Three novel bacterial strains, Staphylococcus epidermidis, Streptococcus salivarius, and Streptococcus anginosus, were cultured from human gastric biopsy tissue from Colombian, South America patients with a high risk for gastric cancer. Bacteria were sequenced using Illumina MiSeq technology for phylogenetic characterization and identification of genetic mechanisms conferring pathogenic or protective potential.

Gastric cancer is the fifth most common cancer and the fifth leading cause of cancer deaths worldwide. Chronic infection by the bacterium Helicobacter pylori is the most prominent gastric cancer risk factor, but only 1-3% of infected individuals will develop gastric cancer. Cigarette smoking is another independent gastric cancer risk factor, and H. pylori-infected smokers are at a 2-11-fold increased risk of gastric cancer development, but the direct impacts of cigarette smoke on H. pylori pathogenesis remain unknown. In this study, male C57BL/6 mice were infected with H. pylori and began smoking within one week of infection. The mice were exposed to cigarette smoke (CS) five days/week for 8 weeks. CS exposure had no notable impact on gross gastric morphology or inflammatory status compared to filtered-air (FA) exposed controls in mock-infected mice. However, CS exposure significantly blunted H. pylori-induced gastric inflammatory responses, reducing gastric atrophy and pyloric metaplasia development. Despite blunting these classic pathological features of H. pylori infection, CS exposures increased DNA damage within the gastric epithelial cells and accelerated H. pylori-induced dysplasia onset in the INS-GAS gastric cancer model. These data suggest that cigarette smoking may clinically silence classic clinical symptoms of H. pylori infection but enhance the accumulation of mutations and accelerate gastric cancer initiation.

Helicobacter pylori (Hp) is the strongest known risk factor for gastric adenocarcinoma. We previously demonstrated that iron deficiency, a condition of the exposome, augments Hp-induced carcinogenesis. To define mechanisms driving this phenotype, we performed targeted metabolomics in mice which revealed that Hp significantly increased levels of deoxycholic acid (DCA), a carcinogenic secondary bile acid, exclusively under iron-deficient conditions. Further, DCA directly promoted Hp-induced dysplasia. Because bile acids and fatty acids can exert opposing effects on disease, fatty acids were also assessed within the context of iron deficiency and infection. In contrast to bile acids, long-chain fatty acids (LCFAs) were significantly downregulated by Hp under iron-deficient conditions, including levels of palmitic acid, a LCFA with therapeutic potential against gastric cancer. These data indicate that Hp increases levels of carcinogenic secondary bile acids with concordant reductions in protective LCFAs under iron-deficient conditions, suggesting an active interplay between these effectors in cancer risk.

BACKGROUND & AIMS:Immune responses to infection must balance pathogen clearance with minimizing tissue damage and autoimmunity. Chronic gastric inflammation caused by Heliobactor pylori damages the gastric mucosa and promotes carcinogenesis. Glucocorticoids are immunoregulatory hormones that limit immune activation in the stomach. This study aimed to determine how endogenous glucocorticoids regulate the gastric immune response to Helicobacter infection and their impact on preneoplastic lesion development. METHODS:We examined the role of endogenous glucocorticoids in shaping the gastric immune response to Helicobacter felis colonization. Gastric immune cell infiltration, atrophy, metaplasia, and preneoplastic lesion development were evaluated in adrenal-intact and adrenalectomized (ADX) mice. Auto-reactive immunoglobulin G antibodies were assessed using a mouse self-antigen array and by measuring their binding to healthy gastric tissue. RESULTS:Loss of endogenous glucocorticoids led to significantly increased Hfelis-induced gastric T cell infiltration and proinflammatory cytokine expression compared with intact-infected controls. Although all intact mice maintained chronic infection for up to 12 months post-colonization, nearly all ADX mice eradicated Hfelis within 2 to 3 weeks. Despite bacterial clearance, ADX mice continued to exhibit chronic gastric inflammation and developed dysplasia. Autoantibody profiling showed that both intact and ADX groups generated self-reactive immunoglobulin G during active infection. However, only ADX mice sustained autoantibody production following bacterial eradication. CONCLUSIONS:Endogenous glucocorticoids attenuate gastric inflammation during Helicobacter infection, supporting bacterial persistence while maintaining immune tolerance. These findings suggest that heightened immune responses to Hpylori may trigger autoimmune gastritis development, which can persist after Hpylori clearance and continue to drive gastric cancer risk.

Helicobacter pylori (H pylori) successfully and chronically colonizes the gastric mucosa of approximately 43% of the world's population. Infection with this organism is the strongest known risk factor for the development of gastric cancer, and disease development is dependent on several interactive components. One H pylori determinant that augments cancer risk is the strain-specific cag type IV secretion system, which not only translocates a pro-inflammatory and oncogenic protein, CagA, into host cells but also DNA, peptidoglycan, and a lipopolysaccharide intermediate, heptose-1,7-bisphosphate. However, cognate interactions between certain microbial and host constituents can also attenuate pro-inflammatory responses, and H pylori harbors multiple effectors that function differently than the respective counterparts in other mucosal pathogens. In this review, we discuss current data related to mechanisms utilized by H pylori to evade the immune response, sustain its longevity in the host, and further disease progression, as well as implications for developing targeted, immune-based eradication strategies.

Gastric cancer is the fifth most common cancer and the fifth most common cause of cancer-related death globally. The key to improving outcomes lies in effective prevention and early detection, which are critical for successful curative interventions. Helicobacter pylori is the strongest known risk factor for gastric cancer, and eradication of this pathogen is critical for reducing cancer risk. By synthesizing current evidence and exploring the advanced therapeutic approaches, this review provides a comprehensive overview of best practices for mitigating gastric cancer through targeted bacterial intervention.

Helicobacter pylori (Hp) is the strongest known risk factor for gastric adenocarcinoma. We previously demonstrated that iron deficiency, a condition of the exposome, augments Hp-induced carcinogenesis. To define mechanisms driving this phenotype, we performed targeted metabolomics in mice which revealed that Hp significantly increased levels of deoxycholic acid (DCA), a carcinogenic secondary bile acid, exclusively under iron-deficient conditions. Further, DCA directly promoted Hp-induced dysplasia. Because bile acids and fatty acids can exert opposing effects on disease, fatty acids were also assessed within the context of iron deficiency and infection. In contrast to bile acids, long-chain fatty acids (LCFAs) were significantly downregulated by Hp under iron-deficient conditions, including levels of palmitic acid, a LCFA with therapeutic potential against gastric cancer. These data indicate that Hp increases levels of carcinogenic secondary bile acids with concordant reductions in protective LCFAs under iron-deficient conditions, suggesting an active interplay between these effectors in cancer risk.