דו״ח מאומת

Gastric cancer remains a significant global health challenge, with Helicobacter pylori (H. pylori) recognized as a major etiological agent, affecting an estimated 50% of the world's population. There has been a rapidly expanding knowledge of the molecular and pathogenetic mechanisms of H. pylori over the decades. This review summarizes the latest research advances to elucidate the molecular mechanisms underlying the H. pylori infection in gastric carcinogenesis. Our investigation of the molecular mechanisms reveals a complex network involving STAT3, NF-κB, Hippo, and Wnt/β-catenin pathways, which are dysregulated in gastric cancer caused by H. pylori. Furthermore, we highlight the role of H. pylori in inducing oxidative stress, DNA damage, chronic inflammation, and cell apoptosis-key cellular events that pave the way for carcinogenesis. Emerging evidence also suggests the effect of H. pylori on the tumor microenvironment and its possible implications for cancer immunotherapy. This review synthesizes the current knowledge and identifies gaps that warrant further investigation. Despite the progress in our previous knowledge of the development in H. pylori-induced gastric cancer, a comprehensive investigation of H. pylori's role in gastric cancer is crucial for the advancement of prevention and treatment strategies. By elucidating these mechanisms, we aim to provide a more in-depth insights for the study and prevention of H. pylori-related gastric cancer.…

PMID: 39849657

Helicobacter pylori (H. pylori) infect over half of the world's population. The prevalence of H. pylori infection and the predominant genotype of H. pylori virulence factors vary considerably across different geographical regions. H. pylori could uniquely persist for decades in the harsh stomach environment, where it damages the gastric mucosa and changes the pattern of gastric hormone release, thereby affects gastric physiology. By utilizing various virulence factors, H. pylori targets different cellular proteins to modulate the host inflammatory response and initiate multiple "hits" on the gastric mucosa, resulting in chronic gastritis and peptic ulceration. Among the long-term consequences of H. pylori infection is gastric malignancies, particularly gastric cancer (GC) and gastric mucosa-associated lymphoid tissue (MALT) lymphoma. As such, H. pylori has been recognized as a class I carcinogen by the International Agency for Research on Cancer. Despite a close causal link between H. pylori infection and the development of gastric malignancies, the precise mechanisms involved in this process are still obscure. Studies over the past two decades have revealed that H. pylori exert oncogenic effects on gastric mucosa through a complex interaction between bacterial factors, host factors, and environmental factors. Numerous signaling pathways can be activated by H. pylori. In this review, we aim to elaborate on the recent developments in the pathophysiological mechanisms of H. pylori-induced gastric inflammation and gastric cancer.…

PMID: 23981572

As the first bacterium to be deemed a class I carcinogen by the World Health Organization in 1994, <i>Helicobacter pylori</i> has paved the way for studying complex host-pathogen interactions. While 1982 marked the discovery of this helical-shaped microorganism found in gastric biopsies by Drs. Robin Warren and Barry Marshall, it took years to link <i>H. pylori</i> infection to gastric inflammation, ulcers, and adenocarcinoma (recognized by a Nobel Prize in 2005). Further investigations into how <i>H. pylori</i> colonizes the stomach, the identification of key virulence factors (such as VacA, CagA, and outer membrane proteins), and global epidemiological studies solidified the impact of <i>H. pylori</i> on gastric disease. This review details the seminal discovery of <i>H. pylori</i> and subsequent work that cemented its status as a microbial carcinogen. Because chronic <i>H. pylori</i> infection and progressive changes to the tissue environment prior to cancer development can span years/decades, studying <i>H. pylori</i> pathogenesis has been challenging. We focus on the importance of using animal models, in particular mouse models, to recapitulate hallmarks of <i>H. pylori-</i>driven human disease. Finally, we highlight recent findings illustrating how <i>H. pylori</i> has adapted to survive and utilize oxidative stress induced during infection, which potentiates cancer development. Due to the long-lasting nature of <i>H. pylori</i> infection and associated remodeling of the host environment that, in turn, promotes carcinogenesis, <i>H. pylori</i> stands as a model organism for understanding other chronic bacterial infections in humans and pathogen-associated malignancies.…

PMID: 41537594

Helicobacter pylori eradication treatments are widely performed to improve gastric mucosal inflammation, promote ulcer healing, and reduce the incidence of gastric cancer. However, there are several issues associated with H. pylori eradication treatment. First, various treatment regimens are currently used worldwide, and the standard treatment varies with region and country. Second, the antimicrobial resistance of H. pylori is increasing due to indiscriminate antibiotic use. Finally, gut microbiota dysbiosis is potentially induced by H. pylori treatment. Based on current international guidelines and a network meta-analysis comparing the effects of various treatment regimens, nonbismuth quadruple therapies for 10-14 days and vonoprazan-based triple therapy for 7 days are the currently recommended H. pylori treatment regimens. These regimens show good eradication rates of approximately 90%, even in areas where antimicrobial-resistant strains are highly prevalent. However, these regimens still have inherent drawbacks that may promote further increases in antimicrobial resistance and induce gut microbiota dysbiosis because of the empiric use of multiple antibiotics. Key Message: The ideal concept for the present and future H. pylori eradication treatment involves "a simple, cost-effective strategy that fosters compliance without having a negative impact on the gut microbiota or contributing to future antimicrobial resistance." One interesting possibility that may fulfill this concept is a dual therapy involving vonoprazan and amoxicillin. This is the simplest treatment regimen that provides acceptable eradication rates, improves safety and tolerability, and minimizes the potential for increasing antimicrobial resistance or causing gut microbiota dysbiosis.…

PMID: 34662879

Helicobacter pylori (H. pylori) is a well-known pathogen that infects approximately half of the world's population. It is a pathogenic agent with potential health hazards related to diverse diseases, especially digestive diseases, such as chronic gastritis, peptic ulcer, and gastric carcinoma. In clinical, antibiotics are commonly applied in eradication therapy of H. pylori. However, the increase in antibiotic resistance and side effects has induced the failure of eradication therapy. Recent studies have shown that probiotic supplementation has promising application prospects. It can restore the gastrointestinal microbiota balance and prevent dysbacteriosis caused by antibiotics. Furthermore, it has been reported to have direct or indirect inhibitory effects on H. pylori. Probiotics may have a beneficial effect on H. pylori eradication. However, the strain, dosages, duration times, and safety of probiotic supplementation need further study before clinical applications.…

PMID: 36344628

<h4>Background & aims</h4>Helicobacter pylori (H. pylori) infection is the principal cause of peptic ulcer disease, MALT lymphoma and non-cardia gastric cancer. The major advances in diagnostics and treatment, eradication success are threatened by rising antimicrobial resistance and concerns about disruption of the normal microbiome. This review summarizes current unresolved issues in H. pylori treatment, with a focus on resistance, optimal regimens, ecological impact, and emerging therapies.<h4>Methods</h4>Extensive review of randomized controlled trials, meta-analyses, international consensus guidelines, molecular epidemiology studies, microbiome analyses, and translational research related to H. pylori eradication, resistance, microbiome effects, and novel therapies.<h4>Results</h4>Global resistance to clarithromycin, metronidazole, and fluoroquinolones significantly undermines the performance of traditionally effective antimicrobial therapies. The corner stone of successful antimicrobial therapy is susceptibility-guided therapy but remains of limited use with H. pylori because of lack of infrastructure. Eradication regimens potentially induce substantial alterations in gut and gastric microbiota and expand the antimicrobial resistome. Probiotics and N-acetylcysteine offer at best very modest improvements in eradication and tolerability. Novel and still experimental platforms, including engineered phage therapy, antimicrobial peptides, nanoparticle-delivered urease inhibitors, biofilm-targeting agents and vaccines show promise. Implementation gaps, persistent use of suboptimal regimens, and global inequities constrain the impact of available therapies.<h4>Conclusions</h4>Optimizing H. pylori treatment requires evidence-based regimen selection, precision-guided strategies, antimicrobial stewardship and equitable access to essential medications. Advances in molecular diagnostics, antimicrobial development, and implementation science are all critical to reducing the global burden of H. pylori-associated disease and gastric cancer.…

PMID: 41905430

Colonization of the human stomach by Helicobacter pylori and its role in causing gastric cancer is one of the richest examples of a complex relationship among human cells, microbes, and their environment. It is also a puzzle of enormous medical importance given the incidence and lethality of gastric cancer worldwide. We review recent findings that have changed how we view these relationships and affected the direction of gastric cancer research. For example, recent data have indicated that subtle mismatches between host and microbe genetic traits greatly affect the risk of gastric cancer. The ability of H pylori and its oncoprotein CagA to reprogram epithelial cells and activate properties of stemness show the sophisticated relationship between H pylori and progenitor cells in the gastric mucosa. The observation that cell-associated H pylori can colonize the gastric glands and directly affect precursor and stem cells supports these observations. The ability to mimic these interactions in human gastric organoid cultures as well as animal models will allow investigators to more fully unravel the extent of H pylori control on the renewing gastric epithelium. Finally, our realization that external environmental factors, such as dietary components and essential micronutrients, as well as the gastrointestinal microbiota, can change the balance between H pylori's activity as a commensal or a pathogen has provided direction to studies aimed at defining the full carcinogenic potential of this organism.…

PMID: 26385073

Helicobacter pylori infection is a major cause of chronic gastritis, which can progress to a more serious gastroduodenal disease, such as a peptic ulcer, gastric cancer, or gastric mucosa-associated lymphoid tissue. Typically acquired during childhood, H. pylori infection persists throughout life if left untreated, affecting nearly half of the world population, with prevalence varying based on geographic location and sanitation standards. The bacterium exhibits unique adaptations that enable colonization of the gastric epithelium in acidic environments. Its pathogenesis of H. pylori involves bacterial virulence factors, host immune interactions, and environmental influences, leading to varied disease outcomes. The established role of H. pylori in gastric cancer underscores the importance of screening and treatment. Diagnosis relies on invasive tests, such as endoscopy and the non-invasive tests including stool, breath and serological methods" with test selection based on patient history and resource availability. Standard treatments combine acid suppression with antibiotics and/or bismuth. However, rising antibiotic resistance poses a major challenge, emphasizing the need for antibiotic susceptibility testing, resistance surveillance, and improved antibiotic stewardship in managing H. pylori infections.…

PMID: 41457244

Helicobacter pylori infection is a major cause of chronic gastritis, which can progress to a more serious gastroduodenal disease, such as a peptic ulcer, gastric cancer, or gastric mucosa-associated lymphoid tissue. Typically acquired during childhood, H. pylori infection persists throughout life if left untreated, affecting nearly half of the world population, with prevalence varying based on geographic location and sanitation standards. The bacterium exhibits unique adaptations that enable colonization of the gastric epithelium in acidic environments. Its pathogenesis of H. pylori involves bacterial virulence factors, host immune interactions, and environmental influences, leading to varied disease outcomes. The established role of H. pylori in gastric cancer underscores the importance of screening and treatment. Diagnosis relies on invasive tests, such as endoscopy and the non-invasive tests including stool, breath and serological methods" with test selection based on patient history and resource availability. Standard treatments combine acid suppression with antibiotics and/or bismuth. However, rising antibiotic resistance poses a major challenge, emphasizing the need for antibiotic susceptibility testing, resistance surveillance, and improved antibiotic stewardship in managing H. pylori infections.…

PMID: 41457244

Despite the established efficacy of <i>Helicobacter pylori</i> eradication in reducing gastric cancer (GC) incidence, a significant residual risk persists in successfully treated individuals, driven by lasting pathological alterations termed "oncogenic memory," including irreversible mucosal damage (e.g., intestinal metaplasia), residual pro-inflammatory and epigenetic "molecular scars," and gastric microbiome dysbiosis. This perspective synthesizes current evidence to advocate for a paradigm shift from a singular focus on pathogen clearance towards a comprehensive, risk-adapted management strategy. We propose a novel, dual-dimensional framework centered on a multidimensional risk assessment that integrates OLGA/OLGIM staging, demographic, lifestyle, and genetic factors to stratify post-eradication individuals into distinct risk categories. The framework subsequently outlines tailored surveillance protocols-specifying endoscopy frequency and advanced biomarker application-leverages technological support from AI-assisted endoscopy and molecular testing, and details differentiated resource allocation models based on regional GC incidence and economic development. This integrated approach provides a practical roadmap for implementing precision prevention, aiming to mitigate the lingering GC risk and ultimately reduce the global disease burden through a dynamic, lifelong management system beyond eradication. To facilitate implementation, we provide a user-ready risk calculator that operationalizes the multidimensional score for cohort-level application.…

PMID: 41767558