Gastric tumors have been divided based on their location—cardiac and distal. The former refers to the small paracardial area, while the latter refers to the rest of it. The most popular classification in terms of histology is the Laurén classification, which distinguishes between two types of gastric cancer (GC)—intestinal and diffuse. The first GC subtype is often associated with Helicobacter Pylori and lifestyle, which includes a high intake of table salt and alcohol, a low supply of fruits and vegetables, or smoking. It is estimated that about 15–20% of tumors do not fall under Laurén’s classification and are, therefore, considered intermediate tumors. Clinically, GC can also be divided according to its early or advanced stage. Early gastric cancers refer to small tumors (2–5 cm) that take the form of invasive carcinoma of the gastric mucosa or submucosa. Detection of lesions at their early stage is associated with relatively good survival.
1. Helicobacter Pylori as a Carcinogen
A constant object of research by scientists is the link between bacterial infections and cancer. Although the topic is quite controversial, at this point, it is known that
Helicobacter pylori promote the development of GC. The cancer process is a multi-year, multi-stage process that most often begins with chronic gastritis. The vast majority of GC cases are associated with
Helicobacter pylori infection (about 60%)
[1][2], which is classified as a Gram-negative bacterium, and its natural site of occurrence is the surface of gastric mucosal epithelial cells. Infection with the bacterium of the
Helicobacteraceae family is believed to occur as early as childhood, which explains the reduced ability of gastric mucosal lining cells to produce hydrochloric acid with age. Moreover, it is estimated that more than 50% of people worldwide are infected. Undoubtedly, a peculiar feature of
Helicobacter pylori is its ability to colonize the stomach for decades, as well as its ability to provide appropriate adaptive conditions surrounding the pathogen by producing large amounts of urease. This enzyme contributes to the degradation of urea to carbon dioxide and ammonia, which, in turn, increases the pH in the stomach due to a previous reduction in hydrochloric acid secretion
[1][2][3][4].
The International Agency for Research on Cancer (IARC) and the World Health Organization (WHO) have recognized
Helicobacter pylori infection as an important type I carcinogen in the development of GC, but the pathomechanism of the bacterium’s effect on gastric cancer progression is not fully understood, due to the multilevel impact of the pathogen. However, it is known that
Helicobacter pylori is associated with superficial gastritis and associated inflammation, and this, in turn, promotes a predisposition to gastric ulcers and adenocarcinoma. The literature data indicate that the bacterium of the genus
Helicobacteraceae contributes to structural changes in the gastric epithelium, thereby causing abnormalities in its function. The above course appears to be crucial in the initial stages of carcinogenesis. The process of progression of gastric and duodenal ulceration is initiated by inflammation caused by
Helicobacter pylori followed by a decrease in the number of D cells responsible for the production of somatostatin, which, in turn, acts as a somatoliberin antagonist. As a result, there is an increased secretion of hydrochloric acid, which is induced by the hormone produced by G-cells in the gastric body—gastrin
[2][3][4][5].
This is because it is emphasized that gastric cancer of the intestinal type is the domain of people of the African race. In contrast, GC with the proximal location of the tumor is the domain of people of the Caucasian race. In addition, it has been proven that environmental factors, as well as lifestyle, play key roles.
Helicobacter pylori is an important factor in increasing the risk of developing GC, and a meta-analysis conducted by Hooi et al. in 2017
[6] stresses that the highest incidence of the carcinogenic pathogen is found in Africa, Latin America, the Caribbean, and Asia. The lowest incidence, on the other hand, was attributed to North America and Oceania. The reasons for the above geographical distribution in terms of
Helicobacter pylori incidence are attributed to socioeconomic factors, such as the level of urbanization, access to clean water, sanitation, professional education, and environmental awareness. Analyses of the prevalence of infection with the pathogenic bacterium should take into account the fact that populations are sometimes mixed, which can affect the statistics. Nevertheless,
Helicobacter pylori infection is often transmitted via the fecal-oral route, so in developing countries without access to clean water, failure to practice proper hygiene, as well as limited access to medical care, may contribute to a higher incidence of infection compared to developed countries
[6][7].
2. Gastric Microbiota
Scientific reports relating to the presence of
Helicobacter pylori in the gastrointestinal tract have sparked greater interest in the stomach microbiota as a so-called “ecological niche.” It turns out that the stomach environment is populated by bacteria with a high degree of diversity, and their density is estimated at 10
1–10
3 CFU (colony-forming units). Studies of the gastric microbiota are inconclusive. In terms of GC development, the potential role of
Lactobacillus and
Lactococcus bacteria is highlighted. The theoretical causal relationship is seen in their fermentation end product, lactic acid. Most likely, lactate may contribute to tumor progression and enhance angiogenesis. In addition to
Lactobacillus and
Lactococcus bacteria, attention is also drawn to
Nitrospirae bacteria, which are observed in people with GC. There is no doubt that an inadequate diet plays a key role in cancer progression. Thus, in the case of GC, the carcinogenic importance of nitrates, ubiquitous in smoked and cured products—mainly meat—which can consequently lead to the synthesis of N-nitroso compounds, is emphasized. Bacteria of the
Nitrospirae type are involved in the metabolic transformation of nitrates and nitrites, so attention is drawn to the carcinogenic role of N-nitrosamines produced by the described pathogen, which may explain their presence in the stomach of GC patients
[4][8][9][10].
On the other hand, it is emphasized that chronic
Helicobacter pylori infection provides a friendly environment for the growth of new bacteria, through reduced secretion of hydrochloric acid. A study conducted on mice clearly shows that
Helicobacter pylori-infected rodents with concomitant hypergastrinemia have a more complex gastric microbiota in GC compared to healthy animals. A study by Ferreira et al.
[5] showed that patients with chronic gastritis were characterized by increased amounts of bacteria such as
Helicobacter, Streptococcus, Prevontella, and
Neisseria, regardless of the presence of
Helicobacter pylori infection. In contrast,
Citrobacter, Clostridium, and
Lactobacillus were observed in patients with achlorhydria and GC. In addition, the authors of the study highlighted the role of
Citrobacter rodentium in the process of epithelial cell proliferation, which, in turn, promotes the development of colon tumors in rodents with a genetic load for CC
[5]. A 2016 study by Wang et al.
[10], on the other hand, found an increased abundance of
Escherichia-Shigella in GC patients. The researchers also highlighted the potential genotoxic effects of
E. coli in the development of gastric cancer
[10].
3. Gut Microbiota and Gastric Cancer
Each year, the number of published papers in the field of gut microbiota and its impact on the host body increases. According to current knowledge, the microbiota of the lower gastrointestinal tract is the most complex and dynamic ecosystem in the human body. It is well known that intestinal dysbiosis has a positive correlation in the aspect of colorectal cancer
[11][12][13]. At the time of editing this paper, online database search engines displayed access to a few papers relating to the gut microbiota in the aspect of gastric cancer, which may be due to the limitations and analytical difficulties of the microbiome of this section of the gastrointestinal tract. However, there is no doubt that this topic is becoming an increasing object of interest, due to the desire to understand the pathomechanism of the development of malignant neoplasms, which are among the leading causes of death, and to develop chemoprevention methods. Nevertheless, already several years ago, there were the first firm claims that changes in the intestinal microbiome in the gastrointestinal tract may have a significant impact on the development of gastric cancer
[14]. It has also been pointed out that a higher abundance of
Enterobacteriaceae is associated with all types of gastric cancer, which could potentially be useful as a marker of gastric cancer
[15]. It is also worth noting the mechanism by which the microbiota influences carcinogenesis. Chronic inflammation and infections are important causes of gastric cancer development due to carcinogenic mechanisms, such as inducing mutations and altering gene status, promoting angiogenesis and cell proliferation
[16]. The dysbiosis microbiota and its metabolites affect carcinogenesis not only by inducing inflammation and immune dysregulation, leading to genetic instability but also by interfering with drugs used in anticancer therapy
[17].
One effective method of GC prevention is
Helicobacter pylori eradication. Unfortunately, its adverse consequences include an impact on the disruption of the gut microbiota. Individuals with a history of
Helicobacter pylori infection showed a decreased abundance of
Bacteroidetes and increased
Firmicutes and
Proteobacteria [11]. In contrast, those infected with
Helicobacter pylori and simultaneously suffering from the aggressive gastric disease had markedly lower abundances of several
Bifidobacterium species in the lower intestine, indicating a reduced abundance of protective bacteria
[18]. Another study noted an association between
Helicobacter pylori infection and the abundance of bacteria from the genera
Enterococcus,
Lachnoclostridium,
Tyzzerella,
Roseburia,
Butyricicoccus,
Dorea, Halomonas, and
Burkholderiales. Moreover, an association has been observed between intestinal dysbiosis and the incidence of obesity and older age
[19]. In turn, other sources indicate that successful eradication of
Helicobacter pylori potentially restores the gastric microbiota to a state similar to that found in uninfected individuals and has been shown to have beneficial effects on the gut microbiota
[20].
Clinical studies have noted an altered gut microbiota during the perioperative period. In the intestinal microbiota of GC patients, a higher abundance of
Escherichia/Shigella,
Veillonella, and
Clostridium XVIII and a lower abundance of
Bacteroides were observed compared to healthy controls. In contrast, the abundances of
Akkermansia, Escherichia/Shigella,
Lactobacillus, and
Dialister genera changed after surgery
[21]. This indicates the problem of intestinal dysbiosis not only as a potential risk factor for the development of gastric cancer but also as a consequence of its occurrence, which affects the patient’s quality of life and health consequences. In addition, it is noteworthy that the choice of treatment has an impact on the gut microbiota of patients with gastric cancer—the surgery will result in a significant change in the gut microbiota
[22].
Commonly used proton pump inhibitors (PPIs) in the course of
H. pylori infection bear their consequences on the patient’s gut microbiota. The effect of PPIs is to raise the pH of the stomach, which has been disturbed via a pathogen of the
Helicobacteraceae genus. Proper use of PPIs, as prescribed by the doctor, brings the expected therapeutic results. However, it is worth noting that long-term intake of proton pump inhibitors contributes to the development of intestinal disorders such as small intestinal bacterial overgrowth (SIBO) and
C. difficile infections. PPIs are widely available over-the-counter drugs, so statistics on the use of the aforementioned pharmaceuticals may be underestimated. The effect of the discussed group of drugs does not refer only to increasing the pH in the stomach but also to blocking the action of the so-called proton pump or hydrogen-potassium ATPase, which, in turn, contributes to hypochlorhydria, which explains the increased risk of
C. difficile infection and SIBO
[23][24]. The prevalence of small intestinal bacterial overgrowth among gastric cancer patients is confirmed by clinical studies
[21][23][24][25]. A scientific article edited by Liang et al.
[21] highlights the prevalence of SIBO in patients with gastric and colorectal malignancies, as nearly 70% of the study’s participants, claiming to have taken PPIs for a long time, struggled with the intestinal condition addressed
[21].