Katherine S. Garman

Infection with Helicobacter pylori is the major risk factor for gastric cancer worldwide; yet the exact mechanisms behind this link remain unclear. H. pylori -associated tissue changes often disrupt the gastric microbiome, enabling secondary gastric colonization by oral bacteria. Among these secondary colonizers, Fusobacterium species have documented associations with several gastrointestinal cancers. We found that both F. animalis and F. nucleatum invade cultured human gastric adenocarcinoma cells, but F. animalis exhibited higher adherence and invasion, and hypoxic conditions promoted higher bacterial survival. Both adherence and invasion were inhibited by exogenous GalNAc, a glycan commonly observed in membrane glycoproteins of adenocarcinoma cells and a target of the fusobacterial adhesin Fap2. Using a mouse model of stomach metaplasia, we found that F. animalis colonized gastric tissue only after metaplasia onset, growing in multispecies biofilms in the mucus layer, while F. nucleatum colonized neither healthy nor metaplastic gastric tissue. Metaplasia led to upregulation of Gal-GalNAc in the stomach, and reduced gastric acidity allowed higher F. animalis loads in this model. By contrast, inflammation and the presence of H. pylori did not significantly influence stomach colonization by F. animalis . Further assessment of additional Fusobacterium species and strains revealed that whereas all tested species can invade gastric cancer cells in vitro , only F. animalis and F. polymorphum robustly colonize the metaplastic gastric tissue of the mouse model similar to F. animalis . Overall, our data support a model in which H. pylori -induced metaplasia makes the stomach susceptible to secondary infection by other cancer-associated microbes, including some Fusobacterium species. IMPORTANCE: Helicobacter pylori infection is the primary risk factor for gastric cancer worldwide, yet the underlying cancer-promoting mechanisms are not fully defined. Our study shows that metaplasia, a precancerous condition typically triggered by H. pylori and characterized by specific changes in gene expression and tissue remodeling, can enable secondary infection by other cancer-associated bacteria. Specifically, we found that certain species of the genus Fusobacterium , linked to several gastrointestinal cancers, colonize the stomach only after the onset of metaplasia. Metaplasia-associated changes in the stomach include altered surface sugars and reduced acidity, which together may create a more permissive environment for bacterial growth. Our findings support a model in which disruptions of gastric tissue architecture induced by chronic H. pylori infection facilitate colonization by other cancer-related bacteria, contributing to the growing body of evidence highlighting the role of bacteria in cancer development.

Purpose of the review: Gastric cancer (GC) is a leading cause of cancer-related mortality worldwide. Although Helicobacter pylori (Hp) is a well known, leading risk factor for GC, not all patients with Hp develop malignancy, highlighting the multifactorial mechanisms involved in gastric carcinogenesis. This review summarizes recent insights into GC pathogenesis and the implications for risk stratification, screening surveillance, and prevention. Recent findings: Emerging evidence suggests complex interactions between microbial, genetic, environmental, and immune factors in GC pathogenesis. Chronic Hp induces irreversible changes in the gastric mucosa, underscoring the benefits of early detection and treatment. New data suggest treating Hp in younger adults may be most effective for reducing GC risk. Several microbial pathogens have been associated with GC, an evolving area of research. Recent studies also expand our understanding of hereditary and early-onset GC, including the roles of CDH1 , CTNNA1 , and homologous recombination genes. New data also highlights the contribution of environmental factors such as alcohol and acid-blocking medications on GC risk. Summary: Gastric carcinogenesis involves dynamic interactions between the gastric microbiome, host genetics, immune interactions, and environmental exposures beyond Hp infection. Improved understanding of these processes may inform prevention and early detection strategies in clinical practice.

Objectives: Helicobacter pylori is the strongest risk factor for non-cardia gastric adenocarcinoma, the cancer with the greatest racial disparity in US cancer mortality. The 2017 American College of Gastroenterology guidelines recognized that local H pylori antibiotic resistance data are often unavailable in the United States, highlighted increasing clarithromycin resistance, and recommended that...

INTRODUCTION: We designed a race-conscious study to assess the presence of Helicobacter pylori virulence factor cagA in a retrospective cohort of patients with active H. pylori infection. METHODS: We compared cagA status by race in gastric tissue samples from 473 patients diagnosed with active H. pylori infection from 2015 to 2019. RESULTS: H. pylori + Black patients were 2 times more likely to be cagA + than H. pylori + White patients (82% vs 36%, P < .0001). DISCUSSION: Presence of cagA is common among endoscopy patients with active H. pylori infection; appropriate testing and treatment of H. pylori can both reduce gastric cancer risk and address health disparities.

Background and aims: Inflammatory Bowel Diseases (IBD) are chronic inflammatory conditions influenced heavily by environmental factors. DNA methylation is a form of epigenetic regulation linking environmental stimuli to gene expression changes and inflammation. Here, we investigated how DNA methylation of the TNF promoter differs between inflamed and uninflamed mucosa of IBD patients, including anti-TNF responders and non-responders. Methods: We obtained mucosal biopsies from 200 participants (133 IBD and 67 controls) and analyzed TNF promoter methylation using bisulfite sequencing, comparing inflamed with uninflamed segments, in addition to paired inflamed/uninflamed samples from individual patients. We conducted similar analyses on purified intestinal epithelial cells from bowel resections. We also compared TNF methylation levels of inflamed and uninflamed mucosa from a separate cohort of 15 anti-TNF responders and 17 non-responders. Finally, we sequenced DNA methyltransferase genes to identify rare variants in IBD patients and functionally tested them using rescue experiments in a zebrafish genetic model of DNA methylation deficiency. Results: TNF promoter methylation levels were decreased in inflamed mucosa of IBD patients and correlated with disease severity. Isolated IECs from inflamed tissue showed proportional decreases in TNF methylation. Anti-TNF non-responders showed lower levels of TNF methylation than responders in uninflamed mucosa. Our sequencing analysis revealed two missense variants in DNMT1 , one of which had reduced function in vivo . Conclusions: Our study reveals an association of TNF promoter hypomethylation with mucosal inflammation, suggesting that IBD patients may be particularly sensitive to inflammatory environmental insults affecting DNA methylation. Together, our analyses indicate that TNF promoter methylation analysis may aid in the characterization of IBD status and evaluation of anti-TNF therapy response.

We thank Tavakkoli and colleagues for their interest in our recent review of gastric cancer progress and priorities (1), which included discussion of the higher gastric cancer incidence rates among all racial and ethnic minorities compared with non-Hispanic Whites, and specifically higher mortality rates among Black and Hispanic patients with non-cardia gastric cancer. We concluded that persistent disparities in incidence and mortality warrant risk-stratified prevention and interception strategies. We recognize the point raised by Tavakkoli and colleagues that, while we also reviewed the trend of increasing incidence of early-onset non-cardia gastric cancer among non-Hispanic White women, we did not acknowledge the mounting evidence of a similar trend among Hispanic White persons in the United States. We greatly appreciate Tavakkoli and colleagues bringing our attention to this important aspect of the changing demographics of early-onset non-cardia gastric cancer, and the need for additional research to understand, and ultimately prevent, this highly fatal disease that disproportionately affects racial and ethnic minorities.See the original Letter to the Editor, p. 1270P. Alagesan reports grants from Stead Fellowship during the conduct of the study. J.C. Goodwin reports grants from Emerson Collective outside the submitted work. M. Epplein reports grants from NCI, NIH during the conduct of the study. No disclosures were reported by the other author.This work was supported by Duke Cancer Disparities P20 (CA251657) and the P30 (CA014236) grants through the Duke Cancer Institute.