Abstract
Gastric cancer (GC) is one of the leading causes of cancer-related deaths worldwide. The gastric microbiota plays a critical role in the development of GC. First, Helicobacter pylori (H. pylori) infection is considered a major risk factor for GC. However, recent studies based on microbiota sequencing technology have found that non-H. pylori microbes also exert effects on gastric carcinogenesis. Following the infection of H. pylori, gastric microbiota dysbiosis could be observed; the stomach is dominated by H. pylori and the abundances of non-H. pylori microbes reduce substantially. Additionally, decreased microbial diversity, alterations in the microbial community structure, negative interactions between H. pylori and other microbes, etc. occur, as well. With the progression of gastric lesions, the number of H. pylori decreases and the number of non-H. pylori microbes increases correspondingly. Notably, H. pylori and non-H. pylori microbes show different roles in different stages of gastric carcinogenesis. In the present mini-review, we provide an overview of the recent findings regarding the role of the gastric microbiota, including the H. pylori and non-H. pylori microbes, in the development of GC.
Introduction
Gastric cancer (GC) is one of the leading causes of cancer-related deaths worldwide, ranking fifth in incidence and third in mortality of cancers (). According to World Health Organization International Agency for Research on Cancer (WHO-IARC), the annual burden of GC will increase to approximately 1.8 million new cases and 1.3 million deaths by 2040. Compared with those in 2020, the numbers of new cases and deaths will increase by approximately 63% and 66%, respectively (). Helicobacter pylori (H. pylori) infection is a critical risk factor for GC () and H. pylori was classified by the WHO-IARC as a type I carcinogen (). In recent years, sequencing-based studies focusing on microbiota have shown that patients with GC have gastric microbiota dysbiosis, including reduced microbial diversity, altered microbial community structure, altered compositions, and abnormal bacterial interactions (; ). Furthermore, non-H. pylori microbes might also promote gastric lesions and even GC (; ; ; ). The interactions between H. pylori and other microbes may be also involved in gastric carcinogenesis.
In the present mini-review, we aim to discuss the recent findings regarding the role of gastric microbiota, including H. pylori and non-H. pylori microbes, in the development of GC.
H. pylori infection, eradication, and GC
H. pylori is a gram-negative, flagellated, microaerophilic bacterium belonging to the Campylobacterota phylum, which was first identified in 1982 (). H. pylori colonizes in the stomach and becomes the predominant microbe in stomach after infection (). In terms of the global epidemiology of H. pylori infection, according to a global meta-analysis (), there were about 4.4 billion H. pylori-positive cases worldwide in 2015. The prevalence rate of H. pylori infection varied by region, with the highest prevalence rate in Africa (70.1%, 95% CI: 62.6-77.7%) and the lowest prevalence rate in Oceania (24.4%, 95% CI: 18.5-30.4%). Furthermore, for the temporal trend of H. pylori infection, the prevalence in different regions is stable or decreasing, especially in the developed world and in children (; ).
H. pylori infection is considered a major risk factor for gastric carcinogenesis. Overall, a large-scale pooled analysis of case-control studies nested within prospective cohorts showed that H. pylori infection was associated with nearly six-fold increased risk of non-cardia cancer (). The mechanism that H. pylori induces GC has been explored (; ). First, H. pylori primarily triggers the transition from normal mucosa to non-atrophic gastritis and then initiates precancerous lesions (). The responses after infection are mainly mediated through the action of bacterial virulence factors, including cytotoxin-associated gene A (CagA), vacuolating cytotoxin A (VacA), and other outer membrane proteins (; ). CagA has multiple effects on epithelial cells, including stimulating cell proliferation, reducing epithelial cell apoptosis, etc. (; ; ). Additionally, inflammatory cells can be recruited and oxygen species-induced damage can be induced after CagA and the type IV secretion system (T4SS) activate the inflammatory signaling (; ). VacA can also cause alterations of cells, such as vacuolization and promoting immune regulation (; ). Further, the urease production by H. pylori and the glandular atrophy induced by H. pylori infection lead to reduced acid production and shifts in gastric pH value. As a result, the bacterial colonization environment in the stomach changes and gastric microbiota dysbiosis may occur (; ). The above-mentioned effects promote GC development.
For H. pylori-positive cases, eradication therapy could be given (; ; ). The effect of H. pylori eradication therapy on the GC risk has been evaluated. You et al. reported that, based on a randomized trial with a follow-up of 7.3 years, H. pylori treatment resulted in statistically significant decreases in the combined prevalence of severe chronic atrophic gastritis, intestinal metaplasia, dysplasia, or GC (OR = 0.77, 95% CI: 0.62-0.95) (). With a follow-up of 22 years for this randomized trial, this team found that the protective effect of H pylori treatment on GC incidence (OR= 0.48, 95% CI: 0.32-0.71) and GC death (HR= 0.62, 95% CI: 0.39-0.99) persisted 22 years post-intervention (). Additionally, a recent well-designed meta-analysis enrolling randomized controlled trials (RCTs) with 10 or more years of follow-up found that the GC incidence decreased significantly with H. pylori eradication therapy (RR=0.54, 95% CI: 0.41-0.72); on the other hand, eradication of H. pylori showed significant reductions in GC mortality (RR=0.66, 95% CI: 0.46-0.95) ().
H. pylori associated gastric microbiota dysbiosis
The gastrointestinal microbiota refers to microorganisms lived in the gastrointestinal tracts, which is critical to many aspects of human health (; ). For human immune, the microbiota is key to the induction, training, and function of the host immune system (; ). Regarding the gastric microbiota, due to the high acidity of the stomach, the human stomach was once assumed to be a sterile organ (). However, H. pylori is able to colonize the human gastric mucosa and survive in the highly acidic environment of the stomach (). With the advent of novel techniques for analyzing the microbial community, the unique features of the gastric microbiota have been identified that the major microbes in the healthy human stomach environment are Firmicutes, Bacteroidetes, Actinobacteria, Fusobacteria, and Proteobacteria (; ).
For H. pylori-infected individuals, the stomach is dominated by H. pylori and accordingly, the abundances of non-H. pylori microbes reduce substantially (; ). In addition to the changes of microbial composition, other phenomena of gastric microbiota dysbiosis have also been found. For the microbial alpha diversity, Gantuya et al. reported that individuals infected with H. pylori showed significant decreased microbial diversity compared with H. pylori-negative individuals (). Another study found that there was a negative association between the gastric microbiome diversity and Helicobacter abundance (). In addition to microbial alpha diversity, infection with H. pylori results in alterations of the microbial community structure (beta diversity). According to a population-based study, the H. pylori positive group and negative group were clearly separated according to beta diversity (). Furthermore, studies focusing on the microbial ecological interactions found shifts of the interactions between H. pylori and other microbes in the stomach environment. In detail, according to an Indian study using16S rRNA gene sequencing, the network analyses showed that Helicobacter had negative interactions with other microbes of the gastric microbiome (); another Chinese study reported similar findings (). Regarding the numbers of interactions, Coker et al. found that H. pylori infection reduces the number of gastric microbiome interactions (). However, all the above-mentioned findings were based on statistical analyses of sequencing data. Thus, we need more clinical data supporting current presented concept ().
For H. pylori-positive individuals, the H. pylori eradication could reverse gastric microbiota dysbiosis and exert beneficial effects on the gastric microbiota (). Firstly, for the reduced gastric microbial diversity among H. pylori-positive cases, the diversity could increase significantly after successful eradication of H. pylori (; ). Also, significant differences were observed for the microbial community structure (the beta diversity) following eradication (; ; ; ; ). For the gastric microbiota composition, after removing H. pylori in the stomach environment, the gastric commonly dominant commensals are enriched (; ). Different changes of specific microbes were reported, which may be resulted from different population, sequence methods, and sampling details. The common reported commensals included Firmicutes, Streptococcus, Prevotella., etc. (; ; ; ; ). In terms of interactions between gastric commensal bacteria, a reduction in these interactions was reported after eradication of H. pylori (; ), which were also based on statistical analyses of sequencing data and required further validation. Moreover, due to the development of bioinformatics, microbiota function could be predicted and analyzed. According to the bioinformatic analysis of functional capacity, the bacteria reproduction-related pathways are down-regulated and pathways of gastric acid secretion, etc. are up-regulated (; ), indicating beneficial effect of eradication on the recovery of gastric microbiota. In combination with the prevention effect of H. pylori eradication on GC, the alterations in gastric microbiota after eradication may contribute to the reduction in GC risk; further studies with long-term follow-up are needed ().
The overall features of the gastric microbiota associated with GC
In recent years, the characterization of the gastric microbiota associated with GC has been identified, indicating that gastric microbiota dysbiosis occur in gastric carcinogenesis (). In the year of 2009, the team of Prof. Engstrand compared the gastric microbiota of patients with GC and controls using the terminal restriction fragment length polymorphism (T-RFLP) and 16S rRNA gene cloning and sequencing. They found that diversity indices of GC microbiota were not significantly different from that in controls according to the T-RFLP. In terms of gastric microbiota composition of GC, the abundance of H. pylori was low and the GC microbiota was dominated by the following genera: Streptococcus, Lactobacillus, Veillonella and Prevotella (). However, the sample size of this study was small (only ten patients and five controls); additionally, 16S rRNA sequencing technology and related procedures are not yet developed and extensively used, therefore this work is an initial investigation of this field.
In following decade, other findings have been reported. Firstly, the gastric microbial diversity alteration in GC has been the most focused topic. Several studies reported that compared with the gastritis status, gastric microbial diversity is significantly reduced; analyses showed that the microbial community structure (beta diversity) is significantly altered in GC patients (; ). Similarly, according to studies based on comparison between GC tissues and non-cancerous tissues, GC tissues also have reduced diversity and shifted microbiota structure (). However, the conclusions are inconsistent across studies. For instants, two studies showed that the alpha diversity of GC gastric microbiota was increased (; ). The difference of results may be caused by different populations, sampling sites and stage of gastric disease.
In addition to microbial diversity analysis, with the development of bioinformatics, more in-depth analysis methods have been developed and used. The function prediction analyses have been applied to explore potential mechanisms of gastric carcinogenesis. The most studies did function prediction analyses using PICRUSt (). Ferreira et al. identified the presence of a nitrosating microbial community in GC cases, indicating that nitrate-reducing bacteria may contribute to gastric carcinogenesis (). Meanwhile, a switch towards purine metabolism, D-alanine metabolism, drug metabolism, etc. in GC were reported in another study (). These findings suggested that the microorganisms in the stomach may contribute to the development of GC through specific functional effects. Similarly, these findings need further validation of mechanisms.
The non-H. pylori microbes associated with GC
In addition to H. pylori, more and more studies have been focusing on other non-H. pylori gastric microorganisms. Similar to the bacterial driver-passenger model in the development of colorectal cancer (), the hypothesis of GC has been proposed that: H. pylori, as the “driver”, causes pathological changes of gastric mucosa and dysbiosis of gastric microbiota; with the progression of gastric lesions, the number of H. pylori decreases and the number of other microorganisms in the stomach, i.e. non-H. pylori microbes as the “passengers”, increases correspondingly. These non-H. pylori microbes play an important role in the pathogenesis of GC.
The above hypothesis has been confirmed in animal research. An animal study using hypergastrinemic insulin-gastrin (INS-GAS) transgenic mice found that compared with the specific pathogen free (SPF) INS-GAS mice, the duration of gastric lesions development was longer for germ-free INS-GAS mice; compared with INS-GAS mice infected with H. pylori only, INS-GAS mice with complex gastric microbiota had more severe gastric lesions and an earlier onset of gastrointestinal intraepithelial neoplasia (). Another INS-GAS mice-based study reported that INS-GAS mice coinfected with H. pylori and other intestinal bacteria had a higher rate of development of gastrointestinal intraepithelial neoplasia than those infected with H. pylori alone (). These findings indicate the potential role of non-H. pylori microbes and the interactions between H. pylori and non-H. pylori microbes in gastric carcinogenesis.
More researchers are paying attention to human studies as the hypothesis is supported in animal studies. In a population-based study using the 16S rRNA gene sequencing method, compared with individuals with gastritis, GC showed gastric microbiota dysbiosis and a lower abundance of Helicobacter and the over-representation of intestinal commensals was seen in GC gastric microbiota. In detail, 16 enriched taxa and 13 depleted taxa in GC according to the LEfSe analysis (). Another study comparing gastric microbiota of GC patients and superficial gastritis reported that 21 bacterial taxa were enriched in GC and 10 bacterial taxa were depleted in GC. Specifically, enrichment of oral microbes was observed in the stomach of GC (). In addition to above two cross-sectional studies, a cohort study with a 4-year follow-up reported that Helicobacter abundance was lower in the subjects with progression of gastric lesions compared with non-progression group. Specifically, the remarkable decline in Helicobacter was observed after the progression to stage of dysplasia/GC compared with non-progression controls (). The key non-H. pylori microbes associated with GC are summarized in Table 1. However, inconsistent results were found, necessitating additional validations.
Table 1
| PHYLUM | CLASS | ORDER | FAMILY | GENUS | SPECIES |
|---|---|---|---|---|---|
| Firmicutes | Bacilli | Lactobacillales | Streptococcacaeae | Lactococcus: potential harmful microbes for gastric mucosa (; ; ) | Lactococcus lactis: potential beneficial microbes for gastric mucosa () |
| Streptococcus: potential harmful microbes for gastric mucosa (; ); also reported as potential beneficial microbes for gastric mucosa () | Streptococcus anginosus: potential harmful microbes for gastric mucosa (; ) Streptococcus infantis: potential harmful microbes for gastric mucosa () | ||||
| Bacillales | Bacillaceae | Bacillus: potential harmful microbes for gastric mucosa () | |||
| Lactobacillales | Lactobacillaceae | Lactobacillus: potential harmful microbes for gastric mucosa (; ) | Lactobacillus brevis: potential beneficial microbes for gastric mucosa () Lactobacillus salivarius: potential harmful microbes for gastric mucosa () Lactobacillus fermentum: potential harmful microbes for gastric mucosa () | ||
| Clostridia | Clostridiales | Clostridiaceae | Clostridium: potential harmful microbes for gastric mucosa (; ) | ||
| Bacteroidetes | Bacteroidetes | Bacteroidales | Prevotellaceae | Prevotella: potential harmful microbes for gastric mucosa (; Sung et al., 2020a; ); also reported as potential beneficial microbes for gastric mucosa (; ) | Prevotella melaninogenica: potential harmful microbes for gastric mucosa () Prevotella oris: potential harmful microbes for gastric mucosa () Prevotella intermedia: potential harmful microbes for gastric mucosa () |
| Proteobacteria | Betaproteobacteria | Neisseriales | Neisseriaceae | Neisseria: potential beneficial microbes for gastric mucosa () | |
| Fusobacteria | Fusobacteria | Fusobacterales | Fusobacteriaceae | Fusobacterium: potential harmful microbes for gastric mucosa (; ; ) | Fusobacterium nucleatum: potential harmful microbes for gastric mucosa () |
Key non-H. pylori microbes associated with gastric cancer.
Furthermore, based on the current findings, a panel of differential gastric bacteria can be developed to distinguish GC and the progression of GC with outstanding performance. A recently published meta-analysis, which enrolled six independent studies, reported that eight bacterial taxa could serve as a panel of biomarkers to discriminate GC from superficial gastritis with an area under the curve (AUC) of 0.850 (). Regarding the progression of GC, Kadeerhan et al. reported a combination of four genera (Bacillus, Capnocytophaga, Helicobater, Prevotella) with age and sex to distinguish subjects after lesion progression from non-progression controls (AUC = 0.927) (). In addition to a panel of bacteria, a new single index called Microbial Dysbiosis Index (MDI) has been presented. MDI is calculated by log (total abundance of genera increased in GC/total abundance of genera decreased in GC); a higher value of MDI means a higher risk of GC. The application of MDI has been applied in the evaluation of GC: the GC gastric microbiota had a higher MDI and the findings were confirmed in the validation cohorts ().
The different roles of H. pylori and non-H. pylori microbes in gastric carcinogenesis
The progression of gastric carcinogenesis is detailed in Figure 1. Like bacterial driver-passenger model of colorectal cancer, the development of GC showed similar change pattern of gastric microbiota. Thus, H. pylori and non-H. pylori microbes show different roles in different stages of gastric carcinogenesis. First of all, the load of H. pylori in the stomach increases after the initial infection, especially in the active gastritis stage (). Interestingly, the H. pylori load decreases with the progression of gastric lesions. A population-based study showed that a lower Helicobacter abundance was observed in subjects with the progression of gastric lesions (); another study reported that the abundance of Helicobacter was substantially lower in GC patients than gastritis (). This phenomenon could be explained that, following H. pylori infection, due to the persistence of inflammation and the loss of acid-secreting parietal cells, the gastric environment becomes more favorable for the colonization of other bacteria and progression of lesions are accelerated (). In detail, with the development of gastric lesions, oral or intestinal commensal microbes are enriched (; ; ). However, by the late stage of gastric precancerous lesions, the stomach environment is no longer suitable for H. pylori and the abundance H. pylori of decreases. This phenomenon has been confirmed in human studies (; ). The key roles of H. pylori in different stages of gastric carcinogenesis were shown in the Table 2. In addition to the overall description of the progression of gastric carcinogenesis, the roles of certain bacteria remain to be clarified and further mechanism investigation is needed for a deeper understanding of this issue.
Figure 1
Table 2
| Stages in the development of GC | Descriptions |
|---|---|
| Uninfected stage |
|
| H. pylori-dependent stage |
|
| H. pylori-independent stage |
|
Key roles of H. pylori in gastric carcinogenesis.
Future perspectives
Non-H. pylori microbes and their interactions may also play a critical role in the development of GC. However, inconsistent findings were reported for non-H. pylori microbes associated with GC. Accordingly, further mechanism investigation is needed to validate these potential GC-associated non-H. pylori microbes, such as animal studies. Additionally, most human studies are case-control studies, which compared gastric microbiota of gastric mucosa between GC patients and control population. Due to this study design, we cannot infer a causal relationship between gastric microbiota dysbiosis and development and progression of GC. In other words, it is unclear whether gastric microbiota dysbiosis causes GC or whether GC causes gastric microbiota dysbiosis. Therefore, cohort studies with long-term follow-up are needed to confirm the major findings.
Statements
Author contributions
YG drafted the manuscript, conceptualized the idea, and revised the manuscript. X-SC and M-GZ performed the literature search and revised the manuscript. YG and M-GZ contributed to drawing the figure. BY critically revised the manuscript and supervised the study. All authors contributed to the article and approved the submitted version.
Funding
This work was supported by the National Natural Science Foundation of China (No. 82103727), the fellowship of China Postdoctoral Science Foundation (No. 2021M702221), Guangdong Basic and Applied Basic Research Foundation (No. 2022A1515010957 and 2021A1515011558), Shenzhen Sanming Project (No. SZSM201812059), Shenzhen Key Medical Discipline Construction Fund (No. SZXK040), Shenzhen Science and Technology Program (No. RCBS20210706092408008).
Conflict of interest
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
Publisher’s note
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Summary
Keywords
gastric cancer, gastric microbiota, Helicobacter pylori, carcinogenesis, dysbiosis
Citation
Guo Y, Cao X-S, Zhou M-G and Yu B (2023) Gastric microbiota in gastric cancer: Different roles of Helicobacter pylori and other microbes. Front. Cell. Infect. Microbiol. 12:1105811. doi: 10.3389/fcimb.2022.1105811
Received
23 November 2022
Accepted
21 December 2022
Published
10 January 2023
Volume
12 - 2022
Edited by
Xin Zhou, Stanford University, United Sates
Reviewed by
Kai Fu, Johnson & Johnson, United States; Amin Talebi Bezmin Abadi, Tarbiat Modares University, Iran
Updates
Copyright
© 2023 Guo, Cao, Zhou and Yu.
This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
*Correspondence: Yang Guo, yangguoanny@163.com; Bo Yu, drboyu_derm@126.com
This article was submitted to Intestinal Microbiome, a section of the journal Frontiers in Cellular and Infection Microbiology
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