Introduction

The human intestinal mucosa can be divided into three parts according to structure: epithelial cells, lamina propria, and muscularis mucosa, which are colonized by approximately 1014 populations of microorganisms (Zhang et al. 2015), including bacteria, fungi, and viruses (Dicks et al. 2018). Among them, the number of bacteria exceeds those of other intestinal microbes (Kim and Jazwinski 2018), including more than 1000 types of bacteria, such as Firmicutes, Bacteroides, Actinobacteria, Vibrio, Fusobacterium, Proteobacteria, and Verrucobacteria (Stitaya Sirisinha 2016). The diversity and total amount of the gut microbiota were related to environmental bacteria, eating habits, exercise, stress, aging, intake of probiotics/prebiotics, treatment with antibiotics or other drugs, host immune system, and genetic factors of the patients (Kataoka 2016). Current studies have found that the gut microbiota can protect the human body by helping in the digestion and synthesis of vitamins, thereby further resisting pathogen colonization (Hartmann et al. 2019), and changes in these mechanisms can cause diseases (Thursby and Juge 2017). Presently, several studies have shown that “microbiota dysregulation” is related to digestive tract diseases, such as inflammatory bowel disease (Lehmann et al. 2019), irritable bowel syndrome (Halkjær et al. 2018), liver cirrhosis (Bajaj et al. 2018), and gastrointestinal malignancies (Gunathilake et al. 2019). Furthermore, several studies have estimated the composition of the gut microbiota using fecal specimens (Bagga et al. 2018; Jin et al. 2020). In the past few decades, with the rapid development of deep sequencing technology, especially 16S rRNA sequencing, genomics, and bioinformatics (Chen et al. 2019), the relationship between the gut microbiota and human diseases has become more clearer (Seifert et al. 2019). A set of evidence has shown that microorganisms may cause tumors by promoting inflammation, immune response changes, special protein activation, and carcinogenic metabolite production. However, clarifying the relationship between the gut microbiota and tumors is important for developing targeted tumor therapies.

The human gastrointestinal tract (GIT) has the most abundant bacteria, and its total genomes are 100 times more than host genomes among the digestive tract flora (Thursby and Juge 2017). Studies on gut microbiota disorders and colorectal cancer have been conducted (Liu et al. 2020). Furthermore, in our research, we have found that Clostridium difficile is enriched in the intestinal flora of patients with cancer, and 20.5% of C. difficile colonization is toxigenic in patients with cancer (Fang et al. 2014). In 2016, we explored the relationship between C. difficile and colorectal cancer (Zheng et al. 2017). However, few studies have focused on gastric cancer; recent studies have found that some gut microflora disorders may be correlated with the occurrence of gastric cancer (Hunt et al. 2015; Yu et al. 2020). Recently, we had collected more than 227 fecal samples and performed 16S rRNA to analyze their intestine flora composition (Zhang et al. 2021). The intestinal flora in patients with gastric cancer and healthy individuals were different, and we found that the gut microbiota composition and diversity shifted in patients with gastric cancer; thus, we predicted that a series of microbiota may play a significant role in tumorigenesis and the development of gastric cancer. In this review, we present possible mechanisms to the association between the intestinal microbiota and tumors. The incidence of gastric cancer was ranked fifth among all tumors, and the mortality rate was ranked second (Venerito et al. 2016). Therefore, studying the relationship between gastric cancer and the gut microbiota is worthwhile in clinical diagnosis. Furthermore, from the anatomical perspective of the digestive tract system, the gastric physiological anatomy lies between the esophagus and intestines, and the gut microbiota of the esophagus and intestines may be correlated with gastric cancer. This review summarized the main types and correlation of gut microbiota in gastric cancer, esophageal carcinoma, and small intestine cancer.

Composition of gut microflora regulating cancer development

Inflammatory reaction

Inflammation is a recognized risk factor for various cancers, including gastrointestinal cancers (Arthur et al. 2012). Several studies have found that digestive tract bacteria could induce DNA damage and release of inflammatory mediators by toxins, which are usually a direct contributing factor of cancer occurrence (Tsilimigras et al. 2017). For example, toxin cytotoxin-associated gene A (CagA) in Helicobacter pylori could cause DNA injury in gastric cancer after co-action with host-mediated reactive oxygen species (ROS), inflammatory mediators, and growth factors (Nardone et al. 2017). In addition, some inflammatory factors and related mediators released during the inflammatory response, such as interleukin 6 (IL-6), tumor necrosis factor-alpha (TNF-α), and IL-23, not only aggravate the inflammatory response but also weaken the barrier, increasing the reaction between microorganisms and the host, which ultimately causes cancer (Schwabe and Jobin 2013).

Immune reaction

A series of studies have shown that the host immune system is the key to controlling carcinogenesis in the digestive tract (Tilg et al. 2018). In addition to affecting the local immunity in the mucosa of the digestive tract, the gut microbiota can also initiate a systemic immune response through immune cells (Gopalakrishnan et al. 2018). For example, certain microorganisms in the colonic flora may cause host responses through Th17 cells, which stimulate excessive immune responses, promoting colorectal cancer (Kong and Cai 2019). In addition, studies have found that excessive Fusobacteria in the gut microbiota causes inflammation. The activation of the necrosis factor-kappa B (NF-kB) signaling pathway and T cell-mediated adaptive immune response was also associated with the occurrence of colorectal cancer (Weng et al. 2019).

Specific protein activation

Some microorganisms have host pathway proteins that can participate in carcinogenesis, which can directly regulate cell polarity and growth or participate in cell proliferation, survival, and migration through certain signal transduction pathways to induce tumorigenesis (Garrett 2015). For example, H pylori could enter various cancer-related pathways through its vacuolar cytotoxin (VacA), including the Wnt β-catenin signaling pathway, PI3K/Akt signaling pathway, ERK pathway, and VEGF pathway (Zhang et al. 2019).

Carcinogenic metabolite production

Certain microorganisms in the digestive tract flora could interfere with the physiological functions of the body to produce certain compounds and promote the carcinogenic effects of endogenous or exogenous mutagens. For example, certain bacteria in the intestinal tract can interact with 7α-hydroxyl in the bile acid to produce cytotoxic 7α-dehydroxylation (deoxycholate and gallstone). These compounds can accelerate the carcinogenic effect of mutagens to promote cell proliferation and adenoma growth (Parsonnet 1995). In a study on bile acid and vitamin D cycle, Elizabeth T et al. have found that the occurrence of colorectal cancer is related to the long-term action of lithocholic and deoxycholic acids, the secondary products of bile acid metabolism (Jacobs et al. 2016).

Gut microbiota in gastric cancer

Gastric cancer is anatomically divided into gastric adenocarcinoma and gastroesophageal junction adenocarcinoma, with adenocarcinoma having the highest incidence (Wroblewski and Peek 2016), and histologically divided into the diffuse (undifferentiated type) and intestinal (well-differentiated type) types (Van Cutsem et al. 2016). In recent large-scale studies on the molecular subtype of gastric cancer, the four subtypes have been defined at the genome, transcriptome, and proteome levels(Smyth et al. 2016), but analysis on the gut microbiota in the different types of gastric cancer is limited.

H. pylori

H. pylori is a common bacterial pathogen affecting more than half of all populations worldwide. It can cause gastric and duodenal ulcers. H. pylori infection associated with CagA causes severe gastric cancer due to severe inflammation (Kamboj et al. 2017). Yan-yan Shi et al. have found that CagA in H. pylori can promote cell proliferation, migration, and invasion by inducing an increase in the expression of miR-543 and inhibit autophagy, ultimately leading to epithelial–mesenchymal transition (EMT) (Shi et al. 2019). Most scholars in the study of H. pylori have found that the infection rate of H. pylori is consistent with the incidence of gastric cancer (Amieva and Peek 2016), among whom Yang Guo et al. (2020) has found that H. pylori infection is an important cause of gastric cancer, and eradicating H. pylori can help restore the gastric microbiota to a similar status as found in uninfected individuals (Guo et al. 2020). Besides, some studies have attempted to reduce the incidence of gastric cancer by radically curing H. pylori (Leja et al. 2017). However, in fecal flora, two results were observed: Sarah Talarico et al. (2018) have found that the DNA content of H. pylori in the stool of patients with gastric cancer was six times that of normal people (Talarico et al. 2018), whereas Weiren Liang et al. (2019) have found that H. pylori is not highly expressed in the sequencing of stool flora of patients with gastric cancer patients (Liang et al. 2019).

Shigella spp.

Shigella spp. is a Gram-negative bacillus, composed of Shigella dysenteriae, Shigella flexneri, Shigella boydii, and Shigella sonnei, which can cause bacillary dysentery (Ashida et al. 2009). Shigella spp. can break through the epithelium of the digestive tract, be phagocytosed by macrophages, then activate the type III secretion system, and inject the invading plasmid antigens IpaB, IpaC, and IpaD into the cytoplasm, eventually causing the death of macrophages and the secretion of IL-1, resulting in inflammation (Xu et al. 2019). Liang et al. (2019) have sequenced 20 patients with gastric cancer and 22 healthy persons and found that the abundance of Shigella spp. was significantly increased in patients with gastric cancer compared with that in healthy individuals (Liang et al. 2019).

Lactobacillus spp.

Lactobacillus spp. is a diverse and heterogeneous phylogenetic acid-producing bacterial species (Goldstein et al. 2015), mainly distributed in the GIT (from the oral cavity to feces) and skin (Heeney et al. 2018). Lactobacillus spp. mainly increases N-nitroso compounds and ROS to induce pluripotency to increase EMT and promote non-pyloric (Vinasco et al. 2019). The four aspects of Helicobacter carcinogenic pathway colonization and enhanced production easily promote angiogenesis and the expression of proto-oncogenes, inhibit cell apoptosis, and induce DNA damage and immune tolerance, and its anti-H. pylori microbial properties eventually lead to tumorigenesis (Vinasco et al. 2019). Qi et al. (2019) have sequenced the gut microbiota of 116 patients with gastric cancer and found that the gut microbiota of patients with gastric cancer was abundantly enriched. They have suggested using Lactobacillus spp. as one of the specific indicators for early diagnosis of gastric cancer (Qi et al. 2019). In addition, Eun et al. (2014) have found the same finding in sequencing gastric tissue of patients with gastric cancer (Eun et al. 2014). In our previous study, we have obtained the same results, and we supposed that it can clearly distinguish patients with gastric cancer from healthy individuals (Zhang et al. 2021).

Atopobium spp.

Atopobium spp. belongs to the Coriobacterium family and is a strictly anaerobic microorganism that can produce a large amount of lactic acid (Mendling et al. 2019). Its pathogenic mechanism may be similar to Lactobacillus spp. Wu et al. (2020) have found that the abundance of exotic bacteria in stool samples from 134 patients with gastric cancer was significantly higher than that in stool samples from healthy individuals (Wu et al. 2020). In addition, Atopobium spp. can also be promoted to detect in blood specimens from patients with gastric cancer (Yoon-Keun Kim 2020).

Megasphaera spp.

Megasphaera spp. is a type of anaerobic Gram-stain-negative cocci, which mainly exist in the stomach of cattle and sheep and the feces and intestines of humans (Marchandin et al. 2015). Its role in the digestive tract is mainly fermentation of glucose, fructose, and lactic acid, and the production of large amounts of lactic acid can lead to neurotoxicity (Shetty et al. 2013). Wu et al. (2020) have also found an increase in Megasphaera spp. in the stool of patients with gastric cancer (Wu et al. 2020). Our previous study has also drawn the same conclusion that Megasphaera spp. can better differentiate patients with gastric cancer from healthy individuals (Zhang et al. 2021). Sun et al. (2018) have found that the oral flora of patients with gastric cancer is abundant in Megasphaera spp. in a study involving 37 patients with gastric cancer and 13 healthy controls (Sun et al. 2018).

Streptococcus spp.

Streptococcus spp. is a class of Gram-negative catalase-negative cocci. Different types of Streptococcus spp. are often found as symbiotic bacteria on mucous membranes. Although the asymptomatic colonization rate of Streptococcus spp. was less than 5%, Streptococcus agalactiae could colonize in the urogenital tract and GIT by toxin-mediated and immune-mediated disease mechanisms at a rate of 10–30% (Spellerberg and Brandt 2015). Cihua Zheng et al. (2019) have found that Streptococcus spp. in the gut microbiota of patients with gastric cancer is more abundant than that in the gut microbiota of healthy populations (Zheng et al. 2019). However, this may not be found in gastric biopsies. On contrary, Yang et al. (2016) have found that Streptococcus spp. and Neisseria spp. strains were detected only in low-risk populations compared with high-risk populations from different regions, but found that there might be differences in location distribution among populations in areas high risk of gastric cancer (Yang et al. 2016), suggesting differences in the distribution of this species and population residence.

Veillonella spp.

Veillonella spp. is a Gram-negative oxidase-negative anaerobic bacterium and mainly exists in the oral cavity, genital tract, respiratory tract, and intestines of humans and animals. Veillonella spp. can cause severe human infections, such as endocarditis, osteomyelitis, and artificial joint infection (Carlier 2015). In the study by Qi  et al. (2019), among 116 patients with gastric cancer in the Shanxi Province, Lactobacillus spp., Streptococcus spp., and Veillonella spp. showed good expression compared with healthy subjects (Qi et al. 2019).

Prevotella spp.

Prevotella spp. is an anaerobic Gram-negative microorganism belonging to the Bacteroides phylum. It has a large number of colonization features and low pathogenicity. It is a type of bacteria prone to cause non-H. pylori infection. Its dysfunction in the GIT is associated with inflammation (Ley 2016), characterized by an increase in helper T-type 17 (Th17), inhibition of IL-1 and IL-2, and production of interferon-c cytokine (Larsen 2017). Wu et al. (2020) have found that Prevotella spp. in the intestine flora of patients with gastric cancer has a good diagnostic value compared with that in the intestine flora of healthy people (Wu et al. 2020). In gastric biopsies, Gunathilake et al. (2019) have also found that Prevotella carriers have a higher risk of gastric cancer than non-carriers after sequencing samples from 268 patients with gastric cancer and 288 healthy controls (Gunathilake et al. 2019).

Clostridium spp.

Clostridium spp. is a large group of Gram-positive anaerobic or slightly aerobic Bacillus strains belonging to the Firmicutes phylum (Rainey 2015). Genome sequencing confirmed that this organism contains all genes needed for glycolysis, by which only polysaccharides could not be degraded (Dürre 2016). Clostridium spp. produces toxic factor adhesion A on the cell surface, which binds to E-cadherin on endothelial cells and regulates the cadherin or b-catenin pathway, which enhances the release of transcription factors, oncogenes, and inflammatory genes. In addition, it could also affect the growth and cell proliferation of epithelial cells (Vandana 2020). Liang et al. (2019) have found that the abundance of Clostridium spp. in the gut microbiota of patients with gastric cancer significantly increased compared with that in the gut microbiota of healthy individuals (Liang et al. 2019). Additionally, Hsieh et al. (2018) have found the expression of Clostridium spp. shuttle in gastric cancer tissue from a gastric biopsy performed on patients with gastric cancer in Taiwan (Hsieh et al. 2018). In addition, we have also found the colonization of C. difficile in stool samples from patients with colorectal cancer, and then we revealed several risk factors of C. difficile colonization in Chinese patients with colorectal cancer (Zheng et al. 2017).

Gut microbiota in esophageal carcinoma

Esophageal cancer can be divided into esophageal adenocarcinoma (EAC) and esophageal squamous cell carcinoma (ESCC) according to different histological types. Among them esophageal cancer histological types, ESCC is the most common, accounting for approximately 90% (He et al. 2020). The current clinical analysis of esophageal cancer flora was mainly conducted by biopsy analysis of the esophageal site and the measurement of fecal flora less.

Escherichia coli

E. coli is a member of the Enterobacteriaceae family and is the most common symbiotic bacteria in the GIT of humans and warm-blooded animals. It is mainly based on the serological identification of O (lipopolysaccharide) and H (flagella) antigens to perform a preliminary classification and then divide into pathogenic and non-pathogenic types according to the types of virulence factors that exist and the clinical symptoms of the host. It can cause enteritis, urinary tract infection, sepsis, and other clinical infections (Allocati et al. 2013). Currently, studies have found that most E. coli strains contain polyketide synthase pathogenicity islands encoding colicin. The colicin produced by E. coli can induce oxidative stress, break double-stranded DNA, and interact with growth factors (e.g., hepatocyte growth factor) to cause cell senescence and tumorigenesis (Lopès et al. 2020). Besides, in our early study on E. coli, we found that E. coli topoisomerase I (TopA) plays an important role in disease development. TopA may provide a direct biochemical link between the TopA cleavage complex-mediated cell killing and the iron-mediated cellular oxidative damage (Lu et al. 2011). Cheung et al. (2020) have found significant enrichment of Enterobacterin stool specimens of mice with esophageal cancer (Cheung et al. 2020). In addition, Panebianco et al. (2018) have found that E. coli significantly increases in esophageal tissue microbes of rat models of EAC compared with healthy mice, this study believed that E. coli induces EAC by upregulating the expression of LRs 1–3, 6, 7, and 9 (Panebianco et al. 2018). Besides, another study by Mime et al. (2017) supports this view (Mima et al. 2017).

Prevotella spp.

Li et al. (2020) have compared the fecal microflora in 13 patients with esophageal squamous carcinoma and 49 healthy subjects and found that Prevotella spp. significantly increased in patients with ESCC compared with that in healthy subjects (Li et al. 2020). In addition, Peters et al. (2017) have found similar findings in oral flora samples of 25 patients with ESCC and 50 matched healthy controls (Peters et al. 2017). Furthermore, Liu et al. (2018) have reported that Prevotella spp. could be used as markers for early diagnosis and prognosis evaluation of ESCC (Liu et al. 2018).

Clostridium spp.

In addition, the study by Li et al. (2020) has reported that patients with esophageal cancer have significantly different abundance in Clostridium spp. compared with healthy individuals. In the esophageal tissue, Dariush Nasrollahzadeh and Donghang Li have found that the abundance of Clostridium spp. in patients with ESCC were significantly different from that in healthy individuals (Li et al. 2020; Nasrollahzadeh et al. 2015).

Bacteroides fragilis

Bacteroides fragilis is a common anaerobic bacteria belonging to the Bacteroides phylum. It consists of 80% of human intestinal microflora combined with the Firmicutes phylum (Valguarnera and Wardenburg 2020). According to toxicity differences, they can be classified into non-toxigenic B. fragilis (NTBF) and enterotoxigenic B. fragilis (ETBF). Nowadays, in many studies on the carcinogenesis mechanism of B. fragilis in colon cancer, researchers have believed that B. fragilis can destroy close junctions and increase the permeability of the digestive tract by producing toxins, eventually resulting in inflammation and tumorigenesis (Cheng et al. 2020). Li et al. (2020) have observed the abundant expression of B. fragilis in fecal specimens from patients with esophageal carcinoma compared with healthy controls (Li et al. 2020).

Bacterial flora in small bowel carcinoma

The small intestine is a special organ, rarely a site of malignant or even benign tumors. Presently, more than 40 histological subtypes have been identified. Approximately 30–45% of small bowel cancers are adenocarcinomas, 20–40% are neuroendocrine tumors, 10–20% are lymphomas, and 10–15% are sarcomas (Rondonotti et al. 2018). Although the small intestine accounts for more than 90% of the GIT, the proportion of small bowel cancers among gastrointestinal tumors is only 3% (Pourmand and Itzkowitz 2016). The global incidence rate of small bowel cancers is lower than 0.001% and fluctuates between 0.0003% and 0.002% (Schottenfeld et al. 2009), which may be related to the spatial relationship between the host and microorganisms in the small intestine. Current studies have found that the number and diversity of bacteria in the proximal intestine are less than those of the bacteria in the colon, and the nature of their physical interaction with the host is also different. The epithelial-derived antibacterial factors in the small intestine can maintain the balance of the flora by restricting the growth of bacteria, which may be related to the low incidence of small intestine cancers (Moran et al. 2015). Moreover, in a recent study, Kadosh et al. (2020) has found that the small intestine can convert back mutated p53 to normal p53 (Kadosh et al. 2020). These factors may jointly reduce the incidence of small bowel cancer. Therefore, there is little clinical research on small bowel cancer.

Gut microbiota of precancerous lesions and its application in therapy

The precancerous stage of lesions is a significant period for clinic treatment. Access to and the combination of specific precancerous gut microbiota can accelerate the accuracy of diagnosis of cancers.

Gastric cancer

Precancerous lesions in gastric cancer can be divided into four groups: atrophic gastritis, intestinal metaplasia, gastric mucosal hyperplasia (diffuse or focal-polypoid), and peptic (or gastric) ulcer (Rugge et al. 2013). In clinical practice, acquiring stool samples for these lesions because patients will not be hospitalized for their symptoms are slight.

Gao et al. (2018) have found that phyla of fecal microbiota in patients with gastritis are different from those in normal subjects. They found that the Bacteroidetes family is decreased and the Firmicutes family is increased in patients with gastritis. In addition, Bacteroidetes also decreased in patients with metaplasia, and the average relative abundance of Enterobacteriaceae, a member of the Proteobacteria family, increased in both gastritis and metaplasia (Gao et al. 2018). In our published study, we analyzed fecal specimens from patients with gastritis. We found no difference in diversity between patients with gastritis, and they showed the same gut microbiota characteristics. However, the bacterial communities did not overlap completely between gastritis and gastric cancer. The bacterial phyla, Verrucomicrobia, Chloroflexi, and Acidobacteria, and genera, Bifidobacterium, Anaerococcus, Finegoldia, and DA101, accumulated in patients with gastric cancer, but not those with gastritis. However, the abundance of the genera Dorea and Bacteroides was rich in patients with gastritis, but not in patients with gastric cancer (Zhang et al. 2021).

In terms of gut microbiota treatment, an experiment in Taiwan has shown that the eradication of H. pylori can decrease the incidence of gastric cancer and related precancerous lesions (Chiang et al. 2020).

Esophageal carcinoma

Currently, Barrett’s esophagus is considered a precancerous lesion of esophageal carcinoma (Rustgi and El-Serag 2014). Due to the original anatomical position of the esophagus, researchers usually use the esophageal or oral microbiota, instead of the gut microbiota, to clarify the relationship between microbiota and esophageal carcinoma.

Deng et al. (2021) have collected fecal samples from 23 patients with esophageal carcinoma and found that Lachnospira spp., Bacteroides spp., Streptococcus spp., and Bifidobacterium spp. were good biomarker candidates. These findings demonstrated that the aforementioned biomarker candidates have a good discrimination capability between healthy individuals and patients with esophageal carcinoma (Deng et al. 2021).

Currently, no mature trial exists that used microbiota to cure or decrease the incidence of esophageal carcinoma. In the field of esophageal microbiota exploration, researchers have found that Porphyromonas gingivalis (P. gingivalis) in the esophageal epithelium of patients with ESCC may be associated with the severity and poor prognosis of esophageal cancer (Gao et al. 2016). In addition, this finding has been also observed in oral samples of patients with esophageal cancer (Peters et al. 2017).

Correlation between the gut microbiota and gastric, esophageal, and small bowel cancers

Based on the analysis of the digestive tract flora of patients with gastric, esophageal, and small intestine cancers in the past 5 years, this study found that H. pylori, Shigella spp., Lactobacillus spp., Atopobium spp., Macrococcus spp., Streptococcus spp., Veillonella spp., Prevotella spp., and Clostridium spp. may be related to the development of gastric cancer. In esophageal cancer, studies have considered that E. coli, Prevotella spp., Clostridium spp., and B. fragilis are related to the occurrence of esophageal cancer (Table 1). The incidence of small intestine cancer is low due to the particularity of the small intestine structure and other reasons; thus, clinical studies on the digestive tract flora of patients with small intestine cancer are limited.

Table 1 Studies of intestinal microecological sequencing analysis in gastric cancer and esophageal cancer
Full size table

It is easy to observe that the occurrence of gastric cancer has a certain degree of similarity with that of esophageal cancer, which is manifested by the increase in Clostridium spp. and Prevotella spp. This situation may be similar to the above, and the microbial preference of the digestive tract is related (Gall et al. 2015). It is estimated that approximately 1011 bacterial cells flow from the oral cavity to the stomach daily, and the microbial composition overlaps along the oral cavity, pharynx, esophagus, and intestines. However, few studies have focused on the similarity in microbial composition among upper digestive tract organs. In addition, from the physiological anatomical position and physiological function of the esophagus, it could be assumed that the esophagus plays an important anatomical role in transferring the digestive mass from the oral cavity to the stomach and receiving reflux from the stomach. Simultaneously, the three functions of esophageal stenosis can lead to the retention of residual food and microorganisms, which may increase the risk of invasive cancer or esophageal lesions (Dong et al. 2018). Moreover, from digestive tract flora richness, it is believed that no bacteria could survive in the inhospitable stomach environment except H. pylori. This may be associated with higher intragastric pH values and a decrease in acidity in patients with gastric cancer (Spiegelhauer et al. 2020). Enzymes in gastric juice often play an effective role in low-pH environments, and the ability of the gastric juice to inactivate microorganisms mainly depends on the hydrochloric acid content. Therefore, lower acidity may increase the type and quantity of gastric microflora (Martinsen and Waldum 2019).

Finally, few clinical studies have focused on the gut microbiota of patients with small bowel cancer. The short residence time of the digestive mass in the small intestine reduces the probability of microbial colonization and the role of the intestinal mucosal flora in resisting pathogens (Dethlefsen et al. 2006).

Perspective

Gastrointestinal microflora is an environmental factor closely associated with gastrointestinal tumors occurring recently (Sommer and Bäckhed 2016). Along with the widespread application of 16S rRNA sequencing technology, the relationship between the gut microbiota and cancer is gradually becoming clear. The discovery of this relationship may contribute to the prevention and treatment of cancer, offers new ideas for cancer diagnosis in addition to traditional markers, provides the possibility of targeted therapy, and improves the prognosis and survival of patients. However, two problems remain: one is that studies lack a description of the feedback mechanism between gastric flora and the gut microbiota. The other one is that current clinical studies usually only analyze the gut microbiota of patients with a single digestive tract cancer while ignoring interactions between microbial communities and the physiological functions of local host microorganisms in the digestive tract.

Currently, gastric and colorectal cancers are widely studied with gastric cancer being a high-incidence malignant tumor whose flora has been studied by researchers for nearly 5 years. However, current studies on the gut microbiota of patients with gastric cancer have the aforementioned limitations; that is, they only analyze the flora of gastric cancer itself and do not consider the comprehensive analysis, and most studies have not defined the locations of gastric cancer, such as those in antrum carcinoma, cardia cancer, and gastric body cancer. In addition, the traditional clinical screening index, H. pylori, is currently used in the diagnosis of gastric cancer but is not mentioned in the early diagnosis and treatment manual for gastric cancer by the Chinese Society of Clinical Oncology published in 2019 (Wang et al. 2019).

In the future, the mechanism of the gut microbiota and flora is a key research orientation. Furthermore, the bacterial flora of patients with gastric cancer can be analyzed by histological classification or anatomical location classification, which, combined with relative cancers in other organs of the digestive tract, could determine the highly specific flora in gastric cancer. In addition, transcriptomics and metabolomics methods can help explore the pathogenic mechanisms of these microorganisms.