogen Helicobacter pylori and pinpointed a SNP in the serine protease HtrA (position serine/leucine 171) that significantly correlates with gastric cancer. Our functional studies reveal that the 171S-to-171L mutation triggers HtrA trimer formation and enhances proteolytic activity and cleavage of epithelial junction proteins occludin and tumor-suppressor E-cadherin. 171L-type HtrA, but not 171S-HtrA-possessing H. pylori, inflicts severe epithelial damage, enhances injection of oncoprotein CagA into epithelial cells, increases NF-κB-mediated inflammation and cell proliferation through nuclear accumulation of ß-catenin, and promotes host DNA double-strand breaks, collectively triggering malignant changes. These findings highlight the 171S/L HtrA mutation as a unique bacterial cancer-associated SNP and as a potential biomarker for risk predictions in H. pylori infections.
Asunto(s)
Infecciones por Helicobacter , Helicobacter pylori , Neoplasias Gástricas , Humanos , Proteínas Bacterianas/genética , Proteínas Bacterianas/metabolismo , Helicobacter pylori/genética , Helicobacter pylori/metabolismo , Polimorfismo de Nucleótido Simple , Neoplasias Gástricas/genética , Neoplasias Gástricas/microbiología , Serina Proteasas/genética , Serina Proteasas/metabolismo , Infecciones por Helicobacter/complicaciones , Infecciones por Helicobacter/genética , Infecciones por Helicobacter/metabolismo , Antígenos Bacterianos/metabolismoRESUMEN
Nontuberculous mycobacterial infections are generally believed to be independently acquired from the environment. Although person-to-person transmission of nontuberculous mycobacteria, especially Mycobacterium abscessus subsp. massiliense, is a serious concern among individuals with cystic fibrosis (CF), evidence of its spread among patients without CF has never been established. We unexpectedly found a number of M. abscessus subsp. massiliense cases among patients without CF in a hospital. This study aimed to define the mechanism of M. abscessus subsp. massiliense infection among patients who were ventilator dependent and without CF who had progressive neurodegenerative diseases in our long-term care wards from 2014 to 2018 during suspected nosocomial outbreaks. We conducted whole-genome sequencing of M. abscessus subsp. massiliense isolates from 52 patients and environmental samples. Potential opportunities for in-hospital transmission were analyzed using epidemiological data. M. abscessus subsp. massiliense was isolated from one air sample obtained near a patient without CF who was colonized with M. abscessus subsp. massiliense but not from other potential sources. Phylogenetic analysis of the strains from these patients and the environmental isolate revealed clonal expansion of near-identical M. abscessus subsp. massiliense isolates, with the isolates generally differing by fewer than 22 single nucleotide polymorphisms (SNPs). Approximately half of the isolates differed by fewer than nine SNPs, indicating interpatient transmission. Whole-genome sequencing revealed a potential nosocomial outbreak among patients who were ventilator dependent and without CF. IMPORTANCE The isolation of M. abscessus subsp. massiliense from the air, but not from environmental fluid samples, may suggest airborne transmission. This was the first report to demonstrate person-to-person transmission of M. abscessus subsp. massiliense, even among patients without CF. M. abscessus subsp. massiliense may spread among patients who are ventilator dependent without CF through direct or indirect in-hospital transmission. The current infection control measures should address potential transmission among patients without CF, particularly in facilities that treat patients who are ventilator dependent and patients with preexisting chronic pulmonary diseases, such as CF.
Asunto(s)
Infección Hospitalaria , Fibrosis Quística , Infecciones por Mycobacterium no Tuberculosas , Mycobacterium abscessus , Humanos , Mycobacterium abscessus/genética , Infecciones por Mycobacterium no Tuberculosas/epidemiología , Infecciones por Mycobacterium no Tuberculosas/microbiología , Fibrosis Quística/microbiología , Filogenia , Infección Hospitalaria/epidemiología , Micobacterias no Tuberculosas , Ventiladores MecánicosRESUMEN
Helicobacter pylori antimicrobial resistance is a critical public health issue. Typically, antimicrobial resistance epidemiology reports include only the antimicrobial susceptibility test results for H. pylori. However, this phenotypic approach is less capable of answering queries related to resistance mechanisms and specific mutations found in particular global regions. Whole genome sequencing can help address these two questions while still offering quality control and is routinely validated against AST standards. A comprehensive understanding of the mechanisms of resistance should improve H. pylori eradication efforts and prevent gastric cancer.