Streptococcus anginosus in the development and treatment of precancerous lesions of gastric cancer

Abstract

The microbiota is strongly association with cancer. Studies have shown significant differences in the gastric microbiota between patients with gastric cancer (GC) patients and noncancer patients, suggesting that the microbiota may play a role in the development of GC. Although Helicobacter pylori (H. pylori) infection is widely recognized as a primary risk factor for GC, recent studies based on microbiota sequencing technology have revealed that non-H. pylori microbes also have a significant impact on GC. A recent study discovered that Streptococcus anginosus(S. anginosus) is more prevalent in the gastric mucosa of patients with GC than in that of those without GC. S. anginosus infection can spontaneously induce chronic gastritis, mural cell atrophy, mucoid chemotaxis, and heterotrophic hyperplasia, which promote the development of precancerous lesions of GC (PLGC). S. anginosus also disrupts the gastric barrier function, promotes the proliferation of GC cells, and inhibits apoptosis. However, S. anginosus is underrepresented in the literature. Recent reports suggest that it may cause precancerous lesions, indicating its emerging pathogenicity. Modern novel molecular diagnostic techniques, such as polymerase chain reaction, genetic testing, and Ultrasensitive Chromosomal Aneuploidy Detection, can be used to gastric precancerous lesions via microbial markers. Therefore, we present a concise summary of the relationship between S. anginosus and PLGC. Our aim was to further investigate new methods of preventing and treating PLGC by exploring the pathogenicity of S. anginosus on PLGC.

Key Words: Streptococcus anginosus; Gastric cancer; Precancerous lesions of gastric cancer; Microbiota; Microbiota sequencing technology

Core Tip: Advanced gastric cancer has a very poor prognosis at this stage. Early diagnosis and treatment of precancerous lesions of gastric cancer (PLGC) still need further research. Studies of the microbiota associated with PLGC have found that Streptococcus anginosus (S. anginosus) plays an important role in their development. We explore the mechanism of S. anginosus in PLGC and consider its inclusion in the diagnosis and treatment of PLGC.

INTRODUCTION

Gastric cancer (GC) is a prevalent form of cancer, ranking fifth in terms of frequency worldwide and third in terms of cancer-related deaths[1]. Risk factors include Helicobacter pylori (H. pylori) infection, age, high salt intake, and a diet low in fruits and vegetables. The median survival rate of advanced GC (AGC) is less than 12 months. Therefore, early diagnosis and timely treatment are the only effective strategies[2]. GC is typically diagnosed histologically following endoscopic biopsy, with staging methods including computed tomography (CT), ultrasound endoscopy, positron emission tomography (PET), and laparoscopy. Pathology-based stages of atrophy, intestinal epithelial hyperplasia, and heterogeneous hyperplasia are collectively referred to as precancerous lesions of GC (PLGC).

Numerous studies have demonstrated a substantial correlation between the microbiota and GC. Notable disparities in the gastric microbiota of GC patients compared to those without suggest that microbiota may play a role in GC development[3]. While H. pylori infection is acknowledged as a primary risk factor, non-H. pylori microorganisms also exert significant influence. Research indicates that the oral microbiota, exemplified by Streptococcus anginosus, contributes to the onset of gastrointestinal cancers through modulation of metabolic pathways and carcinogenic induction[4]. Furthermore, viruses such as Epstein-Barr virus (EBV) and fungi like Candida albicans (C. albicans) are recognized for their impact on gastric mucosal carcinogenesis. In contrast, the bacterial community was predominantly composed of five principal phyla: Thick-walled bacteria, Anaplasma, Aspergillus, Actinobacteria, and Clostridia[5].

Recent research has extensively explored the influence of oral microbiota on the progression of GC. A comparative analysis of gene sequencing from oral samples and gastric sinus mucosal samples revealed a significant enrichment of S. anginosus in intestinal epithelialized mucosal samples, with [odds ratios (ORs) = 1.29-1.50, P = 0.004-0.01][6]. Furthermore, another study demonstrated that an infection by S. anginosus spontaneously triggers chronic inflammation, atrophy, mucus chemotaxis, and heterogeneous hyperplasia, thereby facilitating the development of PLGC[7]. The advent of modern molecular diagnostic techniques such as polymerase chain reaction (PCR), genetic testing, and ultrasensitive chromosomal aneuploidy detection now allows for the specific detection of PLGC through the labeling of S. anginosus.

This article provides a succinct overview of the current state of research on PLGC, while also investigating potential correlations between S. anginosus and PLGC. To enhance the efficacy of PLGC treatment, it is suggested that emphasis should be placed on the prevention, diagnosis, and treatment of S. anginosus. This focus could potentially inspire novel ideas and strategies.

DIAGNOSIS AND STAGING OF PLGC, TREATMENT AT THE PRESENT STAGE

Diagnosis of PLGC

PLGC are a series of changes that occur in the middle of the progression from normal chronic gastritis to GC. It is recognized by experts that pre-cancerous stages of GC encompass mucosal atrophic lesions, intestinal epithelial hyperplasia, and heteroplasia. The progression of the heteroplasia stage corresponds to early GC (EGC)[8]. The 5-year survival rate for AGC is less than 20%, while the 5-year survival rate for EGC can be 90%-95%[9]. The advancement of ultrasound, CT, magnetic resonance imaging (MRI), PET, PET/CT, PET/MRI, and gastroscopy has led to a gradual increase in the detection rate of PLGC[10]. Clinical tests for gastric evaluation include barium meal of the digestive tract, enhanced CT of the abdomen, and gastroscopy. However, at the PLGC stage, the gastric mucosal surface vascularity may remain dense and regular, accompanied by deeper fibrous connective tissue and less pronounced mucosal manifestations. This complexity makes it challenging to assess using gastric barium meal radiography[11]. Enhanced CT of the abdomen does not reveal significant early changes in the gastric mucosa and has low sensitivity[12]. PET is highly sensitive, but costly and radioactive, and incorporated into routine examination programs[13]. Consequently, gastroscopy with biopsy has emerged as the preferred method for diagnosis and treatment. The adoption of tools such as magnified gastroscopy, Near-Infrared Biometry, and staining techniques have elevated the detection rate of EGC[14,15]. Nonetheless, the primary challenge in diagnosing PLGC lies in identifying the challenging-to-spot early precancerous mucosa and implementing routine gastroscopic screening[16,17].

Staging of PLGC

Correa's cascade is frequently employed to depict the progression of PLGC, typically represented as inflammation-atrophy-metaplasia-dysplasia-carcinoma[18,19]. Typically, this process can be segmented into the following stages:

Chronic non-atrophic gastritis (also known as chronic superficial gastritis): This is the early stage of PLGC, mainly manifested as chronic inflammation of gastric mucosa. Gastroscopy can see the mucosa red and white, edema, congestion, erosion, etc. There may also be gastric mucosal roughness, erythema, hemorrhagic spots, oozing and other manifestations. There is usually no obvious atrophy or intestinal epithelial hyperplasia[20,21].

Chronic atrophic gastritis (CAG): In this stage, atrophy of the gastric mucosa occurs, gastric glands are reduced and thinned, which is the key stage of PLGC, most of which are caused by H. pylori infection or autoimmunity. Typical endoscopic features include pale, exfoliative changes in the gastric mucosa, increased visibility of the vascular system due to thinning of the gastric mucosa, loss of the gastric folds, and small, dark-red reticulated blood vessels, and larger blue dendritic veins[22-24].

Gastric mucosal intestinal epithelialization: On the basis of CAG, the gastric mucosal epithelium is transformed into small or large intestinal mucosal epithelial tissue, which is called intestinal epithelialization/intestinalization. Gastroscopy reveals small yellowish or white nodules in the gastric mucosa, which show fluffy or flattened punctate and scaly changes. Pigmented gastroscopy shows light blue cristae and white opaque fields. intestinal epithelialization is an important hallmark of PLGC, which can be categorized into mild, moderate, and severe grades based on the degree and extent of intestinalization[25-28].

Dysplasia (atypical hyperplasia, intraepithelial neoplasia): On the basis of intestinalization, the epithelial cells of gastric mucosa show heteroplasia, i.e., there are abnormalities in the shape, size and arrangement of the cells, which is a direct precursor of GC. Dysplasia can also be categorized into mild, moderate and severe. Gastroscopic manifestations often show mild ectodermal hyperplasia as mild irregularity in the ductal structure, moderate as irregularity in the ductal structure and branching, and severe as disorganization of the ductal structure, with different sizes and shapes. Severe dysplasia is indistinguishable from EGC, and surgical treatment is often advocated[29-31].

The staging of PLGC is not absolute, and different pathologists will have different grading criteria. In addition, the development of PLGC is not linear. Some lesions may remain at a certain stage for a long time, while others may rapidly develop into GC. Consequently, the diagnosis and treatment of PLGC necessitate consideration of multiple factors, including the patient's medical history, clinical manifestations, endoscopic findings, and pathological results.

Treatment of PLGC

General management: Patients are advised to modify their dietary structure, avoid spicy, stimulating, raw and cold foods, eat more fresh vegetables and fruits, and try not to eat pickled foods and foods with high nitrite content. Additionally, to quit smoking and drinking, and avoid taking drugs that have damage to the gastric mucosa, such as aspirin. Maintain emotional stability, avoid overwork and late nights, and ensure adequate sleep[32].

Drug therapy: For gastric mucosal inflammation and atrophy, proton pump inhibitors (e.g., omeprazole, lansoprazole, etc.) and gastric mucosal protectors (e.g., aluminum thioglycollate, colloidal bismuth pectin, etc.) can be used. If combined with HP infection, eradication treatment is needed, such as using quadruple therapy. Depending on the specific circumstances, additional treatments may include prokinetic agents, digestive enzyme preparations, and other medications[33]. A multitude of studies have corroborated that TCM offers certain benefits in treating PLGC, including fewer side effects and the ability to provide multi-component and holistic regulation[34].

Surgery: If the gastric precancerous lesion has progressed to the stage of heterogeneous hyperplasia or EGC, surgical treatment needs to be considered. Surgical methods include minimally invasive procedures such as endoscopic mucosal resection and endoscopic mucosal dissection, as well as traditional surgical methods. The optimal surgical strategy must be determined based on the unique circumstances of each patient[18,35].

MICROBIOTA AND PLGC

The microbiota is found throughout our body and the environment in which we live. The strong acidic environment of the stomach has long been widely believed to be unfavorable to the microbiota until H. pylori was discovered and the relationship between stomach-related diseases and microorganisms began to be studied[36]. Due to advances in PCR technology and macrogenomics it has been confirmed that the stomach contains a robust microbiota. As a result, studies on the relationship between gastric microbiota and PLGC have begun to increase[37]. A summary can be found in Table 1.

Table 1 Microorganisms associated with precancerous lesions of gastric cancer.

Microorganisms	Primary site	Potential mechanism	Ref.
Helicobacter pylori	Gastrointestinal tract, oral	Cytotoxin-associated gene A and vacuolar cytotoxin A cause DNA damage. increased genetic instability leads to mutations	Salvatori et al[71]
			Malfertheiner et al[72]
Streptococcus Anginosus	Oral, nasopharyngeal, gastrointestinal tract, vaginal	The streptococcal surface protein TMPC interacts with ANXA2-mediated attachment and colonization. Spontaneously induces progressive chronic gastritis, atrophy, heterotrophic hyperplasia	Fu et al[73]
			Stasiewicz and Karpiński[74]
EBV	Oropharynx, blood, lymphatic system and other tissues and organs	Viral proteins inducing methylation, regulating host gene expression and malignant transformation	Yang et al[75]
		EBV driving DNA hypermethylation, frequent PIK3CA mutations, and the overexpression of JAK2, PD-L1, and PD-L2	Iizasa et al[47]
Candida albicans	Skin, oral, gastrointestinal tract	Reduces the diversity and abundance of fungi in the stomach; destroys the mucosal epithelium, produces carcinogens, triggers chronic inflammation, induces Th17 immune responses, among other mechanisms	Yu and Liu[49]
			Zhong et al[50]
Others	Gastrointestinal tract, oral, etc.	Homogeneity and diversity of the gastric microbiota; the inflammatory response; dysbiosis of the gastric microbiota favors invasion and growth of pathogens and disrupts the mucosal barrier	Stewart et al[37]
			Liao et al[76]

EBV: Epstein-Barr virus.

H. pylori

Numerous studies have established H. pylori as a potent risk factor for PLGC, atrophic gastritis, and intestinal epithelial septosis, especially strains carrying the cag pathogenicity island and the cagA oncoprotein. Clinical evidence suggests that H. pylori has an estimated 50% probability of inducing atrophic gastritis or intestinal metaplasia (IM)[38].

H. pylori causes persistent inflammation of the gastric mucosa, constant production of cytokines to recruit immune cells, production of reactive free radicals that may damage host DNA, leading to glandular atrophy and multifocal expansion of enteric areas over time, and a 5 to 90-fold increase in the risk of GC[39].

Microbiota-metabolite interactions are present in the development of GC. During H. pylori infection, cholesterol-rich lipid rafts on the cell membrane may act as adherents to bacterial pathogens or virulence factors. In turn, altered lipid and cholesterol metabolic pathways in the gastric mucosa after H. pylori eradication may be associated with lipid metabolic reprogramming and lipoprotein-mediated cholesterol entry during PLGC[40]. However, the effect of H. pylori eradication on PLGC remains somewhat controversial.

S. anginosus

In a study analyzing 16S rRNA genes from 81 gastric mucosa samples, it was found that Peptostreptococcus_OTU16, Streptococcus_OTU68, Parvimonas_OTU35, Slackia_OTU174, and Dialister_OTU151 exhibited interactions with GC. The organisms under consideration are believed to correspond to Peptostreptococcus stomatis, S. anginosus, Parvimonas micra, Slackia exigua, and Dialister pneumosintes[41]. The emergence and persistence of gastric atrophy and IM were associated with a distinct cluster of oral bacteria, including Peptostreptococcus, Streptococcus, Parvimonas, Prevotella, Rothia, and Granulicatella[42]. The presence of S. anginosus has been identified in esophageal cancer tissues, albeit less frequently in normal tissues[43]. These bacterial species have also been correlated with inflammatory markers in blood samples, reinforcing the notion that oral bacteria such as S. anginosus might play a role in tumor development[44].

EBV

EBV is a ubiquitous γ herpesvirus, mounting evidence suggests its potential etiologic role in GC[45]. EBV-associated GC (EBVaGC) accounts for approximately 10% of all cancer cases and constitutes a distinct clinicopathologic and molecular subtype[46]. EBV is similar to H. pylori by promoting chronic inflammation and increasing tissue damage. Positive cells proliferate after EBV infection, and B lymphocytes in areas of weakened immune surveillance undergo lysogenic infection, causing EBV infection of gastric epithelial cells[47]. New insights into the mechanism of EBVaGC production are thought to include amplification of chr 9p24.1 (JAK/PD-L1), regulation of methylation and cellular autophagy, EBV lytic cycle reactivation, EBV-miRNA, exosomes, and immunosuppression[48]. Specific mechanisms and characterization of cancer genomic profiles need to be further explored.

Candida albicans

C. albicans is an opportunistic pathogenic fungus that infects immunocompromised hosts, including precancerous states. C. albicans infection increases host susceptibility to cancers such as oral, gastric, and colorectal cancers[49]. C. albicans produces carcinogenic nitrosamines, induces dysbiosis of mucosal bacterial flora, triggers chronic inflammation (including Th17 cell-mediated immune responses) and promotes invasive infections[50].

Other microorganisms

In addition to common microorganisms, other microorganisms associated with PLGC include Firmicutes, Bacteroidetes, Proteobacteria, Actinobacteria and Fusobacteria. Gastric microbial imbalances associated with GC can be detected regularly in gastric biopsies. Patients with intestinal-type GC contain more Lactobacillus coleohominis and Lachnospiraceae[51]. However, the effect of H. pylori on the microorganisms of the gastric mucosa still cannot be ruled out, with reduced microbial diversity, altered microbial community structure, and possible negative interactions between H. pylori and other microorganisms[52].

S. ANGINOSUS AND PLGC

S. anginosus at the present stage of research

S. anginosus, also can be called S. anginosus group (SAG) or Streptococcus milleri group, was isolated and first described by Guthof in 1956 from dental abscesses and other inflammatory lesions of the oral cavity[53]. This is a gram-positive coccobacillus found primarily in the oral cavity, nasopharynx, gastrointestinal tract, and vagina, and can cause invasive pyogenic infections such as abscesses. The SAG comprises three species: S. anginosus, Streptococcus constellatus, and Streptococcus intermedius. There are also subspecies such as Streptococcus pyogenes Willie subspecies and Streptococcus constellatus Viborg subspecies.

S. anginosus is more commonly associated with gastrointestinal and genitourinary tract infections, Streptococcus constellatus has a predisposition to respiratory tract infections, and Streptococcus intermedius is the cause of most head and neck infections and central nervous system infections[54-56].

It has been studied in various systems, with the oral cavity being the most studied aspect of it (Table 2). However, it has a unique mechanism of action in the digestive system.

Table 2 Studies on various systems of Streptococcus anginosus.

Primary site	Developing diseases	Mechanism of action	Subsequent effect	Ref.
Oral	Periodontal abscess	Production of bacteriocins enhances membrane permeability, inhibits the growth of associated species, promotes the development of chronic inflammation and abscesses	Dental periapical abscesses	Fisher and Russell[77]
			OIs	Furuholm et al[78]
Respiratory tract	Lung abscess	Inhalation of oral secretions, direct trauma or surgical bedding, adjacent extension, and hematogenous dissemination	Parapneumonic empyema	Gonzalez et al[79]
Esophagus	Esophageal cancer	Correlated with GrzB+ and CD8+T-cell infiltration in tumor tissues	Esophageal squamous cell carcinoma; Barrett's esophagus	Lv et al[80]
				Wu et al[81]
Stomach	Gastric cancer	Spontaneously induced chronic inflammation, atrophy, mucus chemotaxis, and heterogeneous hyperplasia of the gastric mucosa	PLGC	Yang[7]
				Zhou et al[82]
Intestinal tract	Colorectal cancer	Loss of integrity of the blood mucosal barrier forms pus-filled and infected	Adenocarcinoma of the colon	Rawla et al[83]
Liver	Liver abscess	Causes localized suppurative inflammation destroying hepatocytes and surrounding tissues	PLA	Pilarczyk-Zurek et al[55]
				Morii et al[84]
Genitourinary tract	Genitourinary infections	Invades the bloodstream following urinary tract infections; causes lysis of vaginal epithelial cells	Urinary tract infection	Wu and Zheng[85]
			Aerobic vaginitis	Tao et al[86]
Hearts	Pericarditis, endocarditis	Hematogenous dissemination from distant organs	Bacterial pericarditis; infective endocarditis	Finn et al[87]
Cerebrum	Brain abscess, meningitis	Continuous venous dissemination or hematogenous dissemination from a distant site; invasive pyogenic infection	Subdural hemorrhage	Esplin et al[88]
			Intracranial subdural abscess; hydrocephalus	Sakurai et al[89]

OIs: Odontogenic infections; PLGC: Precancerous lesions of gastric cancer; PLA: Pyogenic liver abscess.

S. anginosus causes Lemierre's syndrome, which promotes the cancerous process by inducing inflammation[57]. Sasaki et al[43] found S. anginosus DNA sequences in samples from esophageal dysplasia, esophageal carcinoma and gastric carcinoma tissues, whereas the noncancerous portion of the esophagus only 7% of cases[43].

The study by Meddings et al[58] showed that the most common microorganisms isolated from pus in patients with culture-positive pyogenic liver abscesses were Streptococcus spp. (29.5%)[58]. A retrospective study of patients with pyogenic liver abscesses showed that the most common causative pathogens were SAG (25%), Klebsiella pneumoniae (21%) and Escherichia coli (16%)[59].

SAG has been shown to cross the mucosal barrier of the gastrointestinal tract and metastasize to extragastrointestinal organs, resulting in abdominal implantation. A study by Wenzler et al[60] found that 18 cases (53% of 34 patients) were the source of gastrointestinal bacteremia, which caused tumors[60].

Mechanism of S. anginosus regulating gastric precancerous lesions

The mechanism underlying the role of S. anginosus in the digestive system remains an area of ongoing research. Existing studies have provided some explanation of the mechanism of S. anginosus action in PLGC by genomic analysis of gastric mucosal samples at different stages of GC[44].

S. anginosus has a marked ability to adapt to pH 3-5 environments and can survive in slightly acidic environments[61]. Streptococcal infections are divided into three main phases: Adherence, invasion, and colonization of host tissues. Streptococcus colonization disarms neutrophil extracellular traps consisting of chromosomal DNA and bactericidal proteins, which are released by neutrophils upon stimulation, i.e., interleukin-8 or hydrogen peroxide, to stimulate the inflammatory response to occur. S. anginosus was demonstrated to undergo a rapid acute inflammatory response in the gastric mucosa of mice, stimulating upregulation of pro-inflammatory cytokines, including Ccl20 and Ccl8, leading to severe gastritis or persistent chronic gastritis[62]. The chronic inflammatory response leads to progressive gastric carcinogenesis, including mural cell atrophy, mucoid chemotaxis, and heterogeneous hyperplasia.

The virulence surface factor TMPC of streptococci can bind to ANXA2 on gastric epithelial cells to trigger downstream activation of bacterial attachment, invasion, and oncogenic MAPK signaling[63]. The MAPK pathway activates three subfamilies involved in GC progression: ERK, JNK, and p-38 kinase. Meanwhile, S. anginosus impairs gastric barrier function, as evidenced by a time-dependent decrease in the expression of tight junction markers CLDN18, OCLN, and ZO-1, whose disruption is a hallmark of gastric tumorigenesis[64].

Pre-cancerous infections of S. anginosus may inhibit the growth and colonization of other microorganisms by competing for nutrients, space, or secretion of antimicrobial substances, leading to elevated gastric pH[65]. A significant increase in streptococci in the stomach with gastric sinusitis was accompanied by a decrease in the Aspergillus phylum and an increase in the thick-walled phylum[66]. S. anginosus is a sulfate-reducing bacterium involved in colonic sulfur metabolism, and the differences in bacterial abundance comparing cancerous and noncancerous tissues may indicate that ecological dysregulation occurs in the environment of the PLGC[41]. Thus, gastric flora dysbiosis and microenvironmental disturbances caused by S. anginosus infections are also possible causes of PLGC.

The effect of S. anginosus on the treatment of PLGC

There is no particularly sophisticated test for S. anginosus, which can only be detected by microbial markers using modern novel molecular diagnostic techniques. And there is no definitive diagnosis of PLGC, which is often confirmed by pathology. Therefore, we hope to achieve the detection and treatment of PLGC by detecting and treating S. anginosus.

There are no standard guidelines for the treatment of S. anginosus, and it is mostly controlled and eradicated by dietary changes and medication.

The effect of dietary therapy on S. anginosus remains incompletely elucidated, mainly in the form of dietary adjustments and abstinence from fatty, sweet, and thick flavors, which help patients to improve their immunity and promote PLGC recovery. Dietary modifications do not directly kill S. anginosus and need to be combined with antibiotics or other treatments.

S. anginosus is usually sensitive to penicillin. The minimal inhibitory concentration (MIC) of penicillin G for S. anginosus ranges between 0.03 and 0.06 μg/mL. The mechanism is the down-regulation of penicillin-binding proteins during the stationary phase of growth, resulting in penicillin target deficiency. In addition to β-lactams, glycopeptides, daptomycin, and linezolid have been shown to be useful in the treatment of S. anginosus[67].

In some cases S. anginosus may be relatively insensitive to penicillin, with a MIC of more than 0.1 μg/mL. There are also studies confirming that all SAG are susceptible to vancomycin. Therefore, initial treatment with vancomycin followed by establishing the MIC for penicillin is a safer approach. Beta-lactam antibiotics remain the antibiotic of choice based on penicillin susceptibility testing[68].

Combination therapy with broad-spectrum antibiotics such as ampicillin, gentamicin, and metronidazole has also been suggested as initial empiric therapy. 134/156 (86%) children discharged from the hospital on oral antibiotics were given amoxicillin, amoxicillin clavulanate, or the first-generation cephalosporin cefadroxil, with fair results[69].

However, the use of antibiotics should be accompanied by attention to the effects of the antibiotics themselves on the gastric mucosa. Antibiotics may cause insufficiency of prostaglandin E, which maintains normal regeneration of the mucosa, through nonspecific inhibition of cyclooxygenase activity. Insufficient prostaglandin E may be detrimental to epithelial cell repair, thereby triggering gastric mucosal injury and exacerbating the progression of PLGC[70].

There is no standardized treatment criteria at this stage, and considerable research is still needed at a later stage to confirm and establish a standard accepted normative treatment modality. Meanwhile the effect of some novel modalities, such as fecal transplantation, on gastric mucosal damage caused by S. anginosus is still under study.

CONCLUSION

With the improvement of living standards and the popularization of gastroscopy, the incidence of GC has increased significantly, but the mortality rate has not decreased. PLGC is a critical period. Most microorganisms affect the development of PLGC. The effect of H. pylori is limited, and other microbiota, such as S. anginosus, promote the development of PLGC with new research progress. Therefore, we synthesize the relationship between microorganisms and PLGC, especially the possible mechanisms by which S. anginosus causes PLGC. It was found that eradication of S. anginosus infections by adopting a positive diet and antibiotic treatment is expected to prevent PLGC. However, because of the few studies, a large number of animal studies and clinical trials are still needed to confirm the association and the specific mechanism of action.

ACKNOWLEDGEMENTS

We gratefully acknowledge the kind cooperation of all authors in the preparation of this paper.