*Helicobacter pylori*: General Comments

**3**

**Chapter 1**

**Abstract**

**1. Introduction**

*Helicobacter pylori* Infection

*Hristo Ilianov Iliev, Hristo Yankov Valkov* 

*and Borislav Georgiev Vladimirov*

*Todor Asenov Angelov, Mila Dimitrova Kovacheva-Slavova,* 

*Helicobacter pylori* (*H. pylori*) is a Gram-negative spiral bacterium commonly found in the stomach. Major part of the world's population is infected with *H. pylori* and is at increased risk of severe gastritis, peptic ulcer disease, and gastric cancer. Most studied virulence factors of the bacterium are the cytotoxin-associated gene (CagA) and the vacuolating cytotoxin A (VacA). The *H. pylori* infection is diagnosed by invasive (histological examination, culture, and rapid urease test, which require endoscopy and biopsy) and noninvasive methods (serology, urea breath test, and stool antigen test). *H. pylori* eradication is preferred for a long-term prevention of complications. Current treatments consist of antibiotics and adequate PPI dose and can be divided into two strands—with or without bismuth. Achieving an eradication rate of >90% is an indicator for effective treatment. Due to the increasing levels of antibiotic resistance, the standard triple therapy is largely replaced with a quadruple therapy, especially in countries with high resistance rates. Antimicrobial susceptibility testing should be performed after the second-line treatment failure, leading to an individualized patient treatment. Clear explanations and patients' compliance are of great importance for a better outcome.

**Keywords:** *Helicobacter pylori*, virulence factors, diagnostic methods, treatment

In the early 1980s, *Helicobacter pylori* (*H. pylori*) was discovered by Barry Marshall and Robin Warren. They reported its presence on mucosal tissue from the stomach of patients with gastritis and peptic ulcers [1]. Today, it is known that more than half of Earth's population is infected with this Gram-negative spiral bacterium. In most cases, the infection is completely asymptomatic, but it is far from harmless as 10–15% of those infected will develop peptic ulcer disease or gastric cancer [2]. The type and severity of the disease depends on several factors, as characteristics of the colonizing strain, host immune response, smoking, high-salt diet, and presence of other concurrent infections [3]. *H. pylori* strains from different geographical areas show clear phylogeographic features. The bacterium follows the human migration and has co-evolved with humans for over at least 60,000 years [4]. The fecal-oral and oral-oral routes of transmission are most common, with close person-to-person contact required. Strains of *H. pylori* are usually isolated from gastric biopsy tissue specimens, but the bacterium can be recovered also from saliva, gastric reflux fluid, diarrhea, and vomitus. Isolation and transmission from contaminated water supplies and farm animals has also been reported [5]. *H. pylori* is "special" in many ways as it possesses several important enzymes that enable its survival in the hostile acidic environment. Such an enzyme is the urease,

## **Chapter 1** *Helicobacter pylori* Infection

*Todor Asenov Angelov, Mila Dimitrova Kovacheva-Slavova, Hristo Ilianov Iliev, Hristo Yankov Valkov and Borislav Georgiev Vladimirov*

#### **Abstract**

*Helicobacter pylori* (*H. pylori*) is a Gram-negative spiral bacterium commonly found in the stomach. Major part of the world's population is infected with *H. pylori* and is at increased risk of severe gastritis, peptic ulcer disease, and gastric cancer. Most studied virulence factors of the bacterium are the cytotoxin-associated gene (CagA) and the vacuolating cytotoxin A (VacA). The *H. pylori* infection is diagnosed by invasive (histological examination, culture, and rapid urease test, which require endoscopy and biopsy) and noninvasive methods (serology, urea breath test, and stool antigen test). *H. pylori* eradication is preferred for a long-term prevention of complications. Current treatments consist of antibiotics and adequate PPI dose and can be divided into two strands—with or without bismuth. Achieving an eradication rate of >90% is an indicator for effective treatment. Due to the increasing levels of antibiotic resistance, the standard triple therapy is largely replaced with a quadruple therapy, especially in countries with high resistance rates. Antimicrobial susceptibility testing should be performed after the second-line treatment failure, leading to an individualized patient treatment. Clear explanations and patients' compliance are of great importance for a better outcome.

**Keywords:** *Helicobacter pylori*, virulence factors, diagnostic methods, treatment

#### **1. Introduction**

In the early 1980s, *Helicobacter pylori* (*H. pylori*) was discovered by Barry Marshall and Robin Warren. They reported its presence on mucosal tissue from the stomach of patients with gastritis and peptic ulcers [1]. Today, it is known that more than half of Earth's population is infected with this Gram-negative spiral bacterium. In most cases, the infection is completely asymptomatic, but it is far from harmless as 10–15% of those infected will develop peptic ulcer disease or gastric cancer [2]. The type and severity of the disease depends on several factors, as characteristics of the colonizing strain, host immune response, smoking, high-salt diet, and presence of other concurrent infections [3].

*H. pylori* strains from different geographical areas show clear phylogeographic features. The bacterium follows the human migration and has co-evolved with humans for over at least 60,000 years [4]. The fecal-oral and oral-oral routes of transmission are most common, with close person-to-person contact required. Strains of *H. pylori* are usually isolated from gastric biopsy tissue specimens, but the bacterium can be recovered also from saliva, gastric reflux fluid, diarrhea, and vomitus. Isolation and transmission from contaminated water supplies and farm animals has also been reported [5].

*H. pylori* is "special" in many ways as it possesses several important enzymes that enable its survival in the hostile acidic environment. Such an enzyme is the urease,

which breaks down the urea to ammonia and carbon dioxide, hence neutralizing the hydrochloric acid. Moreover, *H. pylori* avoids clearance with the gastric emptying with a number of adhesion molecules and its 4–6 flagella. Important virulence factors are the cytotoxin-associated gene A (CagA) and the vacuolating cytotoxin A (VacA).

Even though *H. pylori* colonization is usually asymptomatic, it leads to chronic active gastritis in most patients and is associated with a number of other gastroduodenal diseases, including gastric and duodenal ulcer disease, distal gastric adenocarcinoma, primary gastric mucosal-associated lymphoid tissue (MALT) lymphoma, dyspepsia, atrophic gastritis, iron deficiency anemia, and idiopathic thrombocytopenic purpura.

This is why *H. pylori* eradication is preferred for a long-term prevention of the above-mentioned complications. Current *H. pylori* treatment consists of antibiotics and adequate PPI dose and can be divided into two strands—with or without bismuth. Achievement of an eradication rate >90% is an indicator for effective treatment [6].

#### **2.** *H. pylori* **virulence factors**

*H. pylori* strains are more virulent and are associated with more severe gastric mucosal damages when there is a cytotoxin-associated gene pathogenicity island (cag PAI) in their genome. The cag PAI region contains ~30 genes encoding a type IV secretion system (T4SS) as well as cytotoxin-associated gene A (CagA). The CagA is delivered into host gastric epithelial cells via T4SS. Inside the cells, CagA undergoes tyrosine phosphorylation at the Glu-Pro-Ile-Tyr-Al (EPIYA) motifs by Src kinases. There is a higher risk for gastric cancer development in chronic infection with *H. pylori* cagA-positive strains. Carcinogenesis requires two major events. One is inactivation of tumor suppressor, and the other is the activation of oncoprotein. *H. pylori* CagA interacts with both of them and successfully disturbs their functions [7].

Vacuolating Cytotoxin (VacA) is also a major virulence factor present in almost all strains, and is highly polymorphic. VacA affects the cells with the induction of vacuole formation, mitochondrial dysfunction, modulation of signal transduction pathways, inhibition of T cell proliferation, and production of inflammatory cytokines. To favor its action, VacA binds to receptors such as receptor protein tyrosine phosphatases (RPTPα and RPTPβ), low-density lipoprotein receptor-related protein-1 (LRP1), fibronectin, CD18, and sphingomyelin. RPTPβ promote to ulceration and LRP1 is involved in the induction of autophagy. There is an interaction between cagA and VacA molecules, which is associated with the pathogenesis of gastric diseases. Therefore, further research on VacA may increase the knowledge of its role in the development of gastric disorders in *H. pylori* infection [7].

*H. pylori* expresses several major adhesins including BabA, SabA, LabA, OipA, and AlpAB. A closer association of the bacteria with the epithelium is thought to be mediated by them. They also increase the inflammation and damage of gastric mucosa by enhanced exposure to other virulence factors.

Duodenal ulcer-promoting gene A, dupA, is present in the tfs4 gene cluster and also the presence of the iceA1 allele of iceA is associated with increased risk for duodenal ulcer disease.

#### **3.** *Helicobacter pylori***-associated diseases**

#### **3.1 Dyspepsia**

According to Rome III, functional dyspepsia (FD) is a symptomatic dyspepsia in the absence of structural or biochemical explanation after appropriate

**5**

cell H+

and K+

Helicobacter pylori *Infection*

dial fullness, and early satiation.

cal regions was conducted [12].

**3.2 Gastritis**

adhesin, LabA [13–15].

*DOI: http://dx.doi.org/10.5772/intechopen.86963*

investigation [8]. There are gastrointestinal symptoms that are associated with chronic dyspepsia as epigastric pain, epigastric burning, uncomfortable postpran-

FD is one of the most common gastrointestinal diseases which affects the quality of life. Chronic dyspepsia symptoms, which are thought to be caused by *H. pylori* infection, are decided to be separated from FD and defined as *H. pylori*-associated dyspepsia (HpD) in the Kyoto Global Consensus Conference held on January 30– February 1, 2014 [9]. In this meeting, patients who remain symptom free 12 months after eradication are considered to be cases of HpD, while patients who continue to experience dyspepsia even after *H. pylori* eradication will be considered as FD [10]. The evidence of the association between *H. pylori* infection and dyspepsia has been increasing. However, it is still unknown why most of individuals with *H. pylori* infection have no symptoms, while some of them have chronic dyspepsia symptoms. Recent meta-analysis of 103 reports containing 312,415 individuals showed that the prevalence of uninvestigated dyspepsia was higher in *H. pylori*-positive individuals (OR 1.18; 95% CI 1.04–1.33) [11]. There is evidence of a small but statistically significant benefit in eradicating *H. pylori* in *H. pylori*-positive dyspepsia. Therefore, the eradication therapy is recommended as first-line therapy for *H. pylori*-positive dyspepsia. Zhao et al. reviewed 14 randomized controlled trials which contained information on the long-term (12 months or more) effects of *H. pylori* eradication on dyspeptic symptoms, and a sub-group analysis on geographi-

*H. pylori* swims through the layers of protective mucus of the gastric mucosa to avoid damage from gastric acid and digestive enzymes. The bacterium is able to interact with the mucins via major adhesins the blood group antigen-binding adhesin (BabA), sialic acid-binding adhesin (SabA), and the lacdiNAc-specific

*H. pylori* activates inflammatory gene when the bacterium reach to gastric epithelial cells. This is possible due to interaction with Toll-like receptor 2 and NOD1 [16], and inflammasomes [17, 18]. Inflammatory signaling in gastric epithelial cells is activated by a number of different mechanisms, resulting in the secretion of cytokines and chemokines, including interleukin-8 (IL-8), IL-1b, tumor necrosis factor alpha (TNFa), IL-6, IL-12, CCL2-5, CCL20, and CXCL1-3 [19]. The chemokines leads to the accumulation of neutrophils, macrophages, mast cells, dendritic

Neutrophils, macrophages, and NK cells contribute to gastritis via the secretion of inflammatory and tissue-damaging factors including reactive oxygen and nitrogen species (ROS and RNS) [20], perforin, and granzymes [21]. However, DCs are semi-mature and tolerogenic in *H. pylori*-infected gastric mucosa that stimulate the development of regulatory T cells (Tregs), which suppress inflammation [22]. It has recently been shown that retinoic acid (RA) is produced by human gastric epithelial cells and DCs regulates the level of inflammation. More intense inflammation and mucosal damage have been observed during *H. pylori* infection, because of reduction in RA [23]. Autoreactive antibodies against molecules, such as the parietal

antibodies may enhance inflammation and damage in the stomach [24]. In addition, the cytokines interferon-gamma (IFNc) and TNFa, secreted by Th1 cells, stimulate macrophages to secrete further pro-inflammatory factors. IL-17A, IL-17F, IL-21, and IL-22, secreted by Th17 cells, also stimulate the expression of ROS, RNS, and chemokines, leading to further inflammation and neutrophil recruitment [25].


cells (DCs), innate lymphoid cells, and lymphocytes—gastritis [4].

*Gastritis - New Approaches and Treatments*

**2.** *H. pylori* **virulence factors**

which breaks down the urea to ammonia and carbon dioxide, hence neutralizing the hydrochloric acid. Moreover, *H. pylori* avoids clearance with the gastric emptying with a number of adhesion molecules and its 4–6 flagella. Important virulence factors are the cytotoxin-associated gene A (CagA) and the vacuolating cytotoxin A (VacA). Even though *H. pylori* colonization is usually asymptomatic, it leads to chronic active gastritis in most patients and is associated with a number of other gastroduodenal diseases, including gastric and duodenal ulcer disease, distal gastric adenocarcinoma, primary gastric mucosal-associated lymphoid tissue (MALT) lymphoma, dyspepsia, atrophic gastritis, iron deficiency anemia, and idiopathic thrombocytopenic purpura. This is why *H. pylori* eradication is preferred for a long-term prevention of the above-mentioned complications. Current *H. pylori* treatment consists of antibiotics and adequate PPI dose and can be divided into two strands—with or without bismuth. Achievement of an eradication rate >90% is an indicator for effective treatment [6].

*H. pylori* strains are more virulent and are associated with more severe gastric mucosal damages when there is a cytotoxin-associated gene pathogenicity island (cag PAI) in their genome. The cag PAI region contains ~30 genes encoding a type IV secretion system (T4SS) as well as cytotoxin-associated gene A (CagA). The CagA is delivered into host gastric epithelial cells via T4SS. Inside the cells, CagA undergoes tyrosine phosphorylation at the Glu-Pro-Ile-Tyr-Al (EPIYA) motifs by Src kinases. There is a higher risk for gastric cancer development in chronic infection with *H. pylori* cagA-positive strains. Carcinogenesis requires two major events. One is inactivation of tumor suppressor, and the other is the activation of oncoprotein. *H. pylori* CagA interacts with both of them and successfully disturbs their functions [7].

Vacuolating Cytotoxin (VacA) is also a major virulence factor present in almost all strains, and is highly polymorphic. VacA affects the cells with the induction of vacuole formation, mitochondrial dysfunction, modulation of signal transduction pathways, inhibition of T cell proliferation, and production of inflammatory cytokines. To favor its action, VacA binds to receptors such as receptor protein tyrosine phosphatases (RPTPα and RPTPβ), low-density lipoprotein receptor-related protein-1 (LRP1), fibronectin, CD18, and sphingomyelin. RPTPβ promote to ulceration and LRP1 is involved in the induction of autophagy. There is an interaction between cagA and VacA molecules, which is associated with the pathogenesis of gastric diseases. Therefore, further research on VacA may increase the knowledge

*H. pylori* expresses several major adhesins including BabA, SabA, LabA, OipA, and AlpAB. A closer association of the bacteria with the epithelium is thought to be mediated by them. They also increase the inflammation and damage of gastric

Duodenal ulcer-promoting gene A, dupA, is present in the tfs4 gene cluster and

also the presence of the iceA1 allele of iceA is associated with increased risk for

According to Rome III, functional dyspepsia (FD) is a symptomatic dyspepsia in the absence of structural or biochemical explanation after appropriate

of its role in the development of gastric disorders in *H. pylori* infection [7].

mucosa by enhanced exposure to other virulence factors.

**3.** *Helicobacter pylori***-associated diseases**

**4**

duodenal ulcer disease.

**3.1 Dyspepsia**

investigation [8]. There are gastrointestinal symptoms that are associated with chronic dyspepsia as epigastric pain, epigastric burning, uncomfortable postprandial fullness, and early satiation.

FD is one of the most common gastrointestinal diseases which affects the quality of life. Chronic dyspepsia symptoms, which are thought to be caused by *H. pylori* infection, are decided to be separated from FD and defined as *H. pylori*-associated dyspepsia (HpD) in the Kyoto Global Consensus Conference held on January 30– February 1, 2014 [9]. In this meeting, patients who remain symptom free 12 months after eradication are considered to be cases of HpD, while patients who continue to experience dyspepsia even after *H. pylori* eradication will be considered as FD [10].

The evidence of the association between *H. pylori* infection and dyspepsia has been increasing. However, it is still unknown why most of individuals with *H. pylori* infection have no symptoms, while some of them have chronic dyspepsia symptoms. Recent meta-analysis of 103 reports containing 312,415 individuals showed that the prevalence of uninvestigated dyspepsia was higher in *H. pylori*-positive individuals (OR 1.18; 95% CI 1.04–1.33) [11]. There is evidence of a small but statistically significant benefit in eradicating *H. pylori* in *H. pylori*-positive dyspepsia. Therefore, the eradication therapy is recommended as first-line therapy for *H. pylori*-positive dyspepsia. Zhao et al. reviewed 14 randomized controlled trials which contained information on the long-term (12 months or more) effects of *H. pylori* eradication on dyspeptic symptoms, and a sub-group analysis on geographical regions was conducted [12].

#### **3.2 Gastritis**

*H. pylori* swims through the layers of protective mucus of the gastric mucosa to avoid damage from gastric acid and digestive enzymes. The bacterium is able to interact with the mucins via major adhesins the blood group antigen-binding adhesin (BabA), sialic acid-binding adhesin (SabA), and the lacdiNAc-specific adhesin, LabA [13–15].

*H. pylori* activates inflammatory gene when the bacterium reach to gastric epithelial cells. This is possible due to interaction with Toll-like receptor 2 and NOD1 [16], and inflammasomes [17, 18]. Inflammatory signaling in gastric epithelial cells is activated by a number of different mechanisms, resulting in the secretion of cytokines and chemokines, including interleukin-8 (IL-8), IL-1b, tumor necrosis factor alpha (TNFa), IL-6, IL-12, CCL2-5, CCL20, and CXCL1-3 [19]. The chemokines leads to the accumulation of neutrophils, macrophages, mast cells, dendritic cells (DCs), innate lymphoid cells, and lymphocytes—gastritis [4].

Neutrophils, macrophages, and NK cells contribute to gastritis via the secretion of inflammatory and tissue-damaging factors including reactive oxygen and nitrogen species (ROS and RNS) [20], perforin, and granzymes [21]. However, DCs are semi-mature and tolerogenic in *H. pylori*-infected gastric mucosa that stimulate the development of regulatory T cells (Tregs), which suppress inflammation [22].

It has recently been shown that retinoic acid (RA) is produced by human gastric epithelial cells and DCs regulates the level of inflammation. More intense inflammation and mucosal damage have been observed during *H. pylori* infection, because of reduction in RA [23]. Autoreactive antibodies against molecules, such as the parietal cell H+ and K+ -ATPase, frequently induce the molecular mimicry of *H. pylori*. These antibodies may enhance inflammation and damage in the stomach [24]. In addition, the cytokines interferon-gamma (IFNc) and TNFa, secreted by Th1 cells, stimulate macrophages to secrete further pro-inflammatory factors. IL-17A, IL-17F, IL-21, and IL-22, secreted by Th17 cells, also stimulate the expression of ROS, RNS, and chemokines, leading to further inflammation and neutrophil recruitment [25].

All of the above makes it clear that the hosts' immune response is one of the major factors involved in the *H. pylori* infection pathogenesis. Thus, cytokines and other chemokines, prostaglandins, and their metabolites, as products of the innate response may be involved in the etiology of *H. pylori*-related diseases.

#### **3.3 Peptic ulcer disease**

Around 95% of duodenal ulcers and around 70% of gastric ulcers are *H. pylori* infection related [26, 27]. Hemorrhage or perforation are relatively common complications and are associated with a significant mortality.

*H. pylori* infection leads to destruction of delta cells by chronic inflammation of the antrum. This leads to a reduction in the level of somatostatin secretion and therefore impaired inhibition of gastrin production by the G cells, causing hypergastrinemia. The elevated gastrin levels overstimulate the acid-producing parietal cells of the undamaged corpus (in the case of antral-predominant gastritis) resulting in hyperchlorhydria. The increased gastric acid output can result in gastric metaplasia of the duodenal epithelium. This allows *H. pylori* to colonize it and cause inflammation, possibly leading to duodenal ulceration.

On the other hand, in patients with corpus-predominant atrophy or pangastritis, the acid output can be normal or reduced, explained by the loss of parietal cells. A state of hypochlorhydria is established, despite increased gastrin production from the *H. pylori*-infected antrum, preventing development of duodenal ulcers. Gastric ulcers develop due to inflammation and damage to the gastric mucosa. Premalignant lesions and gastric adenocarcinoma may also develop [4, 28].

In those with reduced numbers of Tregs in their gastric mucosa, peptic ulceration is more frequently found thus impaired capacity to control the inflammation [19, 29]. The inflammation and damage are enhanced by gastric Th1 and Th17 cells inducing epithelial cells to express higher levels of MHC class II and activation of mitogenactivated protein (MAP) kinases and transcription factors AP-1 and NF-jB [30].

#### **3.4 Gastric adenocarcinoma**

There are approximately 100,000 new cases of gastric cancer each year [31]. A majority of cases are registered in developing countries, half of them occurring in Eastern Asia. It is the fifth most common malignancy worldwide and the third most common cause of cancer-related death diagnosed usually at a late stage [32].

Depending on the location the gastric cancer can be divided into two subtypes:


Cardia gastric cancers are thought to be mostly unrelated to *H. pylori* infection and have similar risk factors to those for esophageal adenocarcinoma and Barrett's esophagus [30]. Up to 89% of cases of non-cardia gastric cancer is attributed to the infection with *H. pylori*. The risk of gastric cancer development for an infected individual is 1–2% [33].

The gastric cancer is classified histologically as two types [34]:

• intestinal—usually exophytic, often ulcerating, and are associated with intestinal metaplasia of the stomach and are more common in proximal (fundus) location.

**7**

**4. Diagnosis**

Helicobacter pylori *Infection*

with diffuse-type.

**3.5 MALT lymphoma**

*DOI: http://dx.doi.org/10.5772/intechopen.86963*

• diffuse-type—poorly differentiated infiltrating lesions, which lead to the thickening of the stomach (linitis plastica) and predominate in younger patients.

Patients with intestinal-type tumors appear to have a better prognosis than those

Chronic gastritis caused by *H. pylori* infection after several decades, leads to gastric gland atrophy, intestinal metaplasia, dysplasia, and finally adenocarcinoma. *H. pylori* eradication therapy reduces the incidence of atrophic gastritis, but the risk of gastric cancer development is reduced only if the eradication is administered prior to pre-malignant changes [35]. ROS/RNS-mediated DNA damage, the silencing of tumor suppressor genes via DNA methylation, histone epigenetic modifications, and epithelial-mesenchymal transition are associated with gastric carcinogenesis [36]. Genetically determined high expression of pro-inflammatory cytokines (IL-6, IL-8, TNFa, IL-1b), low expression of anti-inflammatory cytokines (IL-10, TGFb), or enhanced responsiveness to bacterial components (Toll-like receptors 1, 2, 4, 5, and 9) are associated with a higher risk of gastric adenocarcinoma [37, 38]. In the future, identification of molecular profiles for gastric cancer subtypes will lead to more personalized clinical management, therapeutic targets and biomarkers for screening, prognosis, prediction of response to treatment, and monitoring of gastric cancer progression [39].

Almost all patients with gastric MALT lymphoma have an active *H. pylori* infection with frequency of approximately 0.8 per 100,000 per year. Around 10% of cases are thought to be independent of *H. pylori*, but may be due to perhaps gastric non-pylori Helicobacters or undiagnosed *H. pylori* infection. Formation of lymphoid follicles in the gastric mucosa is induced by *H. pylori*-mediated inflammation, which is not present in the uninfected stomach [40]. Chronic inflammation and continuous antigenic stimulation lead to uncontrolled expansion of marginal zone B cells in these lymphoid follicles [41]. The tumor cells are commonly localized in the gastric mucosa and often remain to this site. However, in approximately 40% of cases, spreading to regional lymph nodes and more distant mucosal sites occurs. In around half of gastric lymphoma, low-grade MALT lymphomas may transform into more aggressive diffuse large B cell lymphomas (DLBCL), which have a considerably worse prognosis [41]. After *H. pylori* eradication treatment, there is a regression of the low-grade B cell MALT lymphomas. In one-quarter of cases a chromosomal translocation t(11; 18) is found. This is the most common genetic aberration in gastric MALT lymphoma. The non-responsiveness of gastric MALT lymphoma to *H. pylori* eradication therapy is also predicted by the presence of t(11; 18) [42]. Fusion between the activator protein-12 (AP-12) and MALT-1 genes lead to this chromosomal breakage and translocation. The product of this fusion stimulates activation of the transcription factor NF-jB, which regulates the expression of anti-apoptotic genes and cell survival [41]. Mutations in immunoglobulin heavy chain variable region (IGHV) genes are also frequently present [43]. There is growing evidence that host genetic factors play an important role in developing gastric MALT lymphoma.

Diagnosis of *H. pylori* infection can be done with noninvasive methods serology, urea breath test (UBT), stool antigen test (SAT)—and invasive methods histology, culture, PCR, rapid urease test (RUT). Only locally validated tests should *Gastritis - New Approaches and Treatments*

**3.3 Peptic ulcer disease**

**3.4 Gastric adenocarcinoma**

individual is 1–2% [33].

location.

All of the above makes it clear that the hosts' immune response is one of the major factors involved in the *H. pylori* infection pathogenesis. Thus, cytokines and other chemokines, prostaglandins, and their metabolites, as products of the innate

Around 95% of duodenal ulcers and around 70% of gastric ulcers are *H. pylori* infection related [26, 27]. Hemorrhage or perforation are relatively common com-

*H. pylori* infection leads to destruction of delta cells by chronic inflammation of the antrum. This leads to a reduction in the level of somatostatin secretion and therefore impaired inhibition of gastrin production by the G cells, causing hypergastrinemia. The elevated gastrin levels overstimulate the acid-producing parietal cells of the undamaged corpus (in the case of antral-predominant gastritis) resulting in hyperchlorhydria. The increased gastric acid output can result in gastric metaplasia of the duodenal epithelium. This allows *H. pylori* to colonize it and cause

On the other hand, in patients with corpus-predominant atrophy or pangastritis, the acid output can be normal or reduced, explained by the loss of parietal cells. A state of hypochlorhydria is established, despite increased gastrin production from the *H. pylori*-infected antrum, preventing development of duodenal ulcers. Gastric ulcers develop due to inflammation and damage to the gastric mucosa. Pre-

In those with reduced numbers of Tregs in their gastric mucosa, peptic ulceration is more frequently found thus impaired capacity to control the inflammation [19, 29]. The inflammation and damage are enhanced by gastric Th1 and Th17 cells inducing epithelial cells to express higher levels of MHC class II and activation of mitogenactivated protein (MAP) kinases and transcription factors AP-1 and NF-jB [30].

There are approximately 100,000 new cases of gastric cancer each year [31]. A majority of cases are registered in developing countries, half of them occurring in Eastern Asia. It is the fifth most common malignancy worldwide and the third most

Depending on the location the gastric cancer can be divided into two subtypes:

Cardia gastric cancers are thought to be mostly unrelated to *H. pylori* infection and have similar risk factors to those for esophageal adenocarcinoma and Barrett's esophagus [30]. Up to 89% of cases of non-cardia gastric cancer is attributed to the infection with *H. pylori*. The risk of gastric cancer development for an infected

• intestinal—usually exophytic, often ulcerating, and are associated with intestinal metaplasia of the stomach and are more common in proximal (fundus)

common cause of cancer-related death diagnosed usually at a late stage [32].

• Cardia—arising from epithelial cells at the gastroesophageal junction.

The gastric cancer is classified histologically as two types [34]:

• Non-cardia—arising from the distal stomach.

malignant lesions and gastric adenocarcinoma may also develop [4, 28].

response may be involved in the etiology of *H. pylori*-related diseases.

plications and are associated with a significant mortality.

inflammation, possibly leading to duodenal ulceration.

**6**

• diffuse-type—poorly differentiated infiltrating lesions, which lead to the thickening of the stomach (linitis plastica) and predominate in younger patients.

Patients with intestinal-type tumors appear to have a better prognosis than those with diffuse-type.

Chronic gastritis caused by *H. pylori* infection after several decades, leads to gastric gland atrophy, intestinal metaplasia, dysplasia, and finally adenocarcinoma. *H. pylori* eradication therapy reduces the incidence of atrophic gastritis, but the risk of gastric cancer development is reduced only if the eradication is administered prior to pre-malignant changes [35]. ROS/RNS-mediated DNA damage, the silencing of tumor suppressor genes via DNA methylation, histone epigenetic modifications, and epithelial-mesenchymal transition are associated with gastric carcinogenesis [36].

Genetically determined high expression of pro-inflammatory cytokines (IL-6, IL-8, TNFa, IL-1b), low expression of anti-inflammatory cytokines (IL-10, TGFb), or enhanced responsiveness to bacterial components (Toll-like receptors 1, 2, 4, 5, and 9) are associated with a higher risk of gastric adenocarcinoma [37, 38]. In the future, identification of molecular profiles for gastric cancer subtypes will lead to more personalized clinical management, therapeutic targets and biomarkers for screening, prognosis, prediction of response to treatment, and monitoring of gastric cancer progression [39].

#### **3.5 MALT lymphoma**

Almost all patients with gastric MALT lymphoma have an active *H. pylori* infection with frequency of approximately 0.8 per 100,000 per year. Around 10% of cases are thought to be independent of *H. pylori*, but may be due to perhaps gastric non-pylori Helicobacters or undiagnosed *H. pylori* infection. Formation of lymphoid follicles in the gastric mucosa is induced by *H. pylori*-mediated inflammation, which is not present in the uninfected stomach [40]. Chronic inflammation and continuous antigenic stimulation lead to uncontrolled expansion of marginal zone B cells in these lymphoid follicles [41]. The tumor cells are commonly localized in the gastric mucosa and often remain to this site. However, in approximately 40% of cases, spreading to regional lymph nodes and more distant mucosal sites occurs. In around half of gastric lymphoma, low-grade MALT lymphomas may transform into more aggressive diffuse large B cell lymphomas (DLBCL), which have a considerably worse prognosis [41]. After *H. pylori* eradication treatment, there is a regression of the low-grade B cell MALT lymphomas. In one-quarter of cases a chromosomal translocation t(11; 18) is found. This is the most common genetic aberration in gastric MALT lymphoma. The non-responsiveness of gastric MALT lymphoma to *H. pylori* eradication therapy is also predicted by the presence of t(11; 18) [42]. Fusion between the activator protein-12 (AP-12) and MALT-1 genes lead to this chromosomal breakage and translocation. The product of this fusion stimulates activation of the transcription factor NF-jB, which regulates the expression of anti-apoptotic genes and cell survival [41]. Mutations in immunoglobulin heavy chain variable region (IGHV) genes are also frequently present [43]. There is growing evidence that host genetic factors play an important role in developing gastric MALT lymphoma.

#### **4. Diagnosis**

Diagnosis of *H. pylori* infection can be done with noninvasive methods serology, urea breath test (UBT), stool antigen test (SAT)—and invasive methods histology, culture, PCR, rapid urease test (RUT). Only locally validated tests should be used. PPIs have an anti-*H. pylori* activity and decrease the load of *H. pylori* leading to false-negative results on urease test, UBT, and SAT [44]. H2 receptor antagonists have been shown to have minimal effect on the sensitivity of UBT, and antacids do not impair the sensitivity of UBT or SAT. H2-blockers do not have anti-*H. pylori* activity [45–47]. In contrast, the antibacterial activity of antibiotics and bismuth compounds necessitate their discontinuation for 4 weeks to allow an increase of a detectable bacterial load.

From the noninvasive methods, 13C-UBT is the best approach to the diagnosis of *H. pylori* infection, with high sensitivity and specificity [48–50]. It cannot be used in children and pregnant women, because it exposes the patients to radiation [51]. SAT may be less acceptable in some societies, but has a high sensitivity and specificity [6]. Under certain clinical circumstances, it leads to a low bacterial load in the stomach and to a decreased sensitivity of all diagnostic methods except serology. These clinical situations include GI bleeding, atrophic gastritis, gastric MALT lymphoma, and gastric carcinoma. Because serology is able to detect past infection with *H. pylori*, it should not be used as a method to monitor effectiveness of eradication.

In clinical practice, when there is an indication for endoscopy, and there is no contraindication for biopsy, the rapid urease test (RUT) is recommended as a first-line diagnostic test [6]. The sensitivity of biopsy urease tests is approximately 90%, and specificity is in the range of 95–100% [52]. It has been shown that the best biopsy sites for detection of *H. pylori* and assessment of atrophy are the lesser and greater curvature of the mid antrum, and the middle gastric body at the lesser and greater curvature [53]. This is supported by the updated Sydney System [54]. A maximum approach for gastric biopsies includes the incisura region at the lesser curvature. In the case of detection of gastric polyps, ulcerations, and suspicious focal lesions, further biopsies are necessary.

Most cases of *H. pylori* infection can be diagnosed from gastric biopsies using histochemical staining alone. In cases of chronic (active) gastritis in which *H. pylori* is not detected by histochemistry, immunohistochemical testing of *H. pylori* can be used as an accessory test. In the case of normal histology, no immunohistochemical staining should be performed [6].

The value of culture is primarily to perform AST for clarithromycin, levofloxacin, metronidazole, rifamycin, and eventually, amoxicillin and tetracycline. Several studies, using tailored treatments based on *H. pylori* susceptibility to antibiotics in comparison with standard empirical triple therapy, have shown a better eradication rate and may be cost-effective [55, 56].

A panel of serological tests (GastroPanel), including serum Pg (PgI and PgII), gastrin 17 (G-17), and anti-*H. pylori* antibodies, has recently been proposed as "serological biopsy" in dyspeptic patients [57, 58]. In populations with a low prevalence of atrophic gastritis, the negative predictive value of the GastroPanel in identifying atrophic gastritis is as high as 97% (95% CI 95–99%) [59].

In the post-treatment evaluation, UBT is a valid and reliable test in the assessment of *H. pylori* eradication [60]. SAT can be used as an alternative [61]. Testing to prove eradication should be performed at least 4–8 weeks after completion of *H. pylori* therapy. PPI should be discontinued for at least 2 weeks [48, 61–63].

#### **5. Treatment**

#### **Recommended treatment regimens** [64]:

**Clarithromycin triple—**PPI (standard or double dose twice daily) **+** clarithromycin (500 mg twice daily) **+** amoxicillin (1 g twice daily) **OR** metronidazole (500 mg three times daily) for 14 days.

**9**

Helicobacter pylori *Infection*

daily) for 10–14 days.

**Suggested** [64]:

7–10 days.

(500 mg twice daily) for 5–7 days.

azole (500 mg twice daily) 7 days.

daily) **+** amoxicillin (1 g twice daily) for 14 days.

imidazole5 (500 mg twice daily) for 5–7 days.

ing the dose, frequency, and duration of the antibiotic.

*DOI: http://dx.doi.org/10.5772/intechopen.86963*

**Bismuth quadruple—**PPI (standard dose twice daily) **+** bismuth subcitrate (120–300 mg 4 times daily) or subsalicylate (300 mg 4 times daily) **+** tetracycline (500 mg 4 times daily) **+** metronidazole (250 mg 4 times daily or 500 mg 3–4 times

daily) **+** amoxicillin (1 g twice daily) **+** nitroimidazole (500 mg twice daily).

**Concomitant—**PPI (standard dose twice daily) **+** clarithromycin (500 mg twice

**Sequential—**PPI (standard dose twice daily) **+** amoxicillin (1 g twice daily) for 5–7 days **then** PPI + clarithromycin (500 mg twice daily) + nitroimidazole5

**Hybrid—**PPI (standard dose twice daily) **+** amoxicillin (1 g twice daily) for 7 days **then** PPI **+** amoxicillin **+** clarithromycin (500 mg twice daily) **+** nitroimid-

**Levofloxacin triple—**PPI (standard dose twice daily) **+** levofloxacin (500 mg

**Levofloxacin sequential—**PPI (standard or double dose twice daily) **+** amoxicillin (1 g twice daily) for 5–7 days **then** PPI **+** levofloxacin (500 mg daily) **+** nitro-

Eradication rates of *H. pylori* have been declining, because of the increasing resistance rates to antibiotics worldwide [65]. Such evidence comes from studies in Europe, Japan, Korea, China, Iran, Greece, Bulgaria, and others [66–71]. Clarithromycin resistance rates have now reached ~30% in Italy and Japan, ~40% in Turkey, and ~50% in China, although rates in Sweden and Taiwan were ~15%. The standard triple therapy is less effective nowadays, because of a number of reasons such as lower compliance, high gastric acidity, high bacterial load, and bacterial strains, but mainly due to the increase in *H. pylori* resistance to clarithromycin. *H. pylori* is now an inconstantly susceptible bacterium (10–50% resistant) except in Northern Europe. The choice of therapy should be based on the frequency of metronidazole and dual clarithromycin and metronidazole resistance. If metronidazole resistance is almost negligible (e.g., Japan), replacing clarithromycin for metronidazole in triple therapy (i.e., PPI-metronidazole-amoxicillin) shows excellent cure rates [72]. However, metronidazole resistance can be partially overcome by increas-

All non-BQTs will be less effective in regions with dual resistance to clarithromycin and metronidazole >15% [73]. Non-bismuth quadruple concomitant therapy, prescribed for 14 days, can be an effective alternative in regions with high clarithromycin resistance (15–40%) but low to intermediate metronidazole resistance (<40%) [74]. Bismuth-containing quadruple therapies are the treatment of choice when we have high (>15%) dual clarithromycin and metronidazole resistance. Ideally, clarithromycin should be avoided and a combination of alternative antibiotics. If bismuth is not available in high dual clarithromycin and metronidazole resistance areas, levofloxacin [75], rifabutin [76], and high dose dual (PPI + amoxicillin) [77] treatments can be considered. Quadruple therapy with a PPI, bismuth, and a combination of two antibiotics, among furazolidone, tetracycline, metronidazole, and amoxicillin, has been successfully tested (>90% cure rates) against *H. pylori* strains resistant to metronidazole, fluoroquinolones, and clarithromycin [78] and now is the recommended first-line treatment [79]. BQT should be considered effective provided the doses are sufficient and the duration should be extended to 14 days, unless 10 day therapies are proven effective locally [80, 81]. The combination of PPI, bismuth, metronidazole, and tetracycline

**LOAD—**Levofloxacin (250 mg daily) + omeprazole (double dose daily) + nitazoxanide (500 mg twice daily) + doxycycline (100 mg daily) for *Gastritis - New Approaches and Treatments*

increase of a detectable bacterial load.

focal lesions, further biopsies are necessary.

staining should be performed [6].

rate and may be cost-effective [55, 56].

**Recommended treatment regimens** [64]:

(500 mg three times daily) for 14 days.

be used. PPIs have an anti-*H. pylori* activity and decrease the load of *H. pylori* leading to false-negative results on urease test, UBT, and SAT [44]. H2 receptor antagonists have been shown to have minimal effect on the sensitivity of UBT, and antacids do not impair the sensitivity of UBT or SAT. H2-blockers do not have anti-*H. pylori* activity [45–47]. In contrast, the antibacterial activity of antibiotics and bismuth compounds necessitate their discontinuation for 4 weeks to allow an

From the noninvasive methods, 13C-UBT is the best approach to the diagnosis of *H. pylori* infection, with high sensitivity and specificity [48–50]. It cannot be used in children and pregnant women, because it exposes the patients to radiation [51]. SAT may be less acceptable in some societies, but has a high sensitivity and specificity [6]. Under certain clinical circumstances, it leads to a low bacterial load in the stomach and to a decreased sensitivity of all diagnostic methods except serology. These clinical situations include GI bleeding, atrophic gastritis, gastric MALT lymphoma, and gastric carcinoma. Because serology is able to detect past infection with *H. pylori*, it should not be used as a method to monitor effectiveness of eradication. In clinical practice, when there is an indication for endoscopy, and there is no contraindication for biopsy, the rapid urease test (RUT) is recommended as a first-line diagnostic test [6]. The sensitivity of biopsy urease tests is approximately 90%, and specificity is in the range of 95–100% [52]. It has been shown that the best biopsy sites for detection of *H. pylori* and assessment of atrophy are the lesser and greater curvature of the mid antrum, and the middle gastric body at the lesser and greater curvature [53]. This is supported by the updated Sydney System [54]. A maximum approach for gastric biopsies includes the incisura region at the lesser curvature. In the case of detection of gastric polyps, ulcerations, and suspicious

Most cases of *H. pylori* infection can be diagnosed from gastric biopsies using histochemical staining alone. In cases of chronic (active) gastritis in which *H. pylori* is not detected by histochemistry, immunohistochemical testing of *H. pylori* can be used as an accessory test. In the case of normal histology, no immunohistochemical

The value of culture is primarily to perform AST for clarithromycin, levofloxacin, metronidazole, rifamycin, and eventually, amoxicillin and tetracycline. Several studies, using tailored treatments based on *H. pylori* susceptibility to antibiotics in comparison with standard empirical triple therapy, have shown a better eradication

A panel of serological tests (GastroPanel), including serum Pg (PgI and PgII), gastrin 17 (G-17), and anti-*H. pylori* antibodies, has recently been proposed as "serological biopsy" in dyspeptic patients [57, 58]. In populations with a low prevalence of atrophic gastritis, the negative predictive value of the GastroPanel in

In the post-treatment evaluation, UBT is a valid and reliable test in the assessment of *H. pylori* eradication [60]. SAT can be used as an alternative [61]. Testing to prove eradication should be performed at least 4–8 weeks after completion of *H.* 

**Clarithromycin triple—**PPI (standard or double dose twice daily) **+** clarithro-

mycin (500 mg twice daily) **+** amoxicillin (1 g twice daily) **OR** metronidazole

identifying atrophic gastritis is as high as 97% (95% CI 95–99%) [59].

*pylori* therapy. PPI should be discontinued for at least 2 weeks [48, 61–63].

**8**

**5. Treatment**

**Bismuth quadruple—**PPI (standard dose twice daily) **+** bismuth subcitrate (120–300 mg 4 times daily) or subsalicylate (300 mg 4 times daily) **+** tetracycline (500 mg 4 times daily) **+** metronidazole (250 mg 4 times daily or 500 mg 3–4 times daily) for 10–14 days.

**Concomitant—**PPI (standard dose twice daily) **+** clarithromycin (500 mg twice daily) **+** amoxicillin (1 g twice daily) **+** nitroimidazole (500 mg twice daily). **Suggested** [64]:

**Sequential—**PPI (standard dose twice daily) **+** amoxicillin (1 g twice daily) for 5–7 days **then** PPI + clarithromycin (500 mg twice daily) + nitroimidazole5 (500 mg twice daily) for 5–7 days.

**Hybrid—**PPI (standard dose twice daily) **+** amoxicillin (1 g twice daily) for 7 days **then** PPI **+** amoxicillin **+** clarithromycin (500 mg twice daily) **+** nitroimidazole (500 mg twice daily) 7 days.

**Levofloxacin triple—**PPI (standard dose twice daily) **+** levofloxacin (500 mg daily) **+** amoxicillin (1 g twice daily) for 14 days.

**Levofloxacin sequential—**PPI (standard or double dose twice daily) **+** amoxicillin (1 g twice daily) for 5–7 days **then** PPI **+** levofloxacin (500 mg daily) **+** nitroimidazole5 (500 mg twice daily) for 5–7 days.

**LOAD—**Levofloxacin (250 mg daily) + omeprazole (double dose daily) + nitazoxanide (500 mg twice daily) + doxycycline (100 mg daily) for 7–10 days.

Eradication rates of *H. pylori* have been declining, because of the increasing resistance rates to antibiotics worldwide [65]. Such evidence comes from studies in Europe, Japan, Korea, China, Iran, Greece, Bulgaria, and others [66–71]. Clarithromycin resistance rates have now reached ~30% in Italy and Japan, ~40% in Turkey, and ~50% in China, although rates in Sweden and Taiwan were ~15%. The standard triple therapy is less effective nowadays, because of a number of reasons such as lower compliance, high gastric acidity, high bacterial load, and bacterial strains, but mainly due to the increase in *H. pylori* resistance to clarithromycin. *H. pylori* is now an inconstantly susceptible bacterium (10–50% resistant) except in Northern Europe. The choice of therapy should be based on the frequency of metronidazole and dual clarithromycin and metronidazole resistance. If metronidazole resistance is almost negligible (e.g., Japan), replacing clarithromycin for metronidazole in triple therapy (i.e., PPI-metronidazole-amoxicillin) shows excellent cure rates [72]. However, metronidazole resistance can be partially overcome by increasing the dose, frequency, and duration of the antibiotic.

All non-BQTs will be less effective in regions with dual resistance to clarithromycin and metronidazole >15% [73]. Non-bismuth quadruple concomitant therapy, prescribed for 14 days, can be an effective alternative in regions with high clarithromycin resistance (15–40%) but low to intermediate metronidazole resistance (<40%) [74]. Bismuth-containing quadruple therapies are the treatment of choice when we have high (>15%) dual clarithromycin and metronidazole resistance. Ideally, clarithromycin should be avoided and a combination of alternative antibiotics. If bismuth is not available in high dual clarithromycin and metronidazole resistance areas, levofloxacin [75], rifabutin [76], and high dose dual (PPI + amoxicillin) [77] treatments can be considered. Quadruple therapy with a PPI, bismuth, and a combination of two antibiotics, among furazolidone, tetracycline, metronidazole, and amoxicillin, has been successfully tested (>90% cure rates) against *H. pylori* strains resistant to metronidazole, fluoroquinolones, and clarithromycin [78] and now is the recommended first-line treatment [79]. BQT should be considered effective provided the doses are sufficient and the duration should be extended to 14 days, unless 10 day therapies are proven effective locally [80, 81]. The combination of PPI, bismuth, metronidazole, and tetracycline lasting 10–14 days achieved ≥85% eradication rate, even in areas with a high prevalence of metronidazole resistance [82–84].

Sequential therapy is more complex and requires switching of antibiotic drugs during the treatment course, which can confuse the patients. Concomitant therapy (PPI, amoxicillin, clarithromycin, and a nitroimidazole administered concurrently) is easier and similar to standard triple therapy and should be the preferred non-bismuth quadruple therapy. Sequential therapy achieves lower cure rates compared to concomitant therapy against clarithromycin-resistant strains [85, 86]. All non-BQTs (concomitant, hybrid, triple, and sequential) lead to excellent cure rates against susceptible *H. pylori* strains, but the cure rate will always be <90% when the rate of dual resistant strains is >5, >9, or >15%, respectively [73].

Response to PPI is individual and determined by cytochrome 2C19 and MDR polymorphisms. Caucasian subjects show a higher prevalence of high metabolizers (56–81%) compared to Asian [74]. Esomeprazole and rabeprazole provide better overall *H. pylori* eradication rates, especially esomeprazole 40 mg twice daily, whereas rabeprazole 10 and 20 mg twice daily [87–92]. By raising pH, *H. pylori* enters the replicative state and become susceptible to amoxicillin and clarithromycin [93].

For second-line treatment, after failure of PPI-clarithromycin-amoxicillin triple therapy, a bismuth-containing quadruple therapy or a fluoroquinolone-containing triple or quadruple therapy are recommended [94]. In theory, any treatment could be used after failure of BQT, including repeating the same BQT with longer duration and high metronidazole dosage. However, treatment that has already failed seems wiser never to be repeated. Bismuth therapies are usually proposed as first-line treatments for areas of high clarithromycin resistance and using a clarithromycin-containing treatment as second-line therapy after failure of a BQT does not seem to be practical. That is why Levofloxacin-based triple therapy, that is known to be effective as second-line therapy after clarithromycin-containing therapy, should also be recommended after failure of a bismuth-containing quadruple regimen [95, 96]. The incidence of side effects are lower with levofloxacincontaining triple therapy than with bismuth-containing quadruple therapy [97]. A sub-group analysis showed similar eradication rates with 500 and 1000 mg) of levofloxacin [97]. However, the efficacy of levofloxacin-based regimens may be affected by an increased prevalence of levofloxacin resistance [98]. Therefore, 14-day bismuth quadruple therapy is a valid second-line treatment for *H. pylori* eradication, especially in areas with high fluoroquinolones resistance. Combining bismuth and levofloxacin in a 14-day quadruple therapy is an effective (≥90% cure rate), simple, and safe second-line strategy in patients [99]. Bismuth overcomes clarithromycin and levofloxacin resistance, because of the synergistic effect with antibiotics [100, 101]. Therefore, the levofloxacin/bismuth-containing quadruple therapy constitutes an encouraging second-line strategy not only in patients failing previous standard triple therapy, but also in non-bismuth quadruple "sequential" or "concomitant" treatments.

After failure of the first-line treatment (clarithromycin based) and second-line treatment (with bismuth-containing quadruple regimen), it is recommended to use the fluoroquinolone-containing regimen as a rescue therapy. After failure of the first-line treatment (triple or non-bismuth quadruple) and second-line treatment (fluoroquinolone-containing therapy), it is recommended to use the bismuth-based quadruple therapy. Furthermore, BQT is not influenced by clarithromycin and fluoroquinolone resistance [102]. However, if a second-line treatment fails, culture with susceptibility testing (AST) or molecular determination of genotype resistance is recommended. Susceptibility-guided triple therapies proved more effective than empirical triple therapies in first-line treatment [55, 103].

**11**

Helicobacter pylori *Infection*

confirmation.

*DOI: http://dx.doi.org/10.5772/intechopen.86963*

**6.** *Helicobacter pylori* **and extragastric diseases**

oping EA, in comparison with the general population [107].

all populations, irrespective of geographical location [112].

**7.** *H. pylori* **and the human microbiota**

Chronic infection with *H. pylori* may be favorable for certain gastroesophageal diseases, asthma, and other allergic disease manifestations and inflammatory bowel diseases (IBD). The beneficial role of *H. pylori* in GERD, Barrett's esophagus (BE), and esophageal adenocarcinoma (EA) requires further clinical and experimental

The reflux of gastric contents and the failure of the esophagus to clear by peristaltic contractions lead to GERD. The severity of the disease depends strongly on the pH of the refluxed gastric juice [104, 105]. Chronic GERDs most likely to cause BE—replacement of the stratified squamous epithelium with a metaplastic columnar epithelium. The inflammation caused by chronic acid exposure appear to promote the development of EA from BE [106]. Patients subjected to endoscopy for any indications have the prevalence of BE, which is approximately 1–2% up to 5–15% in patients with GERD symptoms. Patients with BE have a 30- to 125-fold higher risk for devel-

In 2013, Rubenstein et al. found an inverse correlation of *H. pylori* with erosive

Numerous studies have addressed whether *H. pylori* eradication promotes the development of GERD or associated diseases. However, recent studies have failed to

Inflammatory bowel diseases (IBDs) are chronic relapsing disorders of increasing incidence and two main forms—Crohn's disease and ulcerative colitis. Intestinal inflammation and epithelial injury are characterized for the diseases. In Crohn's disease, inflammation is discontinuous and can affect any part of the gastrointestinal tract and all layers of the bowel wall. In contrast, ulcerative colitis expands continuously from the rectum and affect the superficial layer of the mucosa. Modern hygienic practices and diet have been proposed to account for the increasing incidence of IBD in Western societies associated with changes in the human microbiota composition [113]. A correlation between *H. pylori* infection and IBD has long been suspected by gastroenterologists. There is a lower prevalence of *H. pylori* in IBD patients confirmed by studies, in which active *H. pylori* infection was detected by urea breath test rather than serum IgG or IgA [114–116]. A strong negative association between *H. pylori* colonization and IBD is presented in all meta-analyses and almost all original articles covering the topic [117–119].

*H. pylori* is its best-known component of the stomach microbiota. In healthy conditions the main representatives of gastric microbiota are Streptococcus, Proteobacteria, Firmicutes, Bacteroidetes, and Actinobacteria [120–124]. The exact composition of a healthy gastric microbiota remains uncharacterized. The interaction between the normal microbiota and *H. pylori* has not yet been fully defined. There is some evidence suggesting a predominance of *H. pylori* over other microbes

corroborate an important clinical impact on GERD of *H. pylori* eradication.

esophagitis, especially in patients harboring CagA-positive strains [108]. This evidence was further supported by Korean and Japanese studies, in which *H. pylori* could be negatively linked with the risk and severity of erosive esophagitis [109, 110]. In 2012, Fischbach et al. documented a decreased risk of EA predominantly in patients infected with CagA-positive *H. pylori* strains and recently confirmed a negative association of *H. pylori* with the risk of BE [41, 111]. Nie et al. also found that CagA-positive *H. pylori* strains were associated with a decreased risk of EA in

*Gastritis - New Approaches and Treatments*

prevalence of metronidazole resistance [82–84].

dual resistant strains is >5, >9, or >15%, respectively [73].

lasting 10–14 days achieved ≥85% eradication rate, even in areas with a high

Sequential therapy is more complex and requires switching of antibiotic drugs during the treatment course, which can confuse the patients. Concomitant therapy (PPI, amoxicillin, clarithromycin, and a nitroimidazole administered concurrently) is easier and similar to standard triple therapy and should be the preferred non-bismuth quadruple therapy. Sequential therapy achieves lower cure rates compared to concomitant therapy against clarithromycin-resistant strains [85, 86]. All non-BQTs (concomitant, hybrid, triple, and sequential) lead to excellent cure rates against susceptible *H. pylori* strains, but the cure rate will always be <90% when the rate of

Response to PPI is individual and determined by cytochrome 2C19 and MDR polymorphisms. Caucasian subjects show a higher prevalence of high metabolizers (56–81%) compared to Asian [74]. Esomeprazole and rabeprazole provide better overall *H. pylori* eradication rates, especially esomeprazole 40 mg twice daily, whereas rabeprazole 10 and 20 mg twice daily [87–92]. By raising pH, *H. pylori* enters the replicative state and become susceptible to amoxicillin and clarithromycin [93]. For second-line treatment, after failure of PPI-clarithromycin-amoxicillin triple therapy, a bismuth-containing quadruple therapy or a fluoroquinolone-containing triple or quadruple therapy are recommended [94]. In theory, any treatment could be used after failure of BQT, including repeating the same BQT with longer duration and high metronidazole dosage. However, treatment that has already failed seems wiser never to be repeated. Bismuth therapies are usually proposed as first-line treatments for areas of high clarithromycin resistance and using a clarithromycin-containing treatment as second-line therapy after failure of a BQT does not seem to be practical. That is why Levofloxacin-based triple therapy, that is known to be effective as second-line therapy after clarithromycin-containing therapy, should also be recommended after failure of a bismuth-containing quadruple regimen [95, 96]. The incidence of side effects are lower with levofloxacincontaining triple therapy than with bismuth-containing quadruple therapy [97]. A sub-group analysis showed similar eradication rates with 500 and 1000 mg) of levofloxacin [97]. However, the efficacy of levofloxacin-based regimens may be affected by an increased prevalence of levofloxacin resistance [98]. Therefore, 14-day bismuth quadruple therapy is a valid second-line treatment for *H. pylori* eradication, especially in areas with high fluoroquinolones resistance. Combining bismuth and levofloxacin in a 14-day quadruple therapy is an effective (≥90% cure rate), simple, and safe second-line strategy in patients [99]. Bismuth overcomes clarithromycin and levofloxacin resistance, because of the synergistic effect with antibiotics [100, 101]. Therefore, the levofloxacin/bismuth-containing quadruple therapy constitutes an encouraging second-line strategy not only in patients failing previous standard triple therapy, but also in non-bismuth quadruple "sequential" or

After failure of the first-line treatment (clarithromycin based) and second-line treatment (with bismuth-containing quadruple regimen), it is recommended to use the fluoroquinolone-containing regimen as a rescue therapy. After failure of the first-line treatment (triple or non-bismuth quadruple) and second-line treatment (fluoroquinolone-containing therapy), it is recommended to use the bismuth-based quadruple therapy. Furthermore, BQT is not influenced by clarithromycin and fluoroquinolone resistance [102]. However, if a second-line treatment fails, culture with susceptibility testing (AST) or molecular determination of genotype resistance is recommended. Susceptibility-guided triple therapies proved more effective than

empirical triple therapies in first-line treatment [55, 103].

**10**

"concomitant" treatments.

#### **6.** *Helicobacter pylori* **and extragastric diseases**

Chronic infection with *H. pylori* may be favorable for certain gastroesophageal diseases, asthma, and other allergic disease manifestations and inflammatory bowel diseases (IBD). The beneficial role of *H. pylori* in GERD, Barrett's esophagus (BE), and esophageal adenocarcinoma (EA) requires further clinical and experimental confirmation.

The reflux of gastric contents and the failure of the esophagus to clear by peristaltic contractions lead to GERD. The severity of the disease depends strongly on the pH of the refluxed gastric juice [104, 105]. Chronic GERDs most likely to cause BE—replacement of the stratified squamous epithelium with a metaplastic columnar epithelium. The inflammation caused by chronic acid exposure appear to promote the development of EA from BE [106]. Patients subjected to endoscopy for any indications have the prevalence of BE, which is approximately 1–2% up to 5–15% in patients with GERD symptoms. Patients with BE have a 30- to 125-fold higher risk for developing EA, in comparison with the general population [107].

In 2013, Rubenstein et al. found an inverse correlation of *H. pylori* with erosive esophagitis, especially in patients harboring CagA-positive strains [108]. This evidence was further supported by Korean and Japanese studies, in which *H. pylori* could be negatively linked with the risk and severity of erosive esophagitis [109, 110].

In 2012, Fischbach et al. documented a decreased risk of EA predominantly in patients infected with CagA-positive *H. pylori* strains and recently confirmed a negative association of *H. pylori* with the risk of BE [41, 111]. Nie et al. also found that CagA-positive *H. pylori* strains were associated with a decreased risk of EA in all populations, irrespective of geographical location [112].

Numerous studies have addressed whether *H. pylori* eradication promotes the development of GERD or associated diseases. However, recent studies have failed to corroborate an important clinical impact on GERD of *H. pylori* eradication.

Inflammatory bowel diseases (IBDs) are chronic relapsing disorders of increasing incidence and two main forms—Crohn's disease and ulcerative colitis. Intestinal inflammation and epithelial injury are characterized for the diseases. In Crohn's disease, inflammation is discontinuous and can affect any part of the gastrointestinal tract and all layers of the bowel wall. In contrast, ulcerative colitis expands continuously from the rectum and affect the superficial layer of the mucosa. Modern hygienic practices and diet have been proposed to account for the increasing incidence of IBD in Western societies associated with changes in the human microbiota composition [113]. A correlation between *H. pylori* infection and IBD has long been suspected by gastroenterologists. There is a lower prevalence of *H. pylori* in IBD patients confirmed by studies, in which active *H. pylori* infection was detected by urea breath test rather than serum IgG or IgA [114–116]. A strong negative association between *H. pylori* colonization and IBD is presented in all meta-analyses and almost all original articles covering the topic [117–119].

#### **7.** *H. pylori* **and the human microbiota**

*H. pylori* is its best-known component of the stomach microbiota. In healthy conditions the main representatives of gastric microbiota are Streptococcus, Proteobacteria, Firmicutes, Bacteroidetes, and Actinobacteria [120–124]. The exact composition of a healthy gastric microbiota remains uncharacterized. The interaction between the normal microbiota and *H. pylori* has not yet been fully defined. There is some evidence suggesting a predominance of *H. pylori* over other microbes [120]. Non-*H. pylori Helicobacter* species can cause gastritis, peptic ulcer disease, gastric cancer, and gastric mucosa-associated lymphoid tissue lymphoma [125–130].

*H. pylori* eradication therapy can impair the healthy gut microbiota. The most relevant shifts involved are, respectively, *Bacteroides*, *Bifidobacterium*, *Clostridium*, *Enterobacteriaceae*, and *Lactobacillus* [131]. The most common GI side effects correlated with antibiotic therapy include diarrhea, nausea, vomiting, bloating, and abdominal pain [132]. Antibiotic administration is the main risk factor for the development of *C. difficile* infection [133]. There is insufficient evidence on the effect of different eradication regimens and long-lasting impact of *H. pylori* eradication on the composition of gut microbiota. There are encouraging results, that probiotic supplementation reduce the side effects of eradication [134–144]. Certain probiotics stains may have a better beneficial effect. There are evidence that *Saccharomyces boulardii* decreases the risk and overall adverse effects (RR 0.44, 95% CI 0.31 to 0.64) [145]. A number of meta-analyses of RCTs show a positive result that probiotics has the capacity to increase the efficacy of *H. pylori* eradication therapies [134–144]. Despite these encouraging data, probiotics appear to increase the *H. pylori* eradication rate not by direct effects on *H. pylori*, but with reducing the side effects related to the therapy.

#### **8. Conclusion**

*Helicobacter pylori* has been part of the human population and migration since ancient times. Infection with the bacterium is an extremely significant disease and can lead to severe consequences for infected individuals. Treatment and the rising bacterial resistance are challenges that we encounter in everyday practice, according to the latest guidelines recommendations. We hope that in the future our knowledge will expand and we will be ready to present new approaches for *H. pylori* management, because the bacterium will undoubtedly continue to be part of our microbiome.

#### **Acknowledgments**

The publication of this work was supported by KRKA.

#### **Author details**

Todor Asenov Angelov1 \*, Mila Dimitrova Kovacheva-Slavova1 , Hristo Ilianov Iliev2 , Hristo Yankov Valkov 1 and Borislav Georgiev Vladimirov1

1 Department of Gastroenterology, University Hospital "Tsaritsa Ioanna-ISUL" Medical University of Sofia, Sofia, Bulgaria

2 Medical University of Sofia, Sofia, Bulgaria

\*Address all correspondence to: totodari@gmail.com

© 2019 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

**13**

Helicobacter pylori *Infection*

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[11] Ford AC, Marwaha A, Sood R, Moayyedi P. Global prevalence of, and risk factors for, uninvestigated dyspepsia: A meta-analysis. Gut. Jul 2015;**64**(7):1049-1057. DOI: 10.1136/

[12] Zhao B, Zhao J, Cheng WF, Shi WJ, Liu W, Pan XL, et al. Efficacy of *Helicobacter pylori* eradication therapy on functional dyspepsia: A meta-analysis of randomized controlled studies with 12-month follow-up. Journal of Clinical Gastroenterology. 2014;**48**(3):241-247. DOI: 10.1097/MCG.

[13] Ilver D, Arnqvist A, Ogren J, Frick IM, Kersulyte D, Incecik ET, et al. *Helicobacter pylori* adhesin binding fucosylated histo-blood group antigens

revealed by retagging. Science. 1998;**279**(5349):373-377

[14] Mahdavi J, Sonden B, Hurtig M, Olfat FO, Forsberg L, Roche N, et al. *Helicobacter pylori* SabA adhesin in persistent infection and chronic inflammation. Science. 2002;**297**(5581):573-578. DOI: 10.1126/

[15] Rossez Y, Gosset P, Boneca IG, Magalhaes A, Ecobichon C, Reis CA, et al. The lacdiNAc-specific adhesin LabA mediates adhesion of *Helicobacter* 

*pylori* to human gastric mucosa.

gutjnl-2015-309252

gutjnl-2014-307843

0b013e31829f2e25

science.1069076

[2] Torre LA, Bray F, Siegel RL, Ferlay J, Lortet-Tieulent J, Jemal A. Global cancer statistics, 2012. CA: A Cancer Journal for Clinicians. 2015;**65**(2):87-108. DOI:

[3] Amieva M, Peek RM Jr. Pathobiology of *Helicobacter pylori*-induced gastric cancer. Gastroenterology. 2016;**150**(1): 64-78. DOI: 10.1053/j.gastro.2015.09.004

[4] Atherton JC, Blaser MJ. Coadaptation of *Helicobacter pylori* and humans: Ancient history, modern implications. The Journal of Clinical Investigation. 2009;**119**(9):2475-2487. DOI: 10.1172/

[5] Breckan RK, Paulssen EJ, Asfeldt AM, Kvamme JM, Straume B, Florholmen J. The all-age prevalence of *Helicobacter* 

transmission routes. A population-based study. Helicobacter. 2016;**21**(6):586-595.

Kuipers EJ, Axon AT, et al. Management of *Helicobacter pylori* infection—The Maastricht V/Florence Consensus Report. Gut. 2017;**66**(1):6-30. DOI:

[7] Suzuki H, Warren R, Marshall B. *Helicobacter pylori*. Japan: Springer; 2016. DOI: 10.1007/978-4-431-55705-0.

[8] Tack J, Talley NJ, Camilleri M, Holtmann G, Hu P, Malagelada JR, et al., European Helicobacter and Microbiota Study Group and Consensus Panel. Functional gastroduodenal disorders. Gastroenterology. 2006;**130**(5):1466- 1479. DOI: 10.1053/j.gastro.2005.11.059

*pylori* infection and potential

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10.1136/gutjnl-2016-312288

ISBN: 978-4-431-55704-3

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### **References**

*Gastritis - New Approaches and Treatments*

**12**

**Author details**

**8. Conclusion**

Todor Asenov Angelov1

**Acknowledgments**

Hristo Yankov Valkov 1

Medical University of Sofia, Sofia, Bulgaria

2 Medical University of Sofia, Sofia, Bulgaria

provided the original work is properly cited.

\*Address all correspondence to: totodari@gmail.com

The publication of this work was supported by KRKA.

\*, Mila Dimitrova Kovacheva-Slavova1

*Helicobacter pylori* has been part of the human population and migration since ancient times. Infection with the bacterium is an extremely significant disease and can lead to severe consequences for infected individuals. Treatment and the rising bacterial resistance are challenges that we encounter in everyday practice, according to the latest guidelines recommendations. We hope that in the future our knowledge will expand and we will be ready to present new approaches for *H. pylori* management, because the bacterium will undoubtedly continue to be part of our microbiome.

and Borislav Georgiev Vladimirov1

[120]. Non-*H. pylori Helicobacter* species can cause gastritis, peptic ulcer disease, gastric cancer, and gastric mucosa-associated lymphoid tissue lymphoma [125–130]. *H. pylori* eradication therapy can impair the healthy gut microbiota. The most relevant shifts involved are, respectively, *Bacteroides*, *Bifidobacterium*, *Clostridium*, *Enterobacteriaceae*, and *Lactobacillus* [131]. The most common GI side effects correlated with antibiotic therapy include diarrhea, nausea, vomiting, bloating, and abdominal pain [132]. Antibiotic administration is the main risk factor for the development of *C. difficile* infection [133]. There is insufficient evidence on the effect of different eradication regimens and long-lasting impact of *H. pylori* eradication on the composition of gut microbiota. There are encouraging results, that probiotic supplementation reduce the side effects of eradication [134–144]. Certain probiotics stains may have a better beneficial effect. There are evidence that *Saccharomyces boulardii* decreases the risk and overall adverse effects (RR 0.44, 95% CI 0.31 to 0.64) [145]. A number of meta-analyses of RCTs show a positive result that probiotics has the capacity to increase the efficacy of *H. pylori* eradication therapies [134–144]. Despite these encouraging data, probiotics appear to increase the *H. pylori* eradication rate not by direct effects on *H. pylori*, but with reducing the side effects related to the therapy.

1 Department of Gastroenterology, University Hospital "Tsaritsa Ioanna-ISUL"

© 2019 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium,

, Hristo Ilianov Iliev2

,

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[5] Breckan RK, Paulssen EJ, Asfeldt AM, Kvamme JM, Straume B, Florholmen J. The all-age prevalence of *Helicobacter pylori* infection and potential transmission routes. A population-based study. Helicobacter. 2016;**21**(6):586-595. DOI: 10.1111/hel.12316

[6] Malfertheiner P, Megraud F, O'Morain CA, Gisbert JP, Kuipers EJ, Axon AT, et al. Management of *Helicobacter pylori* infection—The Maastricht V/Florence Consensus Report. Gut. 2017;**66**(1):6-30. DOI: 10.1136/gutjnl-2016-312288

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[8] Tack J, Talley NJ, Camilleri M, Holtmann G, Hu P, Malagelada JR, et al., European Helicobacter and Microbiota Study Group and Consensus Panel. Functional gastroduodenal disorders. Gastroenterology. 2006;**130**(5):1466- 1479. DOI: 10.1053/j.gastro.2005.11.059

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[11] Ford AC, Marwaha A, Sood R, Moayyedi P. Global prevalence of, and risk factors for, uninvestigated dyspepsia: A meta-analysis. Gut. Jul 2015;**64**(7):1049-1057. DOI: 10.1136/ gutjnl-2014-307843

[12] Zhao B, Zhao J, Cheng WF, Shi WJ, Liu W, Pan XL, et al. Efficacy of *Helicobacter pylori* eradication therapy on functional dyspepsia: A meta-analysis of randomized controlled studies with 12-month follow-up. Journal of Clinical Gastroenterology. 2014;**48**(3):241-247. DOI: 10.1097/MCG. 0b013e31829f2e25

[13] Ilver D, Arnqvist A, Ogren J, Frick IM, Kersulyte D, Incecik ET, et al. *Helicobacter pylori* adhesin binding fucosylated histo-blood group antigens revealed by retagging. Science. 1998;**279**(5349):373-377

[14] Mahdavi J, Sonden B, Hurtig M, Olfat FO, Forsberg L, Roche N, et al. *Helicobacter pylori* SabA adhesin in persistent infection and chronic inflammation. Science. 2002;**297**(5581):573-578. DOI: 10.1126/ science.1069076

[15] Rossez Y, Gosset P, Boneca IG, Magalhaes A, Ecobichon C, Reis CA, et al. The lacdiNAc-specific adhesin LabA mediates adhesion of *Helicobacter pylori* to human gastric mucosa.

The Journal of Infectious Diseases. 2014;**210**(8):1286-1295. DOI: 10.1093/ infdis/jiu239

[16] Viala J, Chaput C, Boneca IG, Cardona A, Girardin SE, Moran AP, et al. Nod1 responds to peptidoglycan delivered by the *Helicobacter pylori* cag pathogenicity island. Nature Immunology. 2004;**5**(11):1166-1174

[17] Kim DJ, Park JH, Franchi L, Backert S, Núñez G. The Cag pathogenicity island and interaction between TLR2/NOD2 and NLRP3 regulate IL-1b production in *Helicobacter pylori* infected dendritic cells. European Journal of Immunology. 2013;**43**(10):2650-2658. DOI: 10.1002/ eji.201243281

[18] Vanaja SK, Rathinam VA, Fitzgerald KA. Mechanisms of inflammasome activation: Recent advances and novel insights. Trends in Cell Biology. 2015;**25**(5):308-315. DOI: 10.1016/j.tcb.2014.12.009

[19] Cook KW, Letley DP, Ingram RJ, Staples E, Skjoldmose H, Atherton JC, et al. CCL20/CCR6-mediated migration of regulatory T cells to the *Helicobacter pylori*-infected human gastric mucosa. Gut. 2014;**63**(10):1550-1559. DOI: 10.1136/gutjnl-2013-306253

[20] Italiani P, Boraschi D. From monocytes to M1/M2 macrophages: Phenotypical vs. functional differentiation. Frontiers in Immunology. 2014;**5**:514. DOI: 10.3389/ fimmu.2014.00514

[21] Yun CH, Lundgren A, Azem J, Sjoling A, Holmgren J, Svennerholm AM, et al. Natural killer cells and *Helicobacter pylori* infection: Bacterial antigens and interleukin-12 act synergistically to induce gamma interferon production. Infection and Immunity. 2005;**73**(3):1482-1490

[22] Rizzuti D, Ang M, Sokollik C, Wu T, Abdullah M, Greenfield L, et al. *Helicobacter pylori* inhibits dendritic cell maturation via interleukin-10-mediated activation of the signal transducer and activator of transcription 3 pathway. Journal of Innate Immunity. 2015;**7**(2):199-211. DOI: 10.1159/000368232

[23] Bimczok D, Kao JY, Zhang M, Cochrun S, Mannon P, Peter S, et al. Human gastric epithelial cells contribute to gastric immune regulation by providing retinoic acid to dendritic cells. Mucosal Immunology. May 2015;**8**(3):533-544. DOI: 10.1038/ mi.2014.86

[24] Smyk DS, Koutsoumpas AL, Mytilinaiou MG, Rigopoulou EI, Sakkas LI, Bogdanos DP. *Helicobacter pylori* and autoimmune disease: Cause or bystander. World Journal of Gastroenterology. 2014;**20**(3):613-629. DOI: 10.3748/wjg.v20.i3.613

[25] Oertli M, Sundquist M, Hitzler I, Engler DB, Arnold IC, Reuter S, et al. DC-derived IL-18 drives Treg differentiation, murine *Helicobacter pylori*-specific immune tolerance, and asthma protection. The Journal of Clinical Investigation. 2012;**122**(3):1082-1096. DOI: 10.1172/ JCI61029

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[27] Malfertheiner P. The intriguing relationship of *Helicobacter pylori* infection and acid secretion in peptic ulcer disease and gastric cancer. Digestive Diseases. 2011;**29**(5):459-464. DOI: 10.1159/000332213

[28] Robinson K, Kenefeck R, Pidgeon EL, Shakib S, Patel S, Polson RJ, et al. *Helicobacter pylori*-induced peptic

**15**

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ulcer disease is associated with

[29] Zhou Y, Toh ML, Zrioual S,

intracellular signal transduction pathways and modulation by IL-17RA and IL-17RC RNA interference in AGS gastric adenocarcinoma cells. Cytokine. 2007;**38**(3):157-164. DOI: 10.1016/j.

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[31] Herrero R, Park JY, Forman D. The fight against gastric cancer—The IARC Working Group report. Best Practice & Research. Clinical Gastroenterology. 2014;**28**(6):1107-1114. DOI: 10.1016/j.

[32] Plummer M, Franceschi S, Vignat J, Forman D, de Martel C. Global burden of gastric cancer attributable to

*Helicobacter pylori*. International Journal of Cancer. 2015;**136**(2):487-490. DOI:

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[34] Malfertheiner P, Fry LC, Monkemuller K. Can gastric cancer be prevented by *Helicobacter pylori* eradication? Best Practice &

Research. Clinical Gastroenterology. 2006;**20**(4):709-719. DOI: 10.1016/j.

[35] Na HK, Woo JH. *Helicobacter pylori* induces hypermethylation of CpG islands through upregulation of DNA

Gut. 2008;**57**(10):1375-1385

cyto.2007.06.002

gutjnl-2014-308915

bpg.2014.10.003

10.1002/ijc.28999

bpg.2006.04.005

*DOI: http://dx.doi.org/10.5772/intechopen.86963*

methyltransferase: Possible involvement of reactive oxygen/nitrogen species. Journal of Cancer Prevention. 2014;**19**(4):259-264. DOI: 10.15430/

[36] Ramis IB, Vianna JS, Goncalves CV,

von Groll A, Dellagostin OA, da Silva PE. Polymorphisms of the IL-6, IL-8 and IL-10 genes and the risk of gastric pathology in patients infected with *Helicobacter pylori*. Journal of Microbiology, Immunology, and Infection. 2015;**9**(12):1535-1547. DOI:

10.1016/j.jmii.2015.03.002

[37] El-Omar EM, Ng MT,

by *Helicobacter pylori*. Part of Current Topics in Microbiology and Immunology. Cham, Switzerland: Springer International Publishing AG; 2017;**400**. DOI: 10.1007/978-3-319- 50520-6. ISBN: 978-3-319-50519-0

[39] Genta RM, Hamner HW,

in *Helicobacter pylori* infection: Frequency, distribution, and response to triple therapy. Human Pathology.

subtyping of gastric MALT lymphomas: Implications for prognosis and management. Gut.

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[42] Zucca E, Bertoni F. The spectrum of MALT lymphoma at different sites: Biological and therapeutic relevance.

1993;**24**(6):577-583

2006;**55**(6):886-893

bpg.2014.09.006

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Hold GL. Polymorphisms in toll-like receptor genes and risk of cancer. Oncogene. 2008;**27**(2):244-252

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JCP.2014.19.4.259

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Miossec P. IL-17A versus IL-17F induced

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*Gastritis - New Approaches and Treatments*

The Journal of Infectious Diseases. 2014;**210**(8):1286-1295. DOI: 10.1093/ *Helicobacter pylori* inhibits dendritic cell maturation via interleukin-10-mediated activation of the signal transducer and activator of transcription 3 pathway. Journal of Innate Immunity. 2015;**7**(2):199-211.

[23] Bimczok D, Kao JY, Zhang M, Cochrun S, Mannon P, Peter S, et al. Human gastric epithelial cells contribute

to gastric immune regulation by providing retinoic acid to dendritic cells. Mucosal Immunology. May 2015;**8**(3):533-544. DOI: 10.1038/

[24] Smyk DS, Koutsoumpas AL, Mytilinaiou MG, Rigopoulou EI, Sakkas LI, Bogdanos DP. *Helicobacter pylori* and autoimmune disease: Cause or bystander. World Journal of Gastroenterology. 2014;**20**(3):613-629.

DOI: 10.3748/wjg.v20.i3.613

DC-derived IL-18 drives Treg differentiation, murine *Helicobacter pylori*-specific immune tolerance, and asthma protection. The Journal of Clinical Investigation. 2012;**122**(3):1082-1096. DOI: 10.1172/

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DOI: 10.1159/000332213

[28] Robinson K, Kenefeck R,

Digestive Diseases. 2011;**29**(5):459-464.

Pidgeon EL, Shakib S, Patel S, Polson RJ, et al. *Helicobacter pylori*-induced peptic

DOI: 10.1159/000368232

mi.2014.86

JCI61029

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[17] Kim DJ, Park JH, Franchi L, Backert S, Núñez G. The Cag pathogenicity island and interaction between TLR2/NOD2 and NLRP3 regulate IL-1b production in *Helicobacter pylori* infected dendritic cells. European Journal of Immunology. 2013;**43**(10):2650-2658. DOI: 10.1002/

infdis/jiu239

eji.201243281

[18] Vanaja SK, Rathinam VA, Fitzgerald KA. Mechanisms of inflammasome activation: Recent advances and novel insights. Trends in Cell Biology. 2015;**25**(5):308-315. DOI:

10.1016/j.tcb.2014.12.009

[19] Cook KW, Letley DP, Ingram RJ, Staples E, Skjoldmose H, Atherton JC, et al. CCL20/CCR6-mediated migration of regulatory T cells to the *Helicobacter pylori*-infected human gastric mucosa. Gut. 2014;**63**(10):1550-1559. DOI: 10.1136/gutjnl-2013-306253

[20] Italiani P, Boraschi D. From monocytes to M1/M2 macrophages:

Immunology. 2014;**5**:514. DOI: 10.3389/

[21] Yun CH, Lundgren A, Azem J, Sjoling A, Holmgren J, Svennerholm AM, et al. Natural killer cells and *Helicobacter pylori* infection: Bacterial antigens and interleukin-12 act synergistically

production. Infection and Immunity.

[22] Rizzuti D, Ang M, Sokollik C, Wu T, Abdullah M, Greenfield L, et al.

Phenotypical vs. functional differentiation. Frontiers in

to induce gamma interferon

2005;**73**(3):1482-1490

fimmu.2014.00514

**14**

ulcer disease is associated with inadequate regulatory T cell responses. Gut. 2008;**57**(10):1375-1385

[29] Zhou Y, Toh ML, Zrioual S, Miossec P. IL-17A versus IL-17F induced intracellular signal transduction pathways and modulation by IL-17RA and IL-17RC RNA interference in AGS gastric adenocarcinoma cells. Cytokine. 2007;**38**(3):157-164. DOI: 10.1016/j. cyto.2007.06.002

[30] Colquhoun A, Arnold M, Ferlay J, Goodman KJ, Forman D, Soerjomataram I. Global patterns of cardia and non-cardia gastric cancer incidence in 2012. Gut. 2015;**64**(12):1881-1888. DOI: 10.1136/ gutjnl-2014-308915

[31] Herrero R, Park JY, Forman D. The fight against gastric cancer—The IARC Working Group report. Best Practice & Research. Clinical Gastroenterology. 2014;**28**(6):1107-1114. DOI: 10.1016/j. bpg.2014.10.003

[32] Plummer M, Franceschi S, Vignat J, Forman D, de Martel C. Global burden of gastric cancer attributable to *Helicobacter pylori*. International Journal of Cancer. 2015;**136**(2):487-490. DOI: 10.1002/ijc.28999

[33] Lauren P. The two histological main types of gastric carcinoma: Diffuse and so-called intestinal-type carcinoma. An attempt at a histo-clinical classification. Acta Pathologica et Microbiologica Scandinavica. 1965;**64**:31-49

[34] Malfertheiner P, Fry LC, Monkemuller K. Can gastric cancer be prevented by *Helicobacter pylori* eradication? Best Practice & Research. Clinical Gastroenterology. 2006;**20**(4):709-719. DOI: 10.1016/j. bpg.2006.04.005

[35] Na HK, Woo JH. *Helicobacter pylori* induces hypermethylation of CpG islands through upregulation of DNA

methyltransferase: Possible involvement of reactive oxygen/nitrogen species. Journal of Cancer Prevention. 2014;**19**(4):259-264. DOI: 10.15430/ JCP.2014.19.4.259

[36] Ramis IB, Vianna JS, Goncalves CV, von Groll A, Dellagostin OA, da Silva PE. Polymorphisms of the IL-6, IL-8 and IL-10 genes and the risk of gastric pathology in patients infected with *Helicobacter pylori*. Journal of Microbiology, Immunology, and Infection. 2015;**9**(12):1535-1547. DOI: 10.1016/j.jmii.2015.03.002

[37] El-Omar EM, Ng MT, Hold GL. Polymorphisms in toll-like receptor genes and risk of cancer. Oncogene. 2008;**27**(2):244-252

[38] Tegtmeyer N, Backert S. Molecular Pathogenesis and Signal Transduction by *Helicobacter pylori*. Part of Current Topics in Microbiology and Immunology. Cham, Switzerland: Springer International Publishing AG; 2017;**400**. DOI: 10.1007/978-3-319- 50520-6. ISBN: 978-3-319-50519-0

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[41] Fischbach W. Gastric MALT lymphoma—Update on diagnosis and treatment. Best Practice & Research. Clinical Gastroenterology. 2014;**28**(6):1069-1077. DOI: 10.1016/j. bpg.2014.09.006

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[119] Castano-Rodriguez N, Kaakoush NO, Lee WS,

Mitchell HM. Dual role of *Helicobacter* and *Campylobacter* species in IBD: A systematic review and meta-analysis. Gut. Feb 2017;**66**(2):235-249. DOI: 10.1136/gutjnl-2015-310545

[120] Andersson AF, Lindberg M, Jakobsson H, et al. Comparative analysis

*pylori* infection in patients with inflammatory bowel disease. Journal

of Clinical Gastroenterology.

2003;**36**(1):22-25

i15.4750

0889

*DOI: http://dx.doi.org/10.5772/intechopen.86963*

of human gut microbiota by

2008;**3**:e2836

2009;**4**:e7985

2013;**37**:736-761

2016;**6**:18594

barcoded pyrosequencing. PLoS One.

[121] Bik EM, Eckburg PB, Gill SR, et al. Molecular analysis of the bacterial microbiota in the human stomach. Proceedings of the National Academy of Sciences of the United States of America. 2006;**103**:732-737

[122] Li XX, Wong GLH, To KF, et al. Bacterial microbiota profiling in gastritis without *Helicobacter pylori* infection or non-steroidal antiinflammatory drug use. PLoS One.

[123] Yang I, Nell S, Suerbaum S. Survival in hostile territory: The microbiota of the stomach. FEMS Microbiology Reviews.

[124] Yang I, Woltemate S, Piazuelo MB, et al. Different gastric microbiota compositions in two human populations

with high and low gastric cancer risk in Colombia. Scientific Reports.

[125] Debongnie JC, Donnay M, Mairesse J, et al. Gastric ulcers and *Helicobacter heilmannii*. European Journal of Gastroenterology & Hepatology. 1998;**10**:251-254

[126] Matsumoto T, Kawakubo M, Akamatsu T, et al. Helicobacter

[127] Morgner A, Bayerdörffer E, Meining A, et al. *Helicobacter heilmannii*

and gastric cancer. Lancet.

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[128] Morgner A, Lehn N, Andersen LP, et al. *Helicobacter heilmannii*-associated primary gastric low-grade MALT lymphoma: Complete remission after

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[116] Piodi LP, Bardella M, Rocchia C, Cesana BM, Baldassarri A, Quatrini M. Possible protective effect of 5-aminosalicylic acid on *Helicobacter pylori* infection in patients with inflammatory bowel disease. Journal of Clinical Gastroenterology. 2003;**36**(1):22-25

[117] Wu XW, Ji HZ, Yang MF, Wu L, Wang FY. *Helicobacter pylori* infection and inflammatory bowel disease in Asians: A meta-analysis. World Journal of Gastroenterology. 2015;**21**(15): 4750-4756. DOI: 10.3748/wjg.v21. i15.4750

[118] Rokkas T, Gisbert JP, Niv Y, O'Morain C. The association between *Helicobacter pylori* infection and inflammatory bowel disease based on meta-analysis. United European Gastroenterology Journal. 2015;**3**(6):539-550. DOI: 10.1177/2050 64061558088910.1177\_205064061558 0889

[119] Castano-Rodriguez N, Kaakoush NO, Lee WS, Mitchell HM. Dual role of *Helicobacter* and *Campylobacter* species in IBD: A systematic review and meta-analysis. Gut. Feb 2017;**66**(2):235-249. DOI: 10.1136/gutjnl-2015-310545

[120] Andersson AF, Lindberg M, Jakobsson H, et al. Comparative analysis of human gut microbiota by barcoded pyrosequencing. PLoS One. 2008;**3**:e2836

[121] Bik EM, Eckburg PB, Gill SR, et al. Molecular analysis of the bacterial microbiota in the human stomach. Proceedings of the National Academy of Sciences of the United States of America. 2006;**103**:732-737

[122] Li XX, Wong GLH, To KF, et al. Bacterial microbiota profiling in gastritis without *Helicobacter pylori* infection or non-steroidal antiinflammatory drug use. PLoS One. 2009;**4**:e7985

[123] Yang I, Nell S, Suerbaum S. Survival in hostile territory: The microbiota of the stomach. FEMS Microbiology Reviews. 2013;**37**:736-761

[124] Yang I, Woltemate S, Piazuelo MB, et al. Different gastric microbiota compositions in two human populations with high and low gastric cancer risk in Colombia. Scientific Reports. 2016;**6**:18594

[125] Debongnie JC, Donnay M, Mairesse J, et al. Gastric ulcers and *Helicobacter heilmannii*. European Journal of Gastroenterology & Hepatology. 1998;**10**:251-254

[126] Matsumoto T, Kawakubo M, Akamatsu T, et al. Helicobacter heilmannii sensu stricto-related gastric ulcers: A case report. World Journal of Gastroenterology. 2014;**20**:3376-3382

[127] Morgner A, Bayerdörffer E, Meining A, et al. *Helicobacter heilmannii* and gastric cancer. Lancet. 1995;**346**:511-512

[128] Morgner A, Lehn N, Andersen LP, et al. *Helicobacter heilmannii*-associated primary gastric low-grade MALT lymphoma: Complete remission after

curing the infection. Gastroenterology. 2000;**118**:821-828

[129] Haesebrouck F, Pasmans F, Flahou B, et al. Gastric Helicobacters in domestic animals and nonhuman primates and their significance for human health. Clinical Microbiology Reviews. 2009;**22**:202-223

[130] Stolte M, Kroher G, Meining A, et al. A comparison of *Helicobacter pylori* and *H. heilmannii* gastritis. A matched control study involving 404 patients. Scandinavian Journal of Gastroenterology. 1997;**32**:28-33

[131] Ladirat SE, Schols HA, Nauta A, et al. High-throughput analysis of the impact of antibiotics on the human intestinal microbiota composition. Journal of Microbiological Methods. 2013;**92**:387-397

[132] Marteau P, Rambaud JC. Potential of using lactic acid bacteria for therapy and immunomodulation in man. FEMS Microbiology Reviews. 1993;**12**:207-220

[133] Lessa FC, Mu Y, Bamberg WM, et al. Burden of *Clostridium difficile* infection in the United States. The New England Journal of Medicine. 2015;**372**:825-834

[134] Dang Y, Reinhardt JD, Zhou X, et al. The effect of probiotics supplementation on *Helicobacter pylori* eradication rates and side effects during eradication therapy: A meta-analysis. PLoS One. 2014;**9**:e111030

[135] Lv Z, Wang B, Zhou X, et al. Efficacy and safety of probiotics as adjuvant agents for *Helicobacter pylori* infection: A meta-analysis. Experimental and Therapeutic Medicine. 2015;**9**:707-716

[136] Tong JL, Ran ZH, Shen J, et al. Meta-analysis: The effect of supplementation with probiotics on eradication rates and adverse events during *Helicobacter pylori* eradication therapy. Alimentary Pharmacology & Therapeutics. 2007;**25**:155-168

[137] Wang ZH, Gao QY, Fang JY. Metaanalysis of the efficacy and safety of Lactobacillus-containing and Bifidobacterium-containing probiotic compound preparation in *Helicobacter pylori* eradication therapy. Journal of Clinical Gastroenterology. 2013;**47**:25-32

[138] Zhang M-M, Qian W, Qin Y-Y, et al. Probiotics in *Helicobacter pylori* eradication therapy: A systematic review and meta-analysis. World Journal of Gastroenterology. 2015;**21**:4345-4357

[139] Zheng X, Lyu L, Mei Z. Lactobacillus-containing probiotic supplementation increases *Helicobacter pylori* eradication rate: Evidence from a meta-analysis. Revista Española de Enfermedades Digestivas. 2013;**105**:445-453

[140] Zhu R, Chen K, Zheng Y-Y, et al. Meta-analysis of the efficacy of probiotics in *Helicobacter pylori* eradication therapy. World Journal of Gastroenterology. 2014;**20**:18013-18021

[141] Zou J, Dong J, Yu X. Metaanalysis: Lactobacillus containing quadruple therapy versus standard triple first-line therapy for *Helicobacter pylori* eradication. Helicobacter. 2009;**14**:97-107

[142] Vladimirov B. Treatment of helicobacter-pylori associated diseases. In: Boyanova L, editor. Helicobacter pylori. Norfolk, UK: Caister Academic Press; 2011:237-251

[143] Li S, Huang XL, Sui JZ, et al. Meta-analysis of randomized controlled trials on the efficacy of probiotics in *Helicobacter pylori* eradication therapy in children. European Journal of Pediatrics. 2014;**173**:153-161

**23**

Helicobacter pylori *Infection*

2009;**21**:45-53

2015;**41**:1237-1245

*DOI: http://dx.doi.org/10.5772/intechopen.86963*

[144] Sachdeva A, Nagpal J. Effect of fermented milk-based probiotic preparations on *Helicobacter pylori* eradication: A systematic review and meta-analysis of randomizedcontrolled trials. European Journal of Gastroenterology & Hepatology.

[145] Szajewska H, Horvath A, Kołodziej M. Systematic review with meta-analysis: *Saccharomyces boulardii* supplementation and eradication of *Helicobacter pylori* infection. Alimentary

Pharmacology & Therapeutics.

Helicobacter pylori *Infection DOI: http://dx.doi.org/10.5772/intechopen.86963*

*Gastritis - New Approaches and Treatments*

curing the infection. Gastroenterology.

during *Helicobacter pylori* eradication therapy. Alimentary Pharmacology &

[137] Wang ZH, Gao QY, Fang JY. Metaanalysis of the efficacy and safety of Lactobacillus-containing and Bifidobacterium-containing probiotic compound preparation in *Helicobacter pylori* eradication therapy. Journal of Clinical Gastroenterology.

[138] Zhang M-M, Qian W, Qin Y-Y, et al. Probiotics in *Helicobacter pylori* eradication therapy: A systematic review and meta-analysis. World Journal of Gastroenterology. 2015;**21**:4345-4357

[139] Zheng X, Lyu L, Mei Z. Lactobacillus-containing probiotic supplementation increases *Helicobacter pylori* eradication rate: Evidence from a meta-analysis. Revista Española de Enfermedades Digestivas.

[140] Zhu R, Chen K, Zheng Y-Y, et al. Meta-analysis of the efficacy of probiotics in *Helicobacter pylori* eradication therapy. World Journal of Gastroenterology.

[141] Zou J, Dong J, Yu X. Metaanalysis: Lactobacillus containing quadruple therapy versus standard triple first-line therapy for *Helicobacter pylori* eradication. Helicobacter.

[142] Vladimirov B. Treatment of helicobacter-pylori associated diseases. In: Boyanova L, editor. Helicobacter pylori. Norfolk, UK: Caister Academic

[143] Li S, Huang XL, Sui JZ, et al. Meta-analysis of randomized controlled trials on the efficacy of probiotics in *Helicobacter pylori* eradication therapy in children. European Journal of Pediatrics. 2014;**173**:153-161

2013;**105**:445-453

2014;**20**:18013-18021

2009;**14**:97-107

Press; 2011:237-251

Therapeutics. 2007;**25**:155-168

2013;**47**:25-32

[129] Haesebrouck F, Pasmans F, Flahou B, et al. Gastric Helicobacters in domestic animals and nonhuman primates and their significance for human health. Clinical Microbiology

[130] Stolte M, Kroher G, Meining A, et al. A comparison of *Helicobacter pylori* and *H. heilmannii* gastritis. A matched control study involving 404 patients. Scandinavian Journal of Gastroenterology. 1997;**32**:28-33

[131] Ladirat SE, Schols HA, Nauta A, et al. High-throughput analysis of the impact of antibiotics on the human intestinal microbiota composition. Journal of Microbiological Methods.

[132] Marteau P, Rambaud JC. Potential of using lactic acid bacteria for therapy and immunomodulation in man. FEMS Microbiology Reviews. 1993;**12**:207-220

[133] Lessa FC, Mu Y, Bamberg WM, et al. Burden of *Clostridium difficile* infection in the United States. The New England Journal of Medicine.

Zhou X, et al. The effect of probiotics supplementation on *Helicobacter pylori* eradication rates and side effects during eradication therapy: A meta-analysis.

Reviews. 2009;**22**:202-223

2000;**118**:821-828

2013;**92**:387-397

2015;**372**:825-834

[134] Dang Y, Reinhardt JD,

PLoS One. 2014;**9**:e111030

[135] Lv Z, Wang B, Zhou X, et al. Efficacy and safety of probiotics as adjuvant agents for *Helicobacter pylori* infection: A meta-analysis. Experimental and Therapeutic Medicine. 2015;**9**:707-716

[136] Tong JL, Ran ZH, Shen J, et al. Meta-analysis: The effect of supplementation with probiotics on eradication rates and adverse events

**22**

[144] Sachdeva A, Nagpal J. Effect of fermented milk-based probiotic preparations on *Helicobacter pylori* eradication: A systematic review and meta-analysis of randomizedcontrolled trials. European Journal of Gastroenterology & Hepatology. 2009;**21**:45-53

[145] Szajewska H, Horvath A, Kołodziej M. Systematic review with meta-analysis: *Saccharomyces boulardii* supplementation and eradication of *Helicobacter pylori* infection. Alimentary Pharmacology & Therapeutics. 2015;**41**:1237-1245

**25**

**Chapter 2**

**Abstract**

with urea marked with 13C.

**1. Introduction**

*Helicobacter pylori*: A Pathogen of

*Isidro Favian Bayas-Morejón, Rosa Angélica Tigre-León,* 

*Helicobacter pylori* is considered a pathogen of global interest because it is a microorganism of very easy contagion between the hosts or host. *Helicobacter pylori* infection is now recognized as a problem that causes chronic gastritis, peptic ulcer disease, and lymphoproliferative disorders and is a major risk factor for gastric cancer. The diagnostic methods to detect *H. pylori* are classified such as direct or invasive, when the identification is directly, the bacterium obtained from gastric mucosa biopsy by endoscopy histology with various staining, culture and PCR techniques, while indirect or noninvasive or serological tests such as the breath test

*Helicobacter pylori* is considered a pathogen of global interest because it is a microorganism of very easy contagion between hosts or susceptible hosts. The first isolation of *H. pylori* was in 1982 by Marshall and Warren who ushered us into a

The number of infected by *H. pylori* has been increased considerably, since a third of the world population has it, while the rest do not know if they have it or not; in developing countries there is an infection rate that goes from 60% and 90% of the population, which is not the case in developed countries ranging from 20–40% [2]**.** Gastroduodenal ulcer diseases are a major factor in the development of

According to studies conducted, many of the pathogenic species of *Helicobacter* are of fecal origin. The transmission to human seems to be associated with the consumption of water and raw or undercooked foods [4, 5]**.** In Ecuador, according to the statistics, the poverty quintiles reached up to 2015 are 35% according to INEC data, which are closely related to the lack of basic services such as drinking water and sanitary services,

a common factor in the population being contamination by water and food [6].

The different methods used for diagnosis range from antigenic screening (Ag) to molecular techniques. Antigenic screening techniques have been associated with a high sensitivity of a detection limit of the *Helicobacter pylori* test with a 95% concordance in specificity compared to the ELISA test [7]**.** In plate culture it is usually

Ample Risk to Health

*Edison Riveliño Ramón-Curay*

*and Darwin Alberto Núñez-Torres*

**Keywords:** *H. pylori*, pathogen, risk to human

new era of gastric microbiology [1].

gastric adenocarcinoma and lymphoma [3].

#### **Chapter 2**

## *Helicobacter pylori*: A Pathogen of Ample Risk to Health

*Isidro Favian Bayas-Morejón, Rosa Angélica Tigre-León, Edison Riveliño Ramón-Curay and Darwin Alberto Núñez-Torres*

#### **Abstract**

*Helicobacter pylori* is considered a pathogen of global interest because it is a microorganism of very easy contagion between the hosts or host. *Helicobacter pylori* infection is now recognized as a problem that causes chronic gastritis, peptic ulcer disease, and lymphoproliferative disorders and is a major risk factor for gastric cancer. The diagnostic methods to detect *H. pylori* are classified such as direct or invasive, when the identification is directly, the bacterium obtained from gastric mucosa biopsy by endoscopy histology with various staining, culture and PCR techniques, while indirect or noninvasive or serological tests such as the breath test with urea marked with 13C.

**Keywords:** *H. pylori*, pathogen, risk to human

#### **1. Introduction**

*Helicobacter pylori* is considered a pathogen of global interest because it is a microorganism of very easy contagion between hosts or susceptible hosts. The first isolation of *H. pylori* was in 1982 by Marshall and Warren who ushered us into a new era of gastric microbiology [1].

The number of infected by *H. pylori* has been increased considerably, since a third of the world population has it, while the rest do not know if they have it or not; in developing countries there is an infection rate that goes from 60% and 90% of the population, which is not the case in developed countries ranging from 20–40% [2]**.** Gastroduodenal ulcer diseases are a major factor in the development of gastric adenocarcinoma and lymphoma [3].

According to studies conducted, many of the pathogenic species of *Helicobacter* are of fecal origin. The transmission to human seems to be associated with the consumption of water and raw or undercooked foods [4, 5]**.** In Ecuador, according to the statistics, the poverty quintiles reached up to 2015 are 35% according to INEC data, which are closely related to the lack of basic services such as drinking water and sanitary services, a common factor in the population being contamination by water and food [6].

The different methods used for diagnosis range from antigenic screening (Ag) to molecular techniques. Antigenic screening techniques have been associated with a high sensitivity of a detection limit of the *Helicobacter pylori* test with a 95% concordance in specificity compared to the ELISA test [7]**.** In plate culture it is usually

considered a difficult and tedious technique; the diagnostic method has the advantage of typifying the organism and determining its sensitivity to antibacterial agents. The methods such as endoscopy to obtain a sample through a biopsy are very used nowadays; it is a traumatic and invasive procedure that can cause complications such as infections, perforations, aspiration, bleeding, and incarceration of the endoscope [8].

#### **2. Theoretical framework**

#### **2.1** *Helicobacter pylori*

*Helicobacter pylori* (*H. pylori*) is a spiral bacterium that does not form spores and is Gram-negative, which colonizes the human stomach and is prevalent throughout the world [9]. It has been associated with peptic ulcer disease, gastric adenocarcinoma, and lower grade B-associated lymphoma associated with the mucosa. In addition, it is thought that the organism is involved in other human diseases such as hematological and autoimmune disorders, insulin resistance, and metabolic syndrome [10]. Although almost 50% of the population is infected with *H. pylori* worldwide, the prevalence, incidence, age distribution, and sequelae of infection are significantly different in developed and developing countries.

*Helicobacter pylori* (previously known as *Campylobacter pylori* or pyloridis) was first isolated from humans in 1982 [11]. Since 1994, *H. pylori* has been considered carcinogenic to humans, and it has even been associated with other diseases, such as cerebrovascular accidents, autoimmune thyroiditis, and diabetes mellitus, among others [12]. This bacterium resides in the stomach of most humans and is usually found in the deeper portions of the mucus gel that lines the gastric mucosa or between the mucus layer and the gastric epithelium [13].

The bacterium is one of the most important findings for gastroenterologists, who for years sought answers to multiple intestinal problems. This is how the gastroenterologist Walery Jaworski in 1899 after analyzing samples of human gastric expirations isolated spiral elongated bacteria and called them *Vibrio regula*, and the said results were published in the manual of gastric diseases; however, these findings were not given the importance they deserved to be written in Polish and not in English [14]**.**

So, it took 79 years for the bacteria to be rediscovered by the Australian doctors Barry Marshall and Robin Warren, who managed to make the first isolation through a pure culture in 1979. This rediscovery allowed them to be Nobel Laureates in 2005 [15].

#### **2.2 Microbiological aspects of** *Helicobacter pylori*

Taxonomically, we can describe *H. pylori* because of its size, shape, color, biochemical function, genus, species, and its relationship with other species. *H. pylori* is a slow-growing, spiral-shaped bacterium. It is a small curved bacillus, microaerophilic, and Gram-negative, and mobile by the presence of flagella. The bacillus has rounded ends. These microorganisms measure 0.5–1.0 μm wide by 2.5–4.0 μm long, since they bear a strong resemblance to members of the *Campylobacter* genus [11].

The multiple genotypic and phenotypic characteristics are different from those of *Helicobacter*, so this new genus was established, including *H. cinaedi* and *H. fennelliae*. The two species of *Helicobacter* that cause diarrheal disease, *H. cinaedi* and *H. fennelliae*, are intestinal microorganisms rather than gastric. As for the clinical manifestations of the disease they generate, these bacteria are more similar to *Campylobacter* than *H. pylori* [13]. The clinical characteristics of the infections caused by these *Helicobacter* are similar to those due to *Campylobacter* species.

**27**

Helicobacter pylori*: A Pathogen of Ample Risk to Health*

**2.3 Pathways of contagion or infestation of the guests**

Although in general there is no difference between the sexes, in some developed

The prevalence of *H. pylori* infection in adults of any age in developed countries ranges between 20 and 40% and reaches figures of 60 to 80% in countries considered third world. The most important difference between countries of high and low prevalence is the intensity with which the infection is transmitted in childhood and

Epidemiological and microbiological evidences have several transmission routes that have been proposed in the studies carried out. The gastro-oral, oral-oral, and fecal-oral routes are the most important routes of transmission [12]. Other routes of importance are also breastfeeding and iatrogenic transmission which are also included as alternating forms for the transmission of the pathogen. The possibilities of spreading the pathogen are of three possible vectors that have been suggested to

The prevalence of *H. pylori* infection shows a strong correlation with access to water. Numerous epidemiological studies confirm this, and the World Health Organization includes it in its list of potential emerging pathogenic microorganisms whose transmis-

Through molecular methods, *H. pylori* DNA has been detected in wastewater, drinking water, and other environmental samples throughout the world, and its survival capacity in water, even chlorinated, has been demonstrated. It has also been detected in the drinking water distribution network [20]. These findings indicate that contaminated water and food play a vital role in the survival and spread of

In another study, developed by Moreno et al. [21]; Moreno and Ferrús, [22] *H. pylori* was detected in 46% of more than 100 wastewater samples, 40% were of

On the other hand, *H. pylori* is able to survive in biofilms when it grows under high C:N conditions [23]. The biofilms formed protect microorganisms from the action of adverse agents, increase the availability of nutrients for their growth, and also increase the frequency of transfer of genetic material [24]. Gião et al. [25] observed that *H. pylori* formed biofilms after 24 hours of being in an unfavorable environment. The association of *H. pylori* with biofilm communities within a water distribution system could offer the bacterium protection against disinfection and predation by protozoa, and there are studies that demonstrate the survival of *H.* 

Those foods that have a water activity (aw) >0.97 and a pH between 4.9 and 6.0 theoretically provide the ideal conditions for the survival and development of *H.* 

Vegetables are one of the foods with the highest risk of fecal contamination, since they are in contact with soil and contaminated irrigation water, which would mean the spread of *H. pylori* in the environment and its transmission to humans. Atapoor et al. [30] and Yahaghi et al. [31] in Iran managed to detect and isolate *H. pylori* in percentages higher than 10%, in vegetable samples. Also, Bayas et al. [32]

have detected the pathogen in vegetables by molecular methods.

countries, there is a higher prevalence of infection in men than in women [16].

maintain the viable form of the bacteria: water, food, and animals.

sion by water is plausible, although it has not yet been confirmed [18, 19].

river water samples and, most strikingly, the 66% were public source.

*pylori* within amoebae of free life[26, 27].

**2.5 Foods transmission**

*pylori* [28, 29].

*DOI: http://dx.doi.org/10.5772/intechopen.86789*

early adolescence [17].

**2.4 Water transmission**

*H. pylori*.

#### **2.3 Pathways of contagion or infestation of the guests**

Although in general there is no difference between the sexes, in some developed countries, there is a higher prevalence of infection in men than in women [16].

The prevalence of *H. pylori* infection in adults of any age in developed countries ranges between 20 and 40% and reaches figures of 60 to 80% in countries considered third world. The most important difference between countries of high and low prevalence is the intensity with which the infection is transmitted in childhood and early adolescence [17].

Epidemiological and microbiological evidences have several transmission routes that have been proposed in the studies carried out. The gastro-oral, oral-oral, and fecal-oral routes are the most important routes of transmission [12]. Other routes of importance are also breastfeeding and iatrogenic transmission which are also included as alternating forms for the transmission of the pathogen. The possibilities of spreading the pathogen are of three possible vectors that have been suggested to maintain the viable form of the bacteria: water, food, and animals.

#### **2.4 Water transmission**

*Gastritis - New Approaches and Treatments*

**2. Theoretical framework**

**2.1** *Helicobacter pylori*

not in English [14]**.**

considered a difficult and tedious technique; the diagnostic method has the advantage of typifying the organism and determining its sensitivity to antibacterial agents. The methods such as endoscopy to obtain a sample through a biopsy are very used nowadays; it is a traumatic and invasive procedure that can cause complications such as infections, perforations, aspiration, bleeding, and incarceration of the endoscope [8].

*Helicobacter pylori* (*H. pylori*) is a spiral bacterium that does not form spores and is Gram-negative, which colonizes the human stomach and is prevalent throughout the world [9]. It has been associated with peptic ulcer disease, gastric adenocarcinoma, and lower grade B-associated lymphoma associated with the mucosa. In addition, it is thought that the organism is involved in other human diseases such as hematological and autoimmune disorders, insulin resistance, and metabolic syndrome [10]. Although almost 50% of the population is infected with *H. pylori* worldwide, the prevalence, incidence, age distribution, and sequelae of infection

*Helicobacter pylori* (previously known as *Campylobacter pylori* or pyloridis) was first isolated from humans in 1982 [11]. Since 1994, *H. pylori* has been considered carcinogenic to humans, and it has even been associated with other diseases, such as cerebrovascular accidents, autoimmune thyroiditis, and diabetes mellitus, among others [12]. This bacterium resides in the stomach of most humans and is usually found in the deeper portions of the mucus gel that lines the gastric mucosa or

The bacterium is one of the most important findings for gastroenterologists, who for years sought answers to multiple intestinal problems. This is how the gastroenterologist Walery Jaworski in 1899 after analyzing samples of human gastric expirations isolated spiral elongated bacteria and called them *Vibrio regula*, and the said results were published in the manual of gastric diseases; however, these findings were not given the importance they deserved to be written in Polish and

So, it took 79 years for the bacteria to be rediscovered by the Australian doctors Barry Marshall and Robin Warren, who managed to make the first isolation through a pure culture in 1979. This rediscovery allowed them to be Nobel Laureates in 2005 [15].

Taxonomically, we can describe *H. pylori* because of its size, shape, color, biochemical function, genus, species, and its relationship with other species. *H. pylori* is a slow-growing, spiral-shaped bacterium. It is a small curved bacillus, microaerophilic, and Gram-negative, and mobile by the presence of flagella. The bacillus has rounded ends. These microorganisms measure 0.5–1.0 μm wide by 2.5–4.0 μm long, since they bear a strong resemblance to members of the *Campylobacter* genus [11]. The multiple genotypic and phenotypic characteristics are different from those

of *Helicobacter*, so this new genus was established, including *H. cinaedi* and *H. fennelliae*. The two species of *Helicobacter* that cause diarrheal disease, *H. cinaedi* and *H. fennelliae*, are intestinal microorganisms rather than gastric. As for the clinical manifestations of the disease they generate, these bacteria are more similar to *Campylobacter* than *H. pylori* [13]. The clinical characteristics of the infections caused by these *Helicobacter* are similar to those due to *Campylobacter* species.

are significantly different in developed and developing countries.

between the mucus layer and the gastric epithelium [13].

**2.2 Microbiological aspects of** *Helicobacter pylori*

**26**

The prevalence of *H. pylori* infection shows a strong correlation with access to water. Numerous epidemiological studies confirm this, and the World Health Organization includes it in its list of potential emerging pathogenic microorganisms whose transmission by water is plausible, although it has not yet been confirmed [18, 19].

Through molecular methods, *H. pylori* DNA has been detected in wastewater, drinking water, and other environmental samples throughout the world, and its survival capacity in water, even chlorinated, has been demonstrated. It has also been detected in the drinking water distribution network [20]. These findings indicate that contaminated water and food play a vital role in the survival and spread of *H. pylori*.

In another study, developed by Moreno et al. [21]; Moreno and Ferrús, [22] *H. pylori* was detected in 46% of more than 100 wastewater samples, 40% were of river water samples and, most strikingly, the 66% were public source.

On the other hand, *H. pylori* is able to survive in biofilms when it grows under high C:N conditions [23]. The biofilms formed protect microorganisms from the action of adverse agents, increase the availability of nutrients for their growth, and also increase the frequency of transfer of genetic material [24]. Gião et al. [25] observed that *H. pylori* formed biofilms after 24 hours of being in an unfavorable environment. The association of *H. pylori* with biofilm communities within a water distribution system could offer the bacterium protection against disinfection and predation by protozoa, and there are studies that demonstrate the survival of *H. pylori* within amoebae of free life[26, 27].

#### **2.5 Foods transmission**

Those foods that have a water activity (aw) >0.97 and a pH between 4.9 and 6.0 theoretically provide the ideal conditions for the survival and development of *H. pylori* [28, 29].

Vegetables are one of the foods with the highest risk of fecal contamination, since they are in contact with soil and contaminated irrigation water, which would mean the spread of *H. pylori* in the environment and its transmission to humans. Atapoor et al. [30] and Yahaghi et al. [31] in Iran managed to detect and isolate *H. pylori* in percentages higher than 10%, in vegetable samples. Also, Bayas et al. [32] have detected the pathogen in vegetables by molecular methods.

On the other hand, the ability of *H. pylori* to survive on lettuce leaves forming biofilms has been demonstrated [33].

Milk could also act as a vehicle for *H. pylori*. Several studies have shown that the bacterium is able to survive in inoculated milk stored in refrigeration for more than 6 days or for 3 days at room temperature [34]. In addition, in an investigation developed by Fujimura et al. [35], the presence of the *H. pylori* ureA gene was detected in 13 of 18 samples of raw milk (72.2%) and in 11 of 20 samples of pasteurized milk (55%).

On the other hand, Meng et al. [36] analyzed 11 raw chickens and 18 samples of tuna meat ready for consumption (sushi). *H. pylori* was detected by multiple polymerase chain reaction (m-PCR) in 36% (4/11) of the chickens and 44% (8/18) of the tuna samples.

Studies have also been conducted on the presence of *H. pylori* in shellfish. Fernández et al. [37] detected *H. pylori* DNA in seawater, plankton, and oysters from three different regions of Venezuela. They concluded that mollusks could act as vehicles for *H. pylori* transmission.

#### **2.6 Detection in human samples**

The presence of *H. Pylori* was focused on a study developed by Samie [38], on the prevalence of *Campylobacter*, *Helicobacter*, and *Arcobacter*. By molecular methods, in 322 stool samples from HIV-positive and non-HIV-infected patients in South Africa, they found that *A. butzleri* was the third most frequent species (6.2%), after *Helicobacter pylori* (50.6%) and *Campylobacter jejuni* (10.2%).

#### **2.7 Most common pathologies**

#### *2.7.1 Gastritis*

The term gastritis should be reserved for the histologically demonstrated inflammation of the gastric mucosa. Gastritis is not the mucosal erythema seen during endoscopy, nor is it interchangeable with the term "dyspepsia" [13]. On the other hand, the different etiological factors that cause gastritis are multiple and heterogeneous; to gastritis it has been classified with a chronological base (acute or chronic), such as histological typologies, anatomical distribution or its pathogenic mechanism, clinical correlation, histological data, abdominal pain or dyspepsia, and endoscopic data in gastric mucosal investigation [13].

The pathogenesis of chronic gastritis by *Helicobacter pylori* includes two stages: the first is characterized by the arrival and penetration of the microorganism into the gastric mucus where it sits and multiplies. In the second stage, there is an amplification of the inflammatory response, by the interaction of lymphocytes, neutrophils, macrophages, mastoid cells, and nonimmune cells that, when attracted to the site of the lesion, release a wide variety of chemical mediators such as cytokines, eicosanoids, reactive oxygen metabolites (oxygen free radicals), and the complement system, which perpetuate inflammation [39, 40] (**Figure 1**).

#### *2.7.2 Stomach cancer*

It is the uncontrolled growth of stomach cells. Malignant tumors can originate in each of the three layers: mucosa, muscle, and serosa. This is also known as gastric cancer that originates in the stomach [41]. The risk factor is considered any caused that increases the likelihood of having a disease such as cancer, even though several risk components do not mean that the person will have the disease; Some scientists connoted that the risks that take a person to be more prone to suffer stomach cancer are several such as:

**29**

women [16].

**Figure 1.**

*2.7.3 Risk factors*

*2.7.4 Genetic*

• Blood group A.

meats, among others

*2.7.5 Environmental*

• Radiation.

Helicobacter pylori*: A Pathogen of Ample Risk to Health*

white people who are not of Hispanic origin [41].

Within the genetic risk factors [41], we have:

Among the environmental risk factors [41], we have:

Incidence according to sex: Stomach cancer is more common in men than in

*Second stage of the inflammatory process of the gastric mucosa by H. pylori. Grávalos and González [40].*

Age: The rate of stomach cancer in people over 50 years increases sharply [42]. Ethnic origin: In the United States, stomach cancer is more common among Americans of Hispanic origin, black people, and Asians and islanders compared to

Geography: On a global scale, stomach cancer is more common in Japan, China,

Several risk factors for gastric cancer have been described, which play a fundamental role in their genesis, some of them remain under discussion, and others, on

• Food (variable in each country): dried and salted fish, very spicy foods, and red

• Ingestion of alcohol, hot drinks, and sodium nitrate; chewed tobacco

Eastern and Southern Europe, as well as Central and South America [41].

• Families of patients with gastric cancer: incidence 2–3 times higher

the contrary, have been confirmed more and more clearly [43].

*DOI: http://dx.doi.org/10.5772/intechopen.86789*

Helicobacter pylori*: A Pathogen of Ample Risk to Health DOI: http://dx.doi.org/10.5772/intechopen.86789*

#### **Figure 1.**

*Gastritis - New Approaches and Treatments*

biofilms has been demonstrated [33].

as vehicles for *H. pylori* transmission.

**2.6 Detection in human samples**

**2.7 Most common pathologies**

*2.7.1 Gastritis*

*2.7.2 Stomach cancer*

of the tuna samples.

On the other hand, the ability of *H. pylori* to survive on lettuce leaves forming

Milk could also act as a vehicle for *H. pylori*. Several studies have shown that the bacterium is able to survive in inoculated milk stored in refrigeration for more than 6 days or for 3 days at room temperature [34]. In addition, in an investigation developed by Fujimura et al. [35], the presence of the *H. pylori* ureA gene was detected in 13 of 18 samples of raw milk (72.2%) and in 11 of 20 samples of pasteurized milk (55%). On the other hand, Meng et al. [36] analyzed 11 raw chickens and 18 samples of tuna meat ready for consumption (sushi). *H. pylori* was detected by multiple polymerase chain reaction (m-PCR) in 36% (4/11) of the chickens and 44% (8/18)

Studies have also been conducted on the presence of *H. pylori* in shellfish. Fernández et al. [37] detected *H. pylori* DNA in seawater, plankton, and oysters from three different regions of Venezuela. They concluded that mollusks could act

The presence of *H. Pylori* was focused on a study developed by Samie [38], on the prevalence of *Campylobacter*, *Helicobacter*, and *Arcobacter*. By molecular methods, in 322 stool samples from HIV-positive and non-HIV-infected patients in South Africa, they found that *A. butzleri* was the third most frequent species (6.2%), after

The term gastritis should be reserved for the histologically demonstrated inflammation of the gastric mucosa. Gastritis is not the mucosal erythema seen during endoscopy, nor is it interchangeable with the term "dyspepsia" [13]. On the other hand, the different etiological factors that cause gastritis are multiple and heterogeneous; to gastritis it has been classified with a chronological base (acute or chronic), such as histological typologies, anatomical distribution or its pathogenic mechanism, clinical correlation, histological data, abdominal pain or dyspepsia,

The pathogenesis of chronic gastritis by *Helicobacter pylori* includes two stages:

the first is characterized by the arrival and penetration of the microorganism into the gastric mucus where it sits and multiplies. In the second stage, there is an amplification of the inflammatory response, by the interaction of lymphocytes, neutrophils, macrophages, mastoid cells, and nonimmune cells that, when attracted to the site of the lesion, release a wide variety of chemical mediators such as cytokines, eicosanoids, reactive oxygen metabolites (oxygen free radicals), and the complement system, which perpetuate inflammation [39, 40] (**Figure 1**).

It is the uncontrolled growth of stomach cells. Malignant tumors can originate in each of the three layers: mucosa, muscle, and serosa. This is also known as gastric cancer that originates in the stomach [41]. The risk factor is considered any caused that increases the likelihood of having a disease such as cancer, even though several risk components do not mean that the person will have the disease; Some scientists connoted that the risks that take a person to be more prone to suffer stomach cancer are several such as:

*Helicobacter pylori* (50.6%) and *Campylobacter jejuni* (10.2%).

and endoscopic data in gastric mucosal investigation [13].

**28**

*Second stage of the inflammatory process of the gastric mucosa by H. pylori. Grávalos and González [40].*

Incidence according to sex: Stomach cancer is more common in men than in women [16].

Age: The rate of stomach cancer in people over 50 years increases sharply [42].

Ethnic origin: In the United States, stomach cancer is more common among Americans of Hispanic origin, black people, and Asians and islanders compared to white people who are not of Hispanic origin [41].

Geography: On a global scale, stomach cancer is more common in Japan, China, Eastern and Southern Europe, as well as Central and South America [41].

#### *2.7.3 Risk factors*

Several risk factors for gastric cancer have been described, which play a fundamental role in their genesis, some of them remain under discussion, and others, on the contrary, have been confirmed more and more clearly [43].

#### *2.7.4 Genetic*

Within the genetic risk factors [41], we have:


#### *2.7.5 Environmental*

Among the environmental risk factors [41], we have:


#### *2.7.6 Premalignant*

Within the premalignant risk factors [41], we have:


#### *2.7.7 Stomach lymphoma*

People who have suffered from a certain type of stomach lymphoma, known as lymphoma of lymphatic tissue associated with the mucosa (MALT), have an increased risk of developing adenocarcinoma of the stomach, probably due to infection with *H. pylori* [41] (**Figure 2**).

#### *2.7.8 H. pylori and peptic disorders*

The gastric infection produced by *H. pylori* bacteria in most cases of peptic ulcer is also important in the appearance of lymphomas that originate in the lymphoid tissue (MALT) and in gastric adenocarcinoma [13]. The peptic ulcer is an ulcer that affects the lining of the stomach and is the causes of internal bleeding of the upper digestive tract with severe complications that lead to an adenocarcinoma [13, 40].

#### *2.7.9 Diagnostic methods of H. pylori infection*

The diagnostic methods of *H. pylori* infection have traditionally been classified as direct and indirect; the former is based on the "direct" demonstration of the microorganism by means of the study of samples obtained by gastric biopsy [44]. This technique used is very stressful and uncomfortable for the patient because of the invasive reason.

**31**

Helicobacter pylori*: A Pathogen of Ample Risk to Health*

The other indirect methods are based on the detection of certain characteristics

The presence of the germ can be recognized with the usual hematoxylin and eosin stain, although it is more easily demonstrated with other stains such as Giemsa. The histology not only demonstrates the presence of the microorganism but also informs about the morphological changes of the gastric mucosa [44].

Under optimal conditions *H. pylori* is extremely difficult to grow, due to its demanding nutritional requirements and its slow growth. The cultivation of *H. pylori* is usually slow, the first colonies usually appear between the fifth and seventh days, and it may take up to 10 days. Being a microaerophilic microorganism requires atmospheres with 5–10% of O2, 5–10% of CO2, and 80–90% of N2 at 35–37°C, with a

The selection and inoculation of the bacteria depend on the number and types of tests to be carried out as well as on the factors, type of bacteria, clinical importance of the isolation, availability of the strain, and reliable method of verification [46]. Plate culture has advantages ranging from typifying the organism to determining its sensitivity to antibacterial agents, so it is important to study it from the epidemiological point of view, because it allows knowing the pattern of resistance to different therapeutic regimens with a specificity of the 100% and a lower sensitivity than other diagnostic techniques [3]. This microorganism is also urease, oxidase, and catalase positive, characteristics that are frequently used in the identification of

It is usually considered a difficult and tedious technique. However, adopting a series of minimal precautions, most laboratories achieve the growth of the microor-

Serological techniques only indicate a previous exposure to the microorganism but do not discriminate between people with active infection and disease in healthy individuals with prior exposure to infection [44]. Rapid tests are methods for the detection of antigens and antibodies in serum, plasma, whole blood, and other fluids, which give results in a few minutes [47]. These serological techniques are

The enzyme-linked immunosorbent assay (ELISA) is widely used to perform

In a work done by Siavoshi et al. [49], for the intracellular detection of *H. pylori* in yeast identified in oral samples of newborns, the authors detected *H. pylori* with immunofluorescence using polyclonal antibodies IgG anti-*H. pylori* in a rabbit labeled with FITC, whose concentration was 5000 mg/ml, with a wavelength of 528 nm.

This is a chromatographic immunoassay for the qualitative detection of *H. pylori* antigen in human stool samples, with a relative sensitivity of 94%, a specificity of 95%, and an accuracy of 97.5%, since it is an in vitro technique ad-bio [50].

epidemiological studies on a considerable number of individuals [48].

the microorganism, although its isolation is relatively complex [16].

widely used today for rapid diagnosis in laboratories.

of the bacteria, such as the ability to hydrolyze through urea, and based on the breath test or the response of the immune system through the measurement of specific antibodies. Its primary advantage is its noninvasive nature [44].

*DOI: http://dx.doi.org/10.5772/intechopen.86789*

*2.7.10 Histological techniques*

*2.7.11 Cultivation of H. pylori*

humidity of 90–95% [45].

ganism [44].

*2.7.12 Serology*

*2.7.13 Antigenic screening*

The other indirect methods are based on the detection of certain characteristics of the bacteria, such as the ability to hydrolyze through urea, and based on the breath test or the response of the immune system through the measurement of specific antibodies. Its primary advantage is its noninvasive nature [44].

#### *2.7.10 Histological techniques*

*Gastritis - New Approaches and Treatments*

Within the premalignant risk factors [41], we have:

• Atrophic gastritis, intestinal metaplasm, and dysplasia.

dysplasia 0.4–4% of association with gastric cancer [41].

• Pernicious anemia (20 times more frequent than in normal subjects).

• Gastric polyps: multiple hyperplasia, greater than 2 cm with some degree of

People who have suffered from a certain type of stomach lymphoma, known as lymphoma of lymphatic tissue associated with the mucosa (MALT), have an increased risk of developing adenocarcinoma of the stomach, probably due to infec-

The gastric infection produced by *H. pylori* bacteria in most cases of peptic ulcer is also important in the appearance of lymphomas that originate in the lymphoid tissue (MALT) and in gastric adenocarcinoma [13]. The peptic ulcer is an ulcer that affects the lining of the stomach and is the causes of internal bleeding of the upper digestive tract with severe complications that lead to an adenocarcinoma [13, 40].

The diagnostic methods of *H. pylori* infection have traditionally been classified as direct and indirect; the former is based on the "direct" demonstration of the microorganism by means of the study of samples obtained by gastric biopsy [44]. This technique used is very stressful and uncomfortable for the patient because of

*2.7.6 Premalignant*

*2.7.7 Stomach lymphoma*

the invasive reason.

tion with *H. pylori* [41] (**Figure 2**).

*2.7.8 H. pylori and peptic disorders*

*2.7.9 Diagnostic methods of H. pylori infection*

*Entrance and lodging of H. pylori in the stomach. Grávalos and González [40].*

**30**

**Figure 2.**

The presence of the germ can be recognized with the usual hematoxylin and eosin stain, although it is more easily demonstrated with other stains such as Giemsa. The histology not only demonstrates the presence of the microorganism but also informs about the morphological changes of the gastric mucosa [44].

#### *2.7.11 Cultivation of H. pylori*

Under optimal conditions *H. pylori* is extremely difficult to grow, due to its demanding nutritional requirements and its slow growth. The cultivation of *H. pylori* is usually slow, the first colonies usually appear between the fifth and seventh days, and it may take up to 10 days. Being a microaerophilic microorganism requires atmospheres with 5–10% of O2, 5–10% of CO2, and 80–90% of N2 at 35–37°C, with a humidity of 90–95% [45].

The selection and inoculation of the bacteria depend on the number and types of tests to be carried out as well as on the factors, type of bacteria, clinical importance of the isolation, availability of the strain, and reliable method of verification [46]. Plate culture has advantages ranging from typifying the organism to determining its sensitivity to antibacterial agents, so it is important to study it from the epidemiological point of view, because it allows knowing the pattern of resistance to different therapeutic regimens with a specificity of the 100% and a lower sensitivity than other diagnostic techniques [3]. This microorganism is also urease, oxidase, and catalase positive, characteristics that are frequently used in the identification of the microorganism, although its isolation is relatively complex [16].

It is usually considered a difficult and tedious technique. However, adopting a series of minimal precautions, most laboratories achieve the growth of the microorganism [44].

#### *2.7.12 Serology*

Serological techniques only indicate a previous exposure to the microorganism but do not discriminate between people with active infection and disease in healthy individuals with prior exposure to infection [44]. Rapid tests are methods for the detection of antigens and antibodies in serum, plasma, whole blood, and other fluids, which give results in a few minutes [47]. These serological techniques are widely used today for rapid diagnosis in laboratories.

The enzyme-linked immunosorbent assay (ELISA) is widely used to perform epidemiological studies on a considerable number of individuals [48].

In a work done by Siavoshi et al. [49], for the intracellular detection of *H. pylori* in yeast identified in oral samples of newborns, the authors detected *H. pylori* with immunofluorescence using polyclonal antibodies IgG anti-*H. pylori* in a rabbit labeled with FITC, whose concentration was 5000 mg/ml, with a wavelength of 528 nm.

#### *2.7.13 Antigenic screening*

This is a chromatographic immunoassay for the qualitative detection of *H. pylori* antigen in human stool samples, with a relative sensitivity of 94%, a specificity of 95%, and an accuracy of 97.5%, since it is an in vitro technique ad-bio [50].


**33**

Helicobacter pylori*: A Pathogen of Ample Risk to Health*

through classical microbiology [52] (**Table 1**).

niques are not invasive to patients.

Molecular methods are the names given to all the laboratory techniques used to isolate DNA or extract it in high purity, visualize it to see its state, cut it and paste it (Iglesias [51]), or amplify a region in a huge amount of molecules: fragment cloning in bacteria or other vectors such as viruses as well as polymerase chain reaction

Infectious diseases have become the "spearhead" for the development of molecular diagnostic tests, with more than 50% of the techniques available today. The main explanation for this development is due to the difficulty of detecting a pathogen

*H. pylori* is a microorganism of global interest, given that, in developing countries, the infection overcomes the 60%. Besides, being microorganisms of difficult isolation, the used techniques to culture are insufficient, so that molecular methods and antigen screening are the most recommended for detection, since these tech-

*DOI: http://dx.doi.org/10.5772/intechopen.86789*

*2.7.14 Molecular methods*

(PCR).

**3. Conclusion**

**Author details**

Isidro Favian Bayas-Morejón\*, Rosa Angélica Tigre-León,

\*Address all correspondence to: favian\_bm@hotmail.com

provided the original work is properly cited.

Edison Riveliño Ramón-Curay and Darwin Alberto Núñez-Torres

Universidad Estatal de Bolívar, Facultad de Ciencias Agropecuarias Recursos Naturales y del Ambiente, Centro de Investigación y Desarrollo Biotecnológico

© 2019 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium,

#### **Table 1.**

*Comparison of diagnostic methods for H. pylori.*

#### *2.7.14 Molecular methods*

*Gastritis - New Approaches and Treatments*

Habitual staining of hematoxylin and eosin Giemsa stain

microorganism in specific media under microaerobic conditions The optimum temperature of culture is from 35 to 37°C [53]

Methods for the detection of antigens and antibodies (serum, plasma, and whole blood,

among others) Enzyme-linked immunosorbent assay

Chromatographic immunoassay for the detection of *H. pylori* antigens in stool samples

DNA amplification of the

(ELISA)

pathogen

*Comparison of diagnostic methods for H. pylori.*

**Direct** Histological techniques

**Indirect** Serological techniques

Antigenic screening

Molecular Methods

**Direct and indirect**

Culture Cultivation of the

**Methods Characteristic Advantage Disadvantages**

Demonstrates the presence of the microorganism and reports on changes in the The technique requires samples obtained from a

Proper selection of stain

It is difficult to isolate, since *H. pylori* is very sensitive to drying and to the usual atmospheric conditions (it requires the transport of samples in the shortest possible time) [54]. Samples destined for culture remain viable for approximately 5 hours and when stored in saline at 4°C or for more than 24 hours if stored at 4°C in a transport medium specific for *H.* 

biopsy

fixatives

*pylori* [55]

negative result

organisms [56]

products

reaction

to cross reactions with other

Need to have information on the target DNA sequence Short size of the PCR

The ease with which DNA is amplified requires avoiding the danger of contamination inherent to the multiplier power of the

Rapid laboratory tests It can induce a false-

Rapid laboratory tests Possible false positives due

Great versatility as an analysis technique, sequences are amplified from minute amounts of target DNA, even from DNA contained in a single cell

Another disadvantage is the high contamination of the environment with accompanying biota, which makes it difficult to isolate *H. pylori* independently

mucosa

Isolate the

microorganism to study its behavior (in vitro)

**32**

**Table 1.**

Molecular methods are the names given to all the laboratory techniques used to isolate DNA or extract it in high purity, visualize it to see its state, cut it and paste it (Iglesias [51]), or amplify a region in a huge amount of molecules: fragment cloning in bacteria or other vectors such as viruses as well as polymerase chain reaction (PCR).

Infectious diseases have become the "spearhead" for the development of molecular diagnostic tests, with more than 50% of the techniques available today. The main explanation for this development is due to the difficulty of detecting a pathogen through classical microbiology [52] (**Table 1**).

### **3. Conclusion**

*H. pylori* is a microorganism of global interest, given that, in developing countries, the infection overcomes the 60%. Besides, being microorganisms of difficult isolation, the used techniques to culture are insufficient, so that molecular methods and antigen screening are the most recommended for detection, since these techniques are not invasive to patients.

### **Author details**

Isidro Favian Bayas-Morejón\*, Rosa Angélica Tigre-León, Edison Riveliño Ramón-Curay and Darwin Alberto Núñez-Torres Universidad Estatal de Bolívar, Facultad de Ciencias Agropecuarias Recursos Naturales y del Ambiente, Centro de Investigación y Desarrollo Biotecnológico

\*Address all correspondence to: favian\_bm@hotmail.com

© 2019 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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[17] Figueroa G, Troncoso M, Toledo MS, Faúndez G, Acuña R. Prevalence of serum antibodies to *Helicobacter pylori* VacA and CagA and gastric diseases in Chile. Journal of Medical Microbiology. 2002;**51**(4):300-304

[18] Aziz RK, Khalifa MM, Sharaf RR. Contaminated water as a source of *Helicobacter pylori* infection: A review. Journal of Advanced Research. 2015;**6**(4):539-547

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[31] Yahaghi E, Khamesipour F, Mashayekhi F, Safarpoor Dehkordi F, Hossein SM, Masoudimanesh M, et al. *Helicobacter pylori* in vegetables and salads: Genotyping and antimicrobial resistance properties. BioMed Research International. 2014;**1**:11. Article ID: 757941

[32] Bayas-Morejón IF, González A, Moreno-Mesonero L, Moreno Y, Ferrús M. Detection of *Helicobacter pylori* in vegetables, XXIXth international workshop on *Helicobacter* and microbiota in inflammation on & cancer, Magdeburg-Germany. Helicobacter. 2016;**21**(Suppl 1):69-177. DOI: 10.1111/hel.12344. [PubMed:

[33] Ng CG, Hassanbhai AM, Loke MF,

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[20] Eusebi LH, Zagari RM, Bazzoli F. Epidemiology of *Helicobacter pylori* infection. Helicobacter. 2014;**19**

[21] Moreno Y, Ferrús MA, Alonso JL, Jiménez A, y Hernández J. Use of fluorescent in situ hybridization to evidence the presence of *Helicobacter pylori* in water. Water Research,

[22] Moreno Y, Ferrus MA. Specific detection of cultivable *Helicobacter pylori* cells from wastewater treatment plants. Helicobacter. 2012;**17**(5):327-332

[23] Percival SL, Suleman L. Biofilms and *Helicobacter pylori*: Dissemination

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[24] Donlan RM. Biofilms: Microbial life on surfaces. Emerging Infectious

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[27] Moreno-Mesonero L, Moreno Y, Alonso JL, Ferrús MA. DVC-FISH and PMA-qPCR techniques to assess the survival of *Helicobacter pylori*

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[21] Moreno Y, Ferrús MA, Alonso JL, Jiménez A, y Hernández J. Use of fluorescent in situ hybridization to evidence the presence of *Helicobacter pylori* in water. Water Research, 2003;**37**(9):2251-2256

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[27] Moreno-Mesonero L, Moreno Y, Alonso JL, Ferrús MA. DVC-FISH and PMA-qPCR techniques to assess the survival of *Helicobacter pylori*

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[28] Van-Duynhoven YTHP, De-Jonge R. Transmission of *Helicobacter pylori*: A role for food. Bulletin of the World Health Organization. 2001;**79**(5):455-460

[29] Beuchat LR. Ecological factors influencing survival and growth of human pathogens on raw fruits and vegetables. Microbes and Infection. 2002;**4**(4):413-423

[30] Atapoor S, Safarpoor Dehkordi F, Rahimi E. Detection of *Helicobacter pylori* in various types of vegetables and salads. Jundishapur Journal of Microbiology. 2014;**7**(5):e10013

[31] Yahaghi E, Khamesipour F, Mashayekhi F, Safarpoor Dehkordi F, Hossein SM, Masoudimanesh M, et al. *Helicobacter pylori* in vegetables and salads: Genotyping and antimicrobial resistance properties. BioMed Research International. 2014;**1**:11. Article ID: 757941

[32] Bayas-Morejón IF, González A, Moreno-Mesonero L, Moreno Y, Ferrús M. Detection of *Helicobacter pylori* in vegetables, XXIXth international workshop on *Helicobacter* and microbiota in inflammation on & cancer, Magdeburg-Germany. Helicobacter. 2016;**21**(Suppl 1):69-177. DOI: 10.1111/hel.12344. [PubMed: 27531543]

[33] Ng CG, Hassanbhai AM, Loke MF, Wong HJ, Goh KL, Vadivelu J, et al. *Helicobacter pylori* biofilm— The probable mode and source of transmission? Helicobacter. 2014;**19**(Suppl 1):104

[34] Boehmler G, Gerwert J, Scupin E, Sinell HJ. Epidemiology of *H. pylori* in man: Studies on the survival of the agent in food. Deutsche Medizinische Wochenschrift. 1996;**103**:438-443

**34**

ANUARIO

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[10] Hasni SA. Role of *Helicobacter pylori* infection in autoimmune diseases. Current Opinion in Rheumatology.

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[16] Martel C, Parsonnet J. *Helicobacter pylori* infection and gender: A metaanalysis of population-based prevalence

[17] Figueroa G, Troncoso M, Toledo MS, Faúndez G, Acuña R. Prevalence of serum antibodies to *Helicobacter pylori* VacA and CagA and gastric diseases in Chile. Journal of Medical Microbiology.

[18] Aziz RK, Khalifa MM, Sharaf RR. Contaminated water as a source of *Helicobacter pylori* infection: A review. Journal of Advanced Research.

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978-848-322-359-8

2002;**51**(4):300-304

2015;**6**(4):539-547

Tratamiento actual de la infección por *Helicobacter pylori*. Medicina Clínica

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[5] Guamán JF, Bayas-Morejón F, Arcos V, Tigre-León A, Lucio-Quintana A, Salazar S, et al. Detection of *Helicobacter pylori* from human biological samples (Feces) by antigenic screening and culture. Jundishapur Journal of Microbiology. 2018;**11**(7):e66721

[6] Dirección Nacional de Vigilancia Epidemiológica\_MSP—Ecuador. *Anuario*. Obtenido de Enfermedades Trasmitidas Por Agua Y Alimentos. 2017. https://public.tableau.com/profile/ vvicentee80#!/vizhome/ETAS-2014/

[7] Linear Chemicals S.L. 2017. Website. Obtenido de: http://www.linear.es/ ficheros/archivos/481\_4245125H. PyloriAgcassette25tcas.pdf

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Directrices en Endoscopia

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[36] Meng X, Zhang H, Law J, Tsang R, Tsang T. Detection of *Helicobacter pylori* from food sources by a novel multiplex PCR assay. Journal of Food Safety. 2008;**28**(4):609-619

[37] Fernández M, Contreras M, Suárez P, Gueneau P, García-Amado MA. Use of HP selective medium to detect *Helicobacter pylori* associated with other enteric bacteria in seawater and marine molluscs. Letters in Applied Microbiology. 2007;**45**:213-218

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[39] Jiménez DF. Mediadores Bacterianos de la Inflamacion en La Gastritis. Revista Cubana de Medicina. 1999;**38**:276-283

[40] Grávalos DC, González E. Cancer gastrico. Sociedad Española de Oncología Médica. 2017; pp. 1-16. Available from: https://seom.org/info-sobre-el-cancer/ estomago

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[43] Jiménez DF. Cancer gastrico: Factores de riesgo. Revista Cubana de Oncología. 1998;**14**:171-179

[44] Gisbert J. Infección por Helicobacter pylori. 2016. Obtenido de http://www.

aegastro.es/sites/default/files/archivos/ ayudas-practicas/19\_Infeccion\_por\_ Helicobacter\_pylori.pdf

[45] Ofelia CC, Jorge MQ, Harold BG, Alfonso CM, Edson GC, Milagros DM, et al. Prevalencia de helicobacter pylori en pacientes sintomáticos de consulta externa de la red Rebagliati (EsSalud), Lima, Perú, en el período 2010—2013. Revista de Gastroenterología del Perú. 2016;**36**(1):49-55

[46] Scott B. Diagnóstico Microbiológico. Buenos Aires— Argentina: Panamericana; 2009

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[50] ad-bio H. pylori Ag Prueba Rápida en Casete (muestras fecales). 2017; Obtenido de: http://www.annardx. com/productos/images/productos/ diagnostica/pruebas-rapidas/ad0192chpylori-ag-rev-cpdf.pdf

[51] Iglesias G. Tecnicas de biologia molecular. Desde Mendel hasta las moléculas. 2008;1. Obtenido de: https://genmolecular.com/ tecnicas-de-biologia-molecular/

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*DOI: http://dx.doi.org/10.5772/intechopen.86789*

[52] Farfan BM. Biologia Molecular Aplicada Al Diagnostico Clinico. Revista Médica Clínica Las Condes.

[53] Ferrús A. Survival and viability of *Helicobacter pylori* after inoculation into chlorinated drinking water. Water Research. 2007;**41**(15):3490-3496

[54] Pagola MF. Caracterización de la infección por *Helicobacter pylori* en pacientes con úlcera gástrica. Scielo/

[55] Veenendaal RA, Lichtendahl-Bernards AT, Peña AS, Endtz HP, van Boven CP, Lamers CB. Effect of transport medium and transportation time on culture of *Helicobacter pylori* from gastric biopsy specimens. Journal of Clinical Pathology.

[56] SCREEN. Test Rapido Antigene. Obtenido de: http://www.screenitalia.it/ wp-content/uploads/2017/11/Istruzioni-

Screen-H.PyloriSITA-1.pdf

2015;**26**(6):788-793

Medisur. 2009;**7**(6):3-11

1993;**46**(6):561-563

Helicobacter pylori*: A Pathogen of Ample Risk to Health DOI: http://dx.doi.org/10.5772/intechopen.86789*

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*Gastritis - New Approaches and Treatments*

[35] Fujimura S, Kawamura T, Kato S, Tateno H, Wanatabe A. Detection of *Helicobacter pylori* in cow's milk. Letters in Applied Microbiology. 2002;**35**:504-507

aegastro.es/sites/default/files/archivos/ ayudas-practicas/19\_Infeccion\_por\_

[45] Ofelia CC, Jorge MQ, Harold BG, Alfonso CM, Edson GC, Milagros DM, et al. Prevalencia de helicobacter pylori en pacientes sintomáticos de consulta externa de la red Rebagliati (EsSalud), Lima, Perú, en el período 2010—2013. Revista de Gastroenterología del Perú.

Helicobacter\_pylori.pdf

2016;**36**(1):49-55

[46] Scott B. Diagnóstico Microbiológico. Buenos Aires— Argentina: Panamericana; 2009

Made in Mexico; 2006

Zubirán; 2010

2013;**16**(5):288-294

hpylori-ag-rev-cpdf.pdf

[47] Secretary of Health Secretaria de Salud. Guia para la aplicacion de pruebas rapidas. Mexico: Printed and

[48] Hernández Ramírez D, Cabiedes

J. Immunological Techniques that Support the Diagnosis of the Autoimmune Diseases. México D.F, México: Laboratorio de Inmunología, Departamento de Inmunología y Reumatología, Instituto Nacional de Ciencias Médicas y Nutrición Salvador

[49] Siavoshi F, Taghikhani A, Malekzadeh R, Sarrafnejad A,

Kashanian M, Jamal AS, et al. The role of mother's oral and vaginal yeasts in transmission of *Helicobacter pylori* to neonates. Archives of Iranian Medicine.

[50] ad-bio H. pylori Ag Prueba Rápida en Casete (muestras fecales). 2017; Obtenido de: http://www.annardx. com/productos/images/productos/ diagnostica/pruebas-rapidas/ad0192c-

[51] Iglesias G. Tecnicas de biologia molecular. Desde Mendel hasta las moléculas. 2008;1. Obtenido de: https://genmolecular.com/ tecnicas-de-biologia-molecular/

[36] Meng X, Zhang H, Law J, Tsang R, Tsang T. Detection of *Helicobacter pylori* from food sources by a novel multiplex PCR assay. Journal of Food Safety.

[37] Fernández M, Contreras M, Suárez P, Gueneau P, García-Amado MA. Use of HP selective medium to detect *Helicobacter pylori* associated with other enteric bacteria in seawater and marine molluscs. Letters in Applied Microbiology. 2007;**45**:213-218

2008;**28**(4):609-619

[38] Samie A. Prevalence of

of Infection. 2007;**54**:558-566

campylobacter species, helicobacter pylori and Arcobacter species in stool samples from the Venda region, Limpopo, South Africa: Studies using molecular diagnostic methods. Journal

[39] Jiménez DF. Mediadores Bacterianos de la Inflamacion en La Gastritis. Revista Cubana de Medicina. 1999;**38**:276-283

[40] Grávalos DC, González E. Cancer gastrico. Sociedad Española de Oncología Médica. 2017; pp. 1-16. Available from: https://seom.org/info-sobre-el-cancer/

[41] American Cancer Society. Obtenido de Society, American Cancer Atlanta, Ga: American Cancer. 2016, http://www. cancer.org/cancer-de-estomago-pdf

[42] Hinojosa MM. 2017. Obtenido de: http://www.inen.sld.pe/portal/ documentos/pdf/educacion/091115\_ CANCER%20GASTRICO%20-%20

[43] Jiménez DF. Cancer gastrico: Factores de riesgo. Revista Cubana de

[44] Gisbert J. Infección por Helicobacter pylori. 2016. Obtenido de http://www.

Oncología. 1998;**14**:171-179

**36**

estomago

JEMH.pdf

[53] Ferrús A. Survival and viability of *Helicobacter pylori* after inoculation into chlorinated drinking water. Water Research. 2007;**41**(15):3490-3496

[54] Pagola MF. Caracterización de la infección por *Helicobacter pylori* en pacientes con úlcera gástrica. Scielo/ Medisur. 2009;**7**(6):3-11

[55] Veenendaal RA, Lichtendahl-Bernards AT, Peña AS, Endtz HP, van Boven CP, Lamers CB. Effect of transport medium and transportation time on culture of *Helicobacter pylori* from gastric biopsy specimens. Journal of Clinical Pathology. 1993;**46**(6):561-563

[56] SCREEN. Test Rapido Antigene. Obtenido de: http://www.screenitalia.it/ wp-content/uploads/2017/11/Istruzioni-Screen-H.PyloriSITA-1.pdf

**39**

Section 2

Diversity of Tretaments

for *H. pylori* Infection

Worldwide

## Section 2
