New pathogen for gastric cancer: <i>Streptococcus anginosus</i>

It is well-established that Helicobacter pylori is the major risk factor for gastric cancer (GC). For the past decades, overwhelming studies have focused on H. pylori to elucidate its procarcinogenic mechanisms and establish eradicating modalities. However, H. pylori triggers GC in a “hit and run” manner and largely depletes, rather than persistently involved in gastric tumorigenesis and progression. When gastric intestinal metaplasia occurs, H. pylori eradication fails to reduce the risk of GC.1 In addition, less than 3% of H. pylori-infected individuals eventually develop GC,2 and there should be more contributing factors being taken into account in addition to H. pylori. As gastric tumorigenesis initiates, impaired gastric acid and enzyme secretions facilitate the colonization of diverse microbes. The roles and mechanisms of non-H. pylori microbes in GC have long been underrecognized. To thoroughly depict the non-H. pylori microbiome in GC, we have assessed microbial alterations across various stages of gastric tumorigenesis and identified that Streptococcus anginosus is notably associated with atrophic gastritis, intestinal metaplasia, and GC.3 After H. pylori-eradication, S. anginosus still contributes to persistent gastric inflammation.4 Evidence consistently suggests the involvement of S. anginosus in gastric tumorigenesis, prompting us to investigate its effects and mechanisms.5 Our findings show that S. anginosus can colonize within the stomach of mice. S. anginosus-infected mice exhibit acute gastric mucosal inflammation under pro-inflammatory cytokine production after 2 weeks. Chronic inflammation and precancerous lesions, including atrophy, metaplasia, and low-grade dysplasia occur under S. anginosus long-term exposure, which is similar to the Correa's cascade observed in patients with GC. S. anginosus-infection of germ-free mice demonstrates similar results, indicating the pro-inflammatory and pro-tumorigenic effects of S. anginosus can be sufficient without the involvement of other microbes. In addition, S. anginosus accelerates gastric tumorigenesis in both short-term allograft and long-term chemical-induced GC models. Moreover, S. anginosus infection induces CD8+ T cell exhaustion as well as immunosuppressive cell infiltrations as revealed by single-cell RNA sequencing. Mechanistically, through screening by pull-down assays and mass spectrometry, the surface adhesin TMPC from S. anginosus binds to the annexin A2 receptor on gastric cells, which further activates the mitogen-activated protein kinase (MAPK) signalling. The pro-tumorigenic effects can be abolished through ANXA2 knockout on GC cells or TMPC deletion within S. anginosus. These findings are highly relevant to a variety of issues we have encountered clinically (Figure 1). Prevention is always better than cure. In clinical practice, biomarkers for early detection of GC remain scarce, and a large number of patients are diagnosed at their advanced stages with short survival. Detection of gastric microbiota may open a new area for identifying high-risk populations for GC. Modifiable risk factors are disease-related exposures that can potentially be changed, whereas only a limited number of GC-associated risk factors are modifiable. S. anginosus represents a new modifiable risk factor and is promising to be controlled for suppressing gastric tumorigenesis. S. anginosus mainly originates from the oral cavity, particularly in patients with oral infections such as gingivitis and dental abscesses.6 Therefore, regular dental examinations and maintaining oral hygiene are the simplest and most cost-effective ways to prevent the overabundance of oral pathogens including S. anginosus within the oral cavity. Gastric acid is bactericidal to pathogens, while impaired acid secretion might facilitate S. anginosus translocation and colonization within the stomach. Apart from pathological changes, acid suppressant use is a common factor for decreased acid secretion. It is estimated that approximately 10% of the population in the United States is using acid suppressants, and their inappropriate use without clear indications has raised extensive concerns. Intriguingly, acid-suppressants induce gut microbial alterations, with S. anginosus being the most significantly changed species.7 Epidemiological studies also indicate that acid suppressants are related to a higher risk of GC.8 Acid-suppressant use, S. anginosus translocation, and subsequent GC occurrence are tightly linked together based on current evidence. Thus, appropriate use and de-prescribing of acid-suppressants is essential to ameliorating the burden and mitigating the risks of adverse effects. Specifically targeting S. anginosus in clinical practice remains unfeasible. Antibiotics are non-specific to S. anginosus and will disturb normal gut flora.9 In addition, antibiotics do not guarantee the complete clearance of S. anginosus within the oral cavity and gastrointestinal tract, and the emergence of drug-resistant S. anginosus or other pathogenic strains will be much more intractable. In contrast, probiotics that antagonize S. anginosus represent promising alternatives, and targeted therapy using phage is another viable strategy against S. anginosus. Further investigations are warranted into this field to explore their effectiveness and mechanisms. Taken together, S. anginosus is a new promoter and accelerator involved in GC tumorigenesis throughout different stages. Our findings might be merely the tip of the iceberg of non-H. pylori microbes in gastric tumorigenesis, and will inspire researchers and clinicians to delve deeper into the concealed parts of gastric microbiota. RZ designed the figures and drafted the manuscript. JY and JJS supervised the study and revised the figures and manuscript. All authors approved the final version of the manuscript. This study was supported by RGC Collaborative Research Fund (C4008-23 W), RGC Research Impact Fund Hong Kong (R4032-21F); Strategic Seed Funding Collaboration Research Scheme CUHK (3133344); Strategic Impact Enhancement Fund CUHK (3135509); Impact case for RAE CUHK (3134277). The authors declare no conflict of interest.