Association of Helicobacter pylori CagA seropositivity with gastric precancerous lesions: a systematic review and meta-analysis.

The objective of this meta-analysis is to delineate the association between H. pylori CagA serological status and the prevalence of gastric precancerous lesions (GPL). We searched peer-reviewed articles up to October 2023. The extraction of data from the included studies was carried out as well as the quality assessment. Pooled effect sizes were calculated using a random effect model. Thirteen studies met the inclusion criteria, comprising 2728 patients with GPL and 17 612 controls. The aggregate odds ratio (OR) for the association between serum CagA and GPL was 2.74 (95% CI = 2.25-3.32; P  = 0.00; I 2  = 60.4%), irrespective of H. pylori infection status. Within the H. pylori -infected cohort, the OR was 2.25 (95% CI = 1.99-2.56; P  = 0.00; I 2  = 0.0%). Conversely, among the non-infected individuals, the OR was 1.63 (95% CI = 1.04-2.54; P  = 0.038; I 2  = 0.0%). Heterogeneity was explored using subgroup and meta-regression analyses, indicating that the variability between studies likely stemmed from differences in disease classification. Our results demonstrated robustness and negligible publication bias. The meta-analysis underscores a more pronounced association between H. pylori CagA seropositivity and the risk of developing GPL than between seronegativity and the same risk, irrespective of H. pylori infection status at the time. Additionally, the strength of the association was heightened in the presence of an active H. pylori infection. The implications of these findings advocate for the utility of CagA serostatus as a potential biomarker for screening GPL.

Alloprevotella Can be Considered as a Potential Oral Biomarker in Intestinal Metaphase of Gastric Patients.

Gastric cancer is a malignant tumor with high incidence and death rate. Every year, Approximately 950,000 new cases of gastric cancer occur globally with nearly 700000 deaths,so gastric precancerous lesions(GPL) was crucial and important.At present, the effective diagnostic methods for gastric precancerous lesions are generally gastroscope and pathological changes of gastric mucosal, but those methods were invasive and would bring some pains to patients and not suitable for frequent and large-scale screening of gastric cancer or GPL.This study aimed to look for a sensitive,effective and non-invasive diagnostic method to improve the early diagnosis rate of GLP, and thereby reduce the incidence and death rate of gastric cancer.Tongue diagnosis is one of the classic diagnostic methods in traditional Chinese medicine(TCM).The tongue was closely related to the spleen and stomach.In the study, we collected 133 patients with chronic gastritis, including 53 cases in inflammatory group, 31 cases in atrophic group, and 49 cases in intestinal metaplasia group. and we analyzed the correlation between tongue,microbiota of tongue coating and clinical symptoms of GLP.The results showed that greasy coating was closely related to the intestinal metaphase of patients, indicating that greasy coating was closed link with intestinal metaphase phase of patients.Abundance of 209 genus were significant differences between greasy and non-greasy coating in intestinal metaphase phase of patients, Top10 were Streptococcus,norank_p__Saccharibacteria,Alloprevotella, Atopobium, Megasphaera, Gemella, Moraxella,unclassified_f__Prevotellaceae, Solobacterium and Stomatobaculum. Alloprevotella and Streptococcus were important genus markers and Alloprevotella was selected as a potential oral biomarker to diagnose intestinal metaphase phase of patients, the AUC value is 0.74.

Multimodal metagenomic analysis reveals microbial single nucleotide variants as superior biomarkers for early detection of colorectal cancer.

Microbial signatures show remarkable potentials in predicting colorectal cancer (CRC). This study aimed to evaluate the diagnostic powers of multimodal microbial signatures, multi-kingdom species, genes, and single-nucleotide variants (SNVs) for detecting precancerous adenomas. We performed cross-cohort analyses on whole metagenome sequencing data of 750 samples via xMarkerFinder to identify adenoma-associated microbial multimodal signatures. Our data revealed that fungal species outperformed species from other kingdoms with an area under the ROC curve (AUC) of 0.71 in distinguishing adenomas from controls. The microbial SNVs, including dark SNVs with synonymous mutations, displayed the strongest diagnostic capability with an AUC value of 0.89, sensitivity of 0.79, specificity of 0.85, and Matthews correlation coefficient (MCC) of 0.74. SNV biomarkers also exhibited outstanding performances in three independent validation cohorts (AUCs = 0.83, 0.82, 0.76; sensitivity = 1.0, 0.72, 0.93; specificity = 0.67, 0.81, 0.67, MCCs = 0.69, 0.83, 0.72) with high disease specificity for adenoma. In further support of the above results, functional analyses revealed more frequent inter-kingdom associations between bacteria and fungi, and abnormalities in quorum sensing, purine and butanoate metabolism in adenoma, which were validated in a newly recruited cohort via qRT-PCR. Therefore, these data extend our understanding of adenoma-associated multimodal alterations in the gut microbiome and provide a rationale of microbial SNVs for the early detection of CRC.

Metabolite Alterations and Interactions with Microbiota in Helicobacter pylori-Associated Gastric Lesions.

Metabolites and their interactions with microbiota may be involved in Helicobacter pylori-associated gastric lesion development. This study aimed to explore metabolite alterations upon H. pylori eradication and possible roles of microbiota-metabolite interactions in progression of precancerous lesions. Targeted metabolomics assays and 16S rRNA gene sequencing were conducted to investigate metabolic and microbial alterations of paired gastric biopsy specimens in 58 subjects with successful and 57 subjects with failed anti-H. pylori treatment. Integrative analyses were performed by combining the metabolomics and microbiome profiles from the same intervention participants. A total of 81 metabolites were significantly altered after successful eradication compared to failed treatment, including acylcarnitines, ceramides, triacylglycerol, cholesterol esters, fatty acid, sphingolipids, glycerophospholipids, and glycosylceramides, with P values of <0.05 for all. The differential metabolites showed significant correlations with microbiota in baseline biopsy specimens, such as negative correlations between Helicobacter and glycerophospholipids, glycosylceramide, and triacylglycerol (P < 0.05 for all), which were altered by eradication. The characteristic negative correlations between glycosylceramides and Fusobacterium, Streptococcus, and Gemella in H. pylori-positive baseline biopsy specimens were further noticed in active gastritis and intestinal metaplasia (P < 0.05 for all). A panel including differential metabolites, genera, and their interactions may help to discriminate high-risk subjects who progressed from mild to advanced precancerous lesions in short-term and long-term follow-up periods with areas under the curve (AUC) of 0.914 and 0.801, respectively. Therefore, our findings provide new insights into the metabolites and microbiota interactions in H. pylori-associated gastric lesion progression. IMPORTANCE In this study, a panel was established including differential metabolites, genera, and their interactions, which may help to discriminate high-risk subjects for progression from mild lesions to advanced precancerous lesions in short-term and long-term follow-up.

Is the Physiological Composition of the Vaginal Microbiome Altered in High-Risk HPV Infection of the Uterine Cervix?

BACKGROUND: Cervical cancer is the fourth most common malignancy and fourth leading cause of cancer death in women worldwide. More than 99.7% of cases are caused by human papillomavirus (HPV), while HPV types 16 and 18 cause over 70% of all cervical cancer cases. In this preliminary study, we aimed to investigate the presence of HPV infection and diversity of bacteria associated with bacterial vaginosis. METHODS: Cervical swabs (n = 21) taken from women aged 21-47 years, in seventeen cases, with different degrees of cervical abnormality, and from four healthy women, were tested for the presence of HPV DNA, as well as the bacterial strains associated with bacterial vaginosis, using the real-time PCR method. RESULTS: HPV16 was the dominant genotype in 53% (9/17) of patients with confirmed precancerous lesions (ASCUS, LSIL, and HSIL). In specimens with confirmed cytological abnormalities and hrHPV infection, we detected a wide diversity of microbes, while the most common species were Gardnerella vaginalis, Atopobium vaginae, Prevotella bivia, Ureaplasma parvum, Ureaplasma urealyticum, Leptotrichia amnionii, Bacteroides ureolyticus, and Sneathia sanguinegens. The presence of pathogens did not differ, depending on the degree of precancerous lesions or HPV type. CONCLUSION: In our work, HPV16 dominated in patients with cervical precancerous lesions. We also suggest an increased bacterial diversity of the vaginal microbiome in patients with cervical lesions, for which the HPV virus is largely responsible.

Differential expression of metallothionein and p21 in gastric cancer and some precursor lesions.

OBJECTIVE: Gastric cancer (GC) is a heterogeneous disease with molecular diversity between and within tumors; therefore, searching for altered genes within this cancer is mandatory to reach the proper individualized targeted therapy. Expressions of Metallothionein (MT) and p21 are not uniform in various types of cancers and their predictive value in GC is controversial. This study aimed to assess the role of MT and p21 in intestinal-type GC and some of its precursor lesions. MATERIALS AND METHODS: Immunohistochemical staining for MT and p21 was applied on paraffin blocks belonging to 30 GCs and 51 benign gastric lesions/precancerous lesions [33 chronic gastritis and 18 chronic gastritis with gastric intestinal metaplasia (GIM)]; 27 of them were associated with H. pylori infection. RESULTS: MT expression was dramatically increased while p21 expression was dramatically decreased from chronic gastritis to GIM to GC. In precancerous lesions, H. pylori-positive cases had significantly higher MT expression and lower p21 expression compared to H. pylori-negative cases. In GCs, decreased expression of both MT and p21 was associated with high-grade and advanced-stage cancers. CONCLUSIONS: Both MT and p21 may have a role in the development and progression of GC, and both proteins may be useful for selecting targeted therapy for GC patients.

Biomarkers CDX2, CK20, CK7 in Schoolchildren with Gastritis in the Realization of Familial Predisposition of Stomach Cancer.

We studied the association of expression of CDX2, CK20, CK7 proteins with familial predisposition to stomach cancer in schoolchildren with gastritis and its activity. Gastroscopy with biopsy of the gastric mucosa was performed in 89 schoolchildren aged 7-17 years with gastrointestinal complaints. The morphological study included the diagnosis of gastritis (Sydney classification) and the presence of Helicobacter pylori. The expression of CDX2, CK20, and CK7 was evaluated immunohistochemically. In children with familial predisposition to stomach cancer, the expression of CK20 in the stomach body was significantly increased (p=0.0225). In addition, the expression of CK20 (p=0.0979) and CDX2 (p=0.0849) tended to insrease in the antral compartment. No significant differences in the expression of CK7 in the gastric antrum and body were found. Some features of the expression of CDX2, CK20, and CK7 proteins in children with family predisposition to stomach cancer were revealed.

Predictors for regression and progression of intestinal metaplasia (IM): A large population-based study from low prevalence area of gastric cancer (IM-predictor trial).

BACKGROUND: Gastric intestinal metaplasia (IM) can lead to gastric cancer. Until now, there have been limited studies of predictors for regression and progression of IM. This study aimed to determine risk factors associated with regression or progression of IM for guiding proper management and prevention of gastric cancer. METHODS: 2,025 patients undergoing gastroscopy in Thammasat University Hospital, Thailand were enrolled during September 2017-August 2019. Patients' data including baseline characteristics, laboratory results, and histopathology of gastric biopsies from University medical database were extensively reviewed. RESULTS: 2,025 patients had mean age of 61.3 years and 44.2% were males. Overall H. pylori prevalence was 47.5%. There were 1,551(76.6%) patients with chronic gastritis and 361(17.8%) with IM. Of 400 patients with chronic gastritis having follow-up endoscopy and repeated gastric biopsies, 104(26%) had persistent H. pylori infection and 27(26%) developed IM during mean follow-up time of 24 months. Persistent H. pylori infection was significantly associated with development of IM (OR 3.16, 95%CI 1.56-6.39, p = 0.001). Regression, persistence, and progression of IM were demonstrated in 57.3%, 39.2%, and 3.5% of patients, respectively. Age >65 years, persistent H. pylori infection, and diabetes mellitus were significantly associated with persistent IM or progression to dysplasia with OR 2.47(95%CI 1.33-4.61, p = 0.004), OR 2.64(95%CI 1.13-6.18, p = 0.025), and OR 2.54(95%CI 1.16-5.54, p = 0.019), respectively. Patients without H. pylori infection had more IM regression than patients with persistent infection (60.4%vs.39.4%, p = 0.035). Patients with persistent H. pylori infection significantly had higher IM progression to dysplasia (15.2%vs.2.1%; OR 11.15, 95%CI 1.18-105.24, p = 0.035) than noninfected. During 24 months of study, 30 patients (1.5%) were diagnosed with gastric cancer. CONCLUSION: Regression of IM could be achieved by successful H. pylori eradication. Persistent H. pylori infection was significantly associated with development and progression of IM to dysplasia. Age >65 years and diabetes mellitus were also significant predictors for IM progression.

Cytokine TGF-ß1, TNF-α, IFN-γ and IL-6 Gene Polymorphisms and Localization of Premalignant Gastric Lesions in Immunohistochemically H. pylori-negative Patients.

Background: Cytokines and their gene variants are proven to play a role in pathogenic gastritis and carcinogenesis. The study assesses associations of the cytokine gene polymorphisms with extension of atrophic gastritis/intestinal metaplasia (AGIM) in patients without Helicobacter pylori infection on immunohistochemistry study. Methods: 224 adult consecutive patients undergoing an upper digestive endoscopy were included and grouped according to localization of AGIM: 37 patients with antrum-limited AGIM, 21 corpus-limited AGIM, 15 extended-AGIM (antrum and corpus) and 151 patients had no AGIM. Medical records of the patients were checked and a structured direct interview was applied in order to collect clinical data, including digestive symptoms. In all cases, IFN-γ +874T>A, TGF-ß1 +869T>C, TNF-α-308G>A and -238G>A, and IL-6 -174C>G polymorphisms were genotyped. Results: The mean age was significantly higher in the AGIM group, while the comorbidies were similar among patients with different localization of lesions or in patients without AGIM. There were no significant differences in digestive symptoms, nor in the consumption of non-steroidal anti-inflammatory drugs or proton pump inhibitor with the different extensions of AGIM. There was a significant association between oral anticoagulant consumption and localization of AGIM (P = 0.042), frequency being higher among patients with corpus-limited AGIM than those with no AGIM (P = 0.007, adjusted P = 0.041). TGF-ß1 +869T>C was less frequent among patients with corpus-limited AGIM (n=7, 33.3%) and extended AGIM (n=5, 33.3%) than in antrum-limited AGIM (n=25, 67.6%). There were no other significant differences regarding variant and wild genotype frequencies of IFN-γ +874T>A (86.5%, 81.0%, 86.7%, p=0.814), TNF-α-308G>A (35.1%, 28.6%, 53.3%, p=0.48) and IL-6 -174C>G (70.3%. 61.9%, 73.3% p=0.656) among patients with antrum-limited, corpus-limited or extended AGIM. TGF-ß1 +869T>C was associated with a decreased risk for corpus-affected AGIM (adjusted odds ratio: 0.42, 95% confidence interval: 0.19-0.93, P = 0.032). The dominant inheritance models no revealed significant association for IFN-γ +874T>A, TNF-α-308G>A and IL-6 -174C>G gene polymorphism and the risk of localization of AGIM. Conclusion: TGF-ß1 +869T>C gene polymorphism is associated with a decreased risk for corporeal localization of premalignant lesions, while IFN-γ +874T>A, TNF-α-308G>A and IL-6 -174C>G are not associated with the risk for AGIM in immunohistochemically H. pylori negative patients.

Gastric microbiota composition in patients with corpus atrophic gastritis.

BACKGROUND: In corpus atrophic gastritis (CAG), hypochlorhydria makes plausible the overgrowth of intragastric bacteria, whose role in gastric carcinogenesis is under debate. AIMS: To characterize the antrum/corpus composition of the gastric bacterial microbiota in CAG patients compared to controls without CAG. METHODS: A cross-sectional monocentric study on consecutive patients with known histological diagnosis of CAG undergoing gastroscopy for gastric cancer surveillance and patients without CAG undergoing gastroscopy for dyspepsia or anemia (108 biopsies from 55 patients, median age 61.5). Genomic DNA from one antral and one corpus biopsy from each case (n = 23) and control (n = 32) was extracted. Gastric microbiota was assessed by sequencing hypervariable regions of the 16SrRNA gene. RESULTS: Bacterial abundance and diversity were significantly lower in CAG cases than in controls (p < 0.001). Firmicutes were more frequent in cases, Bacteroidetes and Fusobacteria in controls (p < 0.0001). Streptococcaceae were more abundant in cases (p < 0.0001), Prevotellaceae in controls (p < 0.0001). The genus Streptococcus was positively correlated with severe OLGA/OLGIM stages linked to a higher risk of gastric cancer. CONCLUSION: Gastric bacterial microbiota in CAG showed a reduced abundance and complexity but was characterized by higher colonization of Firmicutes, in particular Streptococcus, increased in subjects with severe atrophy/metaplasia stages at higher risk of gastric cancer.

Microbiome and oral squamous cell carcinoma: a possible interplay on iron metabolism and its impact on tumor microenvironment.

There is increasing evidence showing positive association between changes in oral microbiome and the occurrence of oral squamous cell carcinoma (OSCC). Alcohol- and nicotine-related products can induce microbial changes but are still unknown if these changes are related to cancerous lesion sites. In an attempt to understand how these changes can influence the OSCC development and maintenance, the aim of this study was to investigate the oral microbiome linked with OSCC as well as to identify functional signatures and associate them with healthy or precancerous and cancerous sites. Our group used data of oral microbiomes available in public repositories. The analysis included data of oral microbiomes from electronic cigarette users, alcohol consumers, and precancerous and OSCC samples. An R-based pipeline was used for taxonomic and functional prediction analysis. The Streptococcus spp. genus was the main class identified in the healthy group. Haemophilus spp. predominated in precancerous lesions. OSCC samples revealed a higher relative abundance compared with the other groups, represented by an increased proportion of Fusobacterium spp., Prevotella spp., Haemophilus spp., and Campylobacter spp. Venn diagram analysis showed 52 genera exclusive of OSCC samples. Both precancerous and OSCC samples seemed to present a specific associated functional pattern. They were menaquinone-dependent protoporphyrinogen oxidase pattern enhanced in the former and both 3',5'-cyclic-nucleotide phosphodiesterase (purine metabolism) and iron(III) transport system ATP-binding protein enhanced in the latter. We conclude that although precancerous and OSCC samples present some differences on microbial profile, both microbiomes act as "iron chelators-like" potentially contributing to tumor growth.

Presence of Incipient Fungal Infection in Atypical Squamous Lesions of the Lip.

ABSTRACT: Epidermal barrier disruption caused by atypical squamous proliferations of the lip (SOL) creates an ideal environment for fungal growth. Histologic features of SOL include parakeratosis overlying partial- or full-thickness keratinocyte atypia with or without invasion of the dermis, dermal solar elastosis, and scattered inflammatory cells which are predominantly lymphocytes. Histologic features of SOL with fungal superinfections overlap those seen in primary fungal cheilitis with reactive atypia, creating a diagnostic challenge. One-hundred seventy SOL cases were examined for the presence of fungal elements, and the histological features associated with superinfection were identified. Cases diagnosed as actinic cheilitis with fungal superinfection were carefully examined to rule out the possibility of misdiagnosed primary fungal cheilitis with reactive atypia. Histopathological characteristics commonly present with fungal hyphae included intraepidermal or intradermal neutrophils, bacterial colonies, and erosion or ulceration. Medical record review of those patients treated conservatively with topical antifungals revealed persistent clinical neoplasm and histological evidence of residual SOL on repeat biopsy. Thus, when biopsies exhibit histological overlap between these 2 entities, clinicians should keep a high index of suspicion for underlying SOL and carefully follow these patients if conservative antifungal therapy is initially trialed.

A Comparison of Tumor-Associated and Non-Tumor-Associated Gastric Microbiota in Gastric Cancer Patients.

BACKGROUND: How gastric cancer (GC) incidence is associated with changes in the gastric microbiome has not been firmly established. The present study therefore aims to investigate the microbial communities present within the gastric mucosa of patients with superficial gastritis (SG) or GC. METHODS: Paired tumor and paracancerous samples of the gastric mucosa were collected from 18 patients being surgically treated for GC and from 32 patients with SG being treated via gastroscopy. The gastric microbiome in these samples was then profiled via 16S rRNA sequencing, with a linear discriminant analysis effect size (LEfSe) approach used to identify and compare different bacteria, and with PICRUSt used for predictive functional analyses. RESULTS: GC patients exhibited a distinct gastric microbiota profile from that observed in SG patients. These changes were evident in both tumor and paracancerous tissues from GC patients. Specifically, we found that 6 bacterial genera were specifically enriched in GC tissue samples relative to SG samples, while 18 genera were depleted in these same samples. Based on the differential abundance of these bacteria, we were able to calculate microbial dysbiosis index (MDI) values, which were significantly higher in GC patients than in SG patients. In addition, MDI values were negatively correlated with gastric Shannon index and were positively correlated with relative Helicobacter spp. abundance. Importantly, these MDI values were readily able to discriminate between GC and SG patient samples. Functional analysis suggested that GC patients were more likely to harbor a nitrosating microbial community. CONCLUSIONS: GC patients exhibited a gastric microbiome profile distinct from that observed in SG patients, with these differences being evident in both tumor and paracancerous tissues. Differences in the relative abundance of Helicobacter spp. may be the primary driver of gastric dysbiosis in GC patients.

Metabolome and microbiome alterations in tongue coating of gastric precancerous lesion patients.

Objective: This paper seeks to provide mechanistic insight into the pathological transition through the analysis of metabolites and microorganisms in the tongue coating of gastric precancerous lesions (GPL) patients.Methods: GC-TOF-MS and UHPLC-QE-MS metabolomics, combined with 16S rRNA microbiome techniques, were performed to explore the changes in metabolites and microorganisms in the tongue coating of GPL patients.Results: When compared with 15 controls, 133 metabolites were found to be differentially expressed in 60 GPL cases, of which could be divided into ten categories. Among them, most of the differentially expressed metabolites identified were lipids or lipid-like molecules. These metabolites were implicated in 6 metabolic pathways including glycine, serine and threonine metabolism, arginine and proline metabolism, sphingolipid metabolism, valine, leucine and isoleucine degradation, arachidonic acid metabolism, and tyrosine metabolism. The relative abundances of Alloprevotella, Solobacterium, Rothia, Eikenella, and Aggregatibacter in the GPL group increased significantly relative to the controls and were associated with lipids and lipid-like molecules, organic nitrogen compounds, organic oxygen compounds, phenylpropanoids and polyketides, and organoheterocyclic compounds, respectively.Conclusions: Compared with healthy people, the changes of tongue coating metabolites in GPL patients were mainly characterized by alterations in lipid metabolism and were associated with localized changes in the microbiome.

Dicarbonyl Electrophiles Mediate Inflammation-Induced Gastrointestinal Carcinogenesis.

BACKGROUND & AIMS: Inflammation in the gastrointestinal tract may lead to the development of cancer. Dicarbonyl electrophiles, such as isolevuglandins (isoLGs), are generated from lipid peroxidation during the inflammatory response and form covalent adducts with amine-containing macromolecules. Thus, we sought to determine the role of dicarbonyl electrophiles in inflammation-associated carcinogenesis. METHODS: The formation of isoLG adducts was analyzed in the gastric tissues of patients infected with Helicobacter pylori from gastritis to precancerous intestinal metaplasia, in human gastric organoids, and in patients with colitis and colitis-associated carcinoma (CAC). The effect on cancer development of a potent scavenger of dicarbonyl electrophiles, 5-ethyl-2-hydroxybenzylamine (EtHOBA), was determined in transgenic FVB/N insulin-gastrin (INS-GAS) mice and Mongolian gerbils as models of H pylori-induced carcinogenesis and in C57BL/6 mice treated with azoxymethane-dextran sulfate sodium as a model of CAC. The effect of EtHOBA on mutations in gastric epithelial cells of H pylori-infected INS-GAS mice was assessed by whole-exome sequencing. RESULTS: We show increased isoLG adducts in gastric epithelial cell nuclei in patients with gastritis and intestinal metaplasia and in human gastric organoids infected with H pylori. EtHOBA inhibited gastric carcinoma in infected INS-GAS mice and gerbils and attenuated isoLG adducts, DNA damage, and somatic mutation frequency. Additionally, isoLG adducts were elevated in tissues from patients with colitis, colitis-associated dysplasia, and CAC as well as in dysplastic tumors of C57BL/6 mice treated with azoxymethane-dextran sulfate sodium. In this model, EtHOBA significantly reduced adduct formation, tumorigenesis, and dysplasia severity. CONCLUSIONS: Dicarbonyl electrophiles represent a link between inflammation and somatic genomic alterations and are thus key targets for cancer chemoprevention.

Inflammation-Associated Senescence Promotes Helicobacter pylori-Induced Atrophic Gastritis.

BACKGROUND & AIMS: The association between cellular senescence and Helicobacter pylori-induced atrophic gastritis is not clear. Here, we explore the role of cellular senescence in H pylori-induced atrophic gastritis and the underlying mechanism. METHODS: C57BL/6J mice were infected with H pylori for biological and mechanistic studies in vivo. Gastric precancerous lesions from patients and mouse models were collected and analyzed using senescence-associated beta-galactosidase, Sudan Black B, and immunohistochemical staining to analyze senescent cells, signaling pathways, and H pylori infection. Chromatin immunoprecipitation, luciferase reporter assays, and other techniques were used to explore the underlying mechanism in vitro. RESULTS: Gastric mucosa atrophy was highly associated with cellular senescence. H pylori promoted gastric epithelial cell senescence in vitro and in vivo in a manner that depended on C-X-C motif chemokine receptor 2 (CXCR2) signaling. Interestingly, H pylori infection not only up-regulated the expression of CXCR2 ligands, C-X-C motif chemokine ligands 1 and 8, but also transcriptionally up-regulated the expression of CXCR2 via the nuclear factor-κB subunit 1 directly. In addition, CXCR2 formed a positive feedback loop with p53 to continually enhance senescence. Pharmaceutical inhibition of CXCR2 in an H pylori-infected mouse model attenuated mucosal senescence and atrophy, and delayed further precancerous lesion progression. CONCLUSIONS: Our study showed a new mechanism of H pylori-induced atrophic gastritis through CXCR2-mediated cellular senescence. Inhibition of CXCR2 signaling is suggested as a potential preventive therapy for targeting H pylori-induced atrophic gastritis. GEO data set accession numbers: GSE47797 and GSE3556.

Serrated neoplasia in the colorectum: gut microbiota and molecular pathways.

Colorectal cancer (CRC) is a heterogeneous disease with different gene expression patterns. There are two major colorectal carcinogenesis pathways: conventional adenoma-carcinoma pathway and alternative serrated neoplasia pathway. Apart from the conventional pathway that is typically initiated by characteristic APC mutation and chromosomal instability, the serrated neoplasia pathway is mainly characterized by mutations of BRAF or KRAS, microsatellite instability (MSI), and CpG island methylator phenotype (CIMP). Despite the malignant potential of serrated lesions, they can be easily overlooked during endoscopy screening and even in pathological assessment due to its anatomical location, morphology, and histological features. It has been shown that environmental factors especially the gut microbial composition play a key role in CRC pathogenesis. Thus, the preferential localization of serrated lesions in specific intestine areas suggest that niche-specific microbiota composition might intertwined with host genetic perturbations during the development of serrated lesions. Although serrated lesions and conventional adenomas are biologically different, most studies have focused on conventional adenomas, while the pathophysiology and role of microorganisms in the development of serrated lesions remain elusive. In this review, we discuss on the role of gut microbiota in the serrated neoplasia pathway of colorectal carcinogenesis and its specific clinical and molecular features, and summarize the potential mechanisms involved.

Immunostimulatory membrane proteins potentiate H. pylori-induced carcinogenesis by enabling CagA translocation.

Infection with Helicobacter pylori is the single greatest risk factor for developing gastric adenocarcinoma. In prospective, population-based studies, seropositivity to the uncharacterized H. pylori proteins Hp0305 and Hp1564 was significantly associated with cancer risk in East Asia. However, the mechanism underlying this observation has not been elucidated. Here, we show that Hp0305 and Hp1564 act in concert with previously ascribed H. pylori virulence mechanisms to orchestrate cellular alterations that promote gastric carcinogenesis. In samples from 546 patients exhibiting premalignant gastric lesions, seropositivity to Hp0305 and Hp1564 was significantly associated with increased gastric atrophy across all stomach conditions. In vitro, depletion of Hp0305 and Hp1564 significantly reduced levels of gastric cell-associated bacteria and markedly impaired the ability of H. pylori to stimulate pro-inflammatory cytokine production. Remarkably, our studies revealed that Hp1564 is required for translocation of the oncoprotein CagA into gastric epithelial cells. Our data provide experimental insight into the molecular mechanisms governing novel H. pylori pathogenicity factors that are strongly associated with gastric disease and highlight the potential of Hp0305 and Hp1564 as robust molecular tools that can improve identification of individuals that are highly susceptible to gastric cancer. We demonstrate that Hp0305 and Hp1564 augment H. pylori-mediated inflammation and gastric cancer risk by promoting key bacteria-gastric cell interactions that facilitate delivery of oncogenic microbial cargo to target cells. Thus, therapeutically targeting microbial interactions driven by Hp0305/Hp1564 may enable focused H. pylori eradication strategies to prevent development of gastric malignancies in high-risk populations.

Helicobacter pylori: an evolutionary perspective.

Since the description of Helicobacter pylori (HP) as the most common cause of gastritis and its neoplastic complications, numerous articles have been written about the epidemiology, clinical features, diagnostic methods, histopathology, pathogenesis, molecular biology and treatment of this infection. This review focuses on those aspects of the infection that challenge the universality of the medical implications through the lens of evolutionary science applied to medicine. The divergent epidemiological and clinical outcomes observed in different populations and the possible beneficial aspects of the infection are discussed. Also reviewed are Correa's seminal contributions to our understanding of gastric cancer in particular and postinflammatory tumours in general, and the renewed interest in intestinal metaplasia and its clinical implications.

The Colombian Chemoprevention Trial: 20-Year Follow-Up of a Cohort of Patients With Gastric Precancerous Lesions.

BACKGROUND & AIMS: Helicobacter pylori eradication and endoscopic surveillance of gastric precancerous lesions are strategies to reduce gastric cancer (GC) risk. To our knowledge, this study is the longest prospective cohort of an H pylori eradication trial in a Hispanic population. METHODS: A total of 800 adults with precancerous lesions were randomized to anti-H pylori treatment or placebo. Gastric biopsy samples taken at baseline and 3, 6, 12, 16, and 20 years were assessed by our Correa histopathology score. A generalized linear mixed model with a participant-level random intercept was used to estimate the effect of H pylori status on the score over time. Logistic regression models were used to estimate progression by baseline diagnosis and to estimate GC risk by intestinal metaplasia (IM) subtype and anatomic location. RESULTS: Overall, 356 individuals completed 20 years of follow-up. Anti-H pylori therapy (intention-to-treat) reduced progression of the Correa score (odds ratio [OR], 0.59; 95% confidence interval [CI], 0.38-0.93). H pylori-negative status had a beneficial effect on the score over time (P = .036). Among individuals with IM (including indefinite for dysplasia) at baseline, incidence rates per 100 person-years were 1.09 (95% CI, 0.85-1.33) for low-grade/high-grade dysplasia and 0.14 (95% CI, 0.06-0.22) for GC. Incomplete-type (vs complete-type) IM at baseline presented higher GC risk (OR, 13.4; 95% CI, 1.8-103.8). Individuals with corpus (vs antrum-restricted) IM showed an OR of 2.1 (95% CI, 0.7-6.6) for GC. CONCLUSIONS: In a high-GC-risk Hispanic population, anti-H pylori therapy had a long-term beneficial effect against histologic progression. Incomplete IM is a strong predictor of GC risk.