Helicobacter pylori (H. pylori) infection causes chronic gastritis, which can progress to severe gastroduodenal pathologies, including peptic ulcer, gastric cancer (GC), and gastric mucosa–associated lymphoid tissue (MALT) lymphoma (1). H. pylori is usually transmitted in childhood and persists for life if untreated. The infection affects around half of the population in the world, but prevalence varies according to location and sanitation standards (2). H. pylori has unique properties to colonize gastric epithelium in an acidic environment. The pathophysiology of H. pylori infection is dependent on complex bacterial virulence mechanisms and their interaction with the host immune system and environmental factors, resulting in distinct gastritis phenotypes that determine possible progression to different gastroduodenal pathologies (3). The causative role of H. pylori infection in GC development presents the opportunity for preventive screen-and-treat strategies (4). Invasive, endoscopy-based, and non-invasive methods, including breath, stool, and serological tests, are used in the diagnosis of H. pylori infection. Their use depends on the specific individual patient history and local availability (5). H. pylori treatment consists of a strong acid suppressant in various combinations with antibiotics and/or bismuth (6). The dramatic increase in resistance to key antibiotics used in H. pylori eradication demands antibiotic susceptibility testing, surveillance of resistance, and antibiotic stewardship (7).

GC, which refers to the occurrence of cancer in the stomach cell line, is one of the leading causes of cancer-related deaths and ranks as the fifth most common cancer globally, posing a significant global health challenge (8). GC, being multifactorial cancer, has risk factors that include a family history of GC in first-degree relatives, dietary habits, gender, age, race, H. pylori infection, nutritional status, and a history of invasive diseases such as lymphoma- or gastric-related procedures (9, 10). Studies have suggested the potential role of H. pylori and other bacterial genera in the progression of GC (11, 12). H. pylori, as a destructive member of the gastric microbiota, raises global health concerns due to its association with GC (13). This bacterium recruits neutrophils and lymphocytes to the gastric mucus, stimulating the production of reactive oxygen species (ROS) and inflammatory cytokines through the action of the CagA (cytotoxin-associated gene A) protein. This process gradually stimulates cell proliferation, leading to the development of GC and alterations in the composition of the gastrointestinal (GI) tract microbiota (14–18).

This review represents, to the best of our knowledge, the first comprehensive analysis of the interaction between GC and H. pylori, focusing on their impact on the microbiota. The current study highlights variations in microbiota alterations among individuals with GC, with or without H. pylori infection. Investigating the correlation between the presence of H. pylori and microbiota changes in patients with GC is crucial for developing more effective therapies for H. pylori infection in individuals with GC who are H. pylori–positive. Distinct differences exist between individuals with GC who harbor H. pylori and those who do not. Through multi-omics studies that analyze changes in microbial profiles and metabolite alterations, a diverse range of compositions in the GI tract microbiota has been observed in patients with GC depending on the presence or absence of H. pylori. In fact, individuals with H. pylori–positive GC exhibit very low variation in gastric microbiota and significant changes in GC microbiota, including Firmicutes, Proteobacteria, Bacteroides, Streptococcus, Lactobacillus, Escherichia, and Shigella. Eradicating H. pylori eventually restores the disrupted microbiota in patients with GC (19). Conversely, patients with GC without H. pylori are closely linked to high microbial diversity in the gastric microbiota, a significant increase in Haemophilus and Streptococcus, and an elevation in the abundance of metabolites (20–23). All these changes may be due to the inhibitory effects of H. pylori on the colonization of other microorganisms (24, 25). In addition, the four most dominant strains of gut microbiota in individuals with GC with H. pylori strains, including Enterococcus, Escherichia-Shigella, Bacteroides, and Lactobacillus, contribute to the progression of GC by increasing damage to cancerous tissue (26–28), the levels of tumor necrosis factor–alpha (TNF-α) (29), and unfavorable metabolites (30). Although the relationship between microbiota and metabolites in individuals with GC with H. pylori has not been thoroughly described, it is evident that the secondary metabolites produced by H. pylori elevate the metabolism of citric acid and carbohydrates in the gastric tissue of patients with GC (31), exacerbate inflammation in the gastric tissue by stimulating the activation of C-type lectin receptors (32), and inhibit the interferon-alpha (IFN-α) signaling pathway to evade the immune system (33). The importance of analyzing the differences in metabolic activity between GC cases with and without H. pylori reflects their potential to serve as candidate markers for distinguishing which patients with GC harbor H. pylori or not (20). In addition to alterations in microbiota and metabolic changes, studies indicate histopathological changes such as peptic ulcers and epithelial changes in the gastric mucosa of patients with GC with H. pylori. As mentioned regarding the metabolic changes, these histopathological changes are suitable indicators to determine the presence of H. pylori in GC cases. These histopathological changes were not present in the gastric tissue of patients with GC who were not colonized by H. pylori (34). The primary aim of this study was to review the effect of H. pylori–induced GC on GI microbiota.

We collected original and review articles in this field by searching through PubMed, Google Scholar, Web of Science, and Scopus databases for English language literature published up to 2024. The search was conducted on the basis of “Gastric or stomach cancer,” “Helicobacter pylori–induced gastric cancer,” “H. pylori eradication” AND “Gut microbiota,” or “Microbiome” as keywords. Studies that reported the role of H. pylori–induced GC on GI microbiota and changes in gastric microbiota following successful H. pylori eradication were enrolled.

Microbial diversity and composition change in GC (35). Studies suggest that the diversity and composition of the gastric microbiota differ among patients at different histological stages of GC (11, 36). This issue emphasizes that the imbalance of the gastric microbiota is dynamic. The GC microbiome appears to improve with oral and intestinal bacterial taxa (37). Bacterial genera such as Lactococcus, Bacillus, Prevotella, Veillonella, Leptotrichia (38), Achromobacter, Citrobacter, Rhodococcus, Phyllobacterium (11), Peptostreptococcus, Parvimonas, Slackia, and Dialister (39), which commonly colonize the oral cavity, are enriched in the GC microbiota. Reports indicate diverse geographic regions where bacterial species of intestinal commensals, including Lactobacillus (11, 38, 39), Streptococcaceae (39, 40), Staphylococcus (38, 41), Clostridium (11, 38), and Fusobacterium (38, 39), are consistently enriched in GC. There are controversial results regarding the abundance of Streptococcus and Prevotella between GC and non-cancer patients. Studies indicate that they are both increased (38, 42) and decreased (11, 43) in the GC microbiota. The depletion of Neisseria, Comamonadaceae, Acinetobacter (39), Vogesella, and Helicobacter (11, 40) was identified in the GC microbiota. Neisseria (11) was a genus that showed a decrease in the microbiota of patients with GC from regions with low GC risk. However, Veillonella and Leptotrichia increased in relative abundance in the microbiota of patients with GC from areas with high GC risk (11, 44). Gunathilake et al. showed enrichment of H. pylori, Propionibacterium acnes, and Prevotella copri and a decrease in the abundance Lactococcus lactis in the gastric microbiota of patients with GC (45). In a study from Portugal, Ferreira et al. demonstrated that there was a significant decrease in Helicobacter, Neisseria, Streptococcus, and Prevotella and an increase in abundance Lactobacillus, Citrobacter, Clostridium, Achromobacter, and Rhodococcus in cancer versus non-cancer. The profile of the GC mucosal microbiota obtained from the 16S rRNA gene has shown metabolic activities and biochemistry such as carbohydrate metabolism, carbohydrate digestion, absorption (11, 38, 39), membrane transport (11, 43), and nucleotide/purine metabolism (39, 43) to be significantly increased in GC by enhancing the counts of nitrate-reducing bacteria. Consequently, the functions of nitrate reductase (NR) and nitrite reductase (NiR) are significantly enriched in the microbiota of GC subjects, aligning with Correa’s hypothesis (11, 43, 46).

During the different stages of GC, the diversity and composition of the bacterial microbiome vary significantly. The microbial complex shows a strong correlation with precancerous lesion stages such as atrophic gastritis (AG) and dysplasia. GC and precancerous lesions can be identified by harboring distinguishable bacterial taxa. Furthermore, the microbial structure changes on the basis of the site in patients with GC; for example, Proteobacteria are abundant in the gastric mucosa, whereas Firmicutes have been found abundantly in gastric juice (36). The reduction in gastric mucosal microbiota diversity, due to the widespread colonization of H. pylori, must be considered a determining factor in the association between gastric precancerous lesions and the gastric microbiota. A microbial model derived from H. pylori–positive gastric biopsies and stool samples serves as a critical predictor of precancerous lesions. This is supported by reports of lower bacterial taxa diversity in gastric biopsies from H. pylori–infected individuals compared to those from H. pylori–negative participants. Among H. pylori–infected individuals, there was an increased abundance (from 0.91% to 68.22%) of Epsilonbacteraeota (the fifth validly described class of the phylum Proteobacteria) and decreased levels of Firmicutes (27.55% to 8.18%) and Proteobacteria (36.53% to 13.97%). Moreover, the ratio of Epsilonbacteraeota remained unchanged in stool and gastric juice samples from the H. pylori–positive groups. Consequently, H. pylori is associated with differences in gastric mucosal bacterial diversity between H. pylori–positive and H. pylori–negative samples, underscoring the role of GI bacteria in the development of gastric precancerous lesions (47).

Exploring the potential mechanisms and dysbiosis of GI microbial composition GC involving H. pylori infection has revealed that richness indexes increase after the eradication of H. pylori infection, with approximately 18 microbial taxa altered in the gastric tract sample groups. Additionally, the dysbiotic microbiota in gastric mucosal biopsies correlate with advanced AG, intestinal metaplasia (IM), and dysplasia, and this dysbiosis may be reversed by eradicating H. pylori. Notably, a study observed the coexistence of Helicobacter, Fusobacterial, Neisseria, Prevotella, Veillonella, and Rothia in cases where H. pylori was absent in healthy superficial gastritis. It can be concluded that dysbiosis of microbial diversity contributes to carcinogenesis (19).

In addition to the remarkable diversification and increased interaction of GI bacterial composition following infection with resistant H. pylori, consideration must be given to the metabolic pathways and enrichment of infectious diseases. This aligns with the findings of the study by Liu et al. (2022), wherein energy metabolism, bacterial secretion systems, lipopolysaccharide synthesis, protein folding, and associated processing are enriched in H. pylori–positive groups. Furthermore, the imbalance in gastric mucosal microbiota manifests in the inhibition of beneficial bacterial growth, such as Lactobacillus. Patients with refractory H. pylori infections may be at higher risk of developing GC compared to other groups (48).

Conversely, virulent H. pylori strains may be crucial for gastric colonization, but not sufficient for the development of GC and ulcers. Distinct microbial communities exist not only in the lower GI tract of H. pylori–infected patients but also that in non-infected individuals. Bacteroides and Bifidobacterium colonize the gut tract of H. pylori–positive patients with lower frequency. Notably, H. pylori–infected patients experiencing stomachache exhibit a lower abundance of Bifidobacterium species, which may be directly associated with gastric ulcers and cancer (49).

The gastric microbial composition profile of patients provides insight into the dysbiotic cancer-associated microbiota. Typically, gastric carcinoma is triggered by H. pylori infection, which reduces acid secretion, allowing for the growth of a gastric microbiome with a different composition. This diversification exacerbates the invasion of bacteria into the gastric mucosa and leads to malignancy. By measuring alpha-diversity (α-diversity) using the Shannon index, it has been found that H. pylori influences patients with gastric carcinoma by decreasing the microbial population and enhancing the composition of other bacterial genera, especially intestinal commensals, in comparison to chronic cases. Overall, the gastric microbiota is dominated by five phyla: Proteobacteria, Firmicutes, Bacteroidetes, Actinobacteria, and Fusobacteria.

However, whereas the mentioned phyla colonize both GC and chronic gastritis, patients with gastric carcinoma exhibit an over-presentation of Actinobacteria and Firmicutes, along with a lower abundance of Bacteroidetes and Fusobacteria (11). H. pylori alters the overall structure and composition of the microbiota in the specific stomach microenvironment of GC. In patients with both histopathologically H. pylori–positive and H. pylori–negative statuses, there is a tendency for microbial diversity reduction (lower in H. pylori–positive and higher in H. pylori–negative cases). Dominant phyla in the gastric microbiota of H. pylori–positive groups in normal and peri-tumoral tissues are Proteobacteria and Firmicutes in high proportions. Bacterial composition decreases in the peritumoral and tumoral microhabitats (12). It is noteworthy that certain known oral microbiomes, such as Parvimonas micra, Parvimonas stomatis, Fusobacterium nucleatum, and Gemella, are likely associated with colorectal cancer and may contribute to GC. Reports indicate an abundance of oral microbiomes in GC. The differences in bacterial composition and interactions play a pivotal role in determining the total microbiota assemblage at each stage of gastric carcinoma. Significant changes in microbial diversity are observed in the richness of microbiota between GC, superficial gastritis, and IM, validating the presence of microbial dysbiosis in gastric carcinoma. The lack of compatibility may stem from various background factors, such as gender, age, ethnicity, and the involvement of H. pylori. Consequently, there are fewer interactions among gastric microbes at all stages, with notably more interactions between gastric microbes in H. pylori–negative samples than in H. pylori–positive groups. The interactions of H. pylori with gastric microbes are studied as co-occurring interactions with Methylobacillus, Prevotella, and Arthrobacter, along with co-excluding interactions with Firmicutes (Ruminococcus, Bacillales, and Lactobacillus) (39).

Gastric mucosa–associated lymphoid tissue (MALT) lymphoma is correlated with both the presence and absence of H. pylori. Additionally, the microbiota in patients with MALT lymphoma is observed even in the absence of H. pylori. The microbial composition in the gastric mucosal flora of patients with H. pylori–negative MALT lymphoma significantly decreases. This might suggest that the balance of bacteria in the gastric mucosa is disrupted in patients with MALT lymphoma without the presence of H. pylori. The genera Burkholderia and Sphingomonas are identified abundantly in patients with MALT lymphoma compared to those in control groups. Therefore, Burkholderia and Sphingomonas genera may contribute to the progression of MALT lymphoma. In contrast, the enrichment of Prevotella and Veillonella is lower (50). The weighted principal coordinate analysis demonstrates that the colonization of H. pylori increasingly alters the structure of five genera of microbiota (Proteobacteria, Bacteroides, Fusobacteria, Actinobacteria, and Firmicutes); however, it has little impact on the proportion of other members. Thus, alterations in the GC microbiota by increasing bacterial quantity and diversifying the microbial population could promote cancer-related activities (51). The composition of the gastric microbiota in patients with GC infected with H. pylori is shown in Table 1 .

Several studies demonstrate that individuals who tested positive for H. pylori were three to six times more likely to develop GC in comparison to uninfected controls. So, it suggested that screening for and eliminating H. pylori is a cost-efficient method for averting GC in individuals in their middle ages (73–75). The recognition of this bacterium as a disease-causing agent prompted certain authors to advocate for diverse programs aimed at eradicating the infection within the population, as a means of curtailing the progression of the disease (76). Many studies of randomized clinical trials (RCTs) showed that eradicating H. pylori leads to a decrease in GC incidence among healthy and undergone endoscopic resection of early GC ( Table 2 ).

Infection with H. pylori, a bacterial carcinogen, stands as the primary cause of GC, claiming hundreds of thousands of lives annually. H. pylori infection significantly contributes to gastric microbial dysbiosis, potentially playing a role in carcinogenesis. Successful eradication of H. pylori may restore the gastric microbiota to a state resembling that of uninfected individuals, thereby exhibiting beneficial effects on the gut microbiota. The current study has underscored variations in microbiota changes among individuals with GC with or without H. pylori. Examining the interplay between H. pylori infection and microbiota changes in patients with GC aids in refining therapy for H. pylori infection in individuals with GC and concurrent H. pylori presence. In the future, it is imperative to comprehensively observe changes in intestinal flora from multiple perspectives through more scientific and rational research methods. This approach will enable a thorough and clear understanding of the causes and outcomes of the relationship between GC and intestinal flora, moving beyond mere correlation analysis.