Pathogenesis of Helicobacter Infection in the Development of Gastric Conditions Diagnosis and Management

#### **Chapter 1**

## *Helicobacter pylori* Gastric Infection: Pathogenesis and Clinical Management

*Neha Bisht and Amar P. Garg*

#### **Abstract**

*Helicobacter pylori (H. pylori)* is a Gram-negative bacterium that infects approximately 50% of the world population, and currently, no treatment is satisfactory for its management. Understanding the pathophysiology and pathogenesis mechanisms of *H. pylori* has increased over the years. Proper adherence and colonization of *H. pylori* induce genetic alterations, express numerous virulence factors, and trigger diverse adaptive mechanisms, making possible the colonization of an organ with a highly acidic lumen. The mode for the transmission of infection can be oral-oral or fecal-oral. Various effector proteins or toxins are released by the organism for successful colonization and infection. For the virulence and pathogenicity of *H. pylori*, the virulence factors, host, and environmental factors interplay a very important role. Virulence factors for *H. pylori* enhanced the pathogenicity of cytotoxin-associated antigen A, vacuolating cytotoxin, duodenal ulcer promoting gene A protein, outer inflammatory proteins, and gamma-glutamyl transpeptidase. The host immune system through Th1-polarized response plays a crucial role in the course of infection. The most common symptoms in *H. pylori*-positive individuals are peptic ulcers, gastric adenocarcinomas, and mucosa-associated lymphoid tissue lymphomas, whereas some positive individuals remain asymptomatic. Detection of *H. pylori* infection can be through invasive and noninvasive diagnostic methods. We critically reflect on the infection of *H. pylori* and the virulence and pathogenesis mechanisms of *H. pylori.*

**Keywords:** pathogenesis, virulence factor, colonization, transmission, diagnosis

#### **1. Introduction**

*Helicobacter pylori* (*H. pylori*) is a gram-negative, motile, helical, and microaerophilic (5% O2, 15% CO2 & 80% N, required low concentration of O2 than in the atmosphere) microorganism that is considered as one of the most successful pathogens due to its persistent infection in the human stomach, that inhabits the gastric environment of more than half of the world population of 4.4 billion people worldwide [1–3]. Various shreds of evidence suggest that *H. pylori* are the etiological agent of both extra-gastric and gastric diseases (gastric malignancy, peptic ulcer, chronic gastritis) [4–6]. The main reason for the occurrence of infection among the members of the same family (parents and children) is the route of transmission of *H. pylori* through oral–oral transmission. In this way, during feeding sharing utensils seems to be important for the establishment of infection [7]. Another route for the transmission of infection is fecal-oral, due to the ingestion of contaminated water and unsatisfactory basic sanitation conditions [8]. Improvement of living conditions and socioeconomic status are the two factors that greatly influence the reduction in *H. pylori* infection [9]. It was believed that the gastric environment was sterile because of its high acidity until the discovery of *H. pylori* infection from gastric mucosa by Warren and Marshall's [10, 11]. The bacteria use various mechanisms that provide mobility improvement, robust adherence to epithelial cells, and an enzymatic apparatus that allows the establishment of an appropriate microenvironment for the perpetuation of infection [12–15]. Certain virulence factors are responsible for the potential pathogenicity of infection such as vacuolating cytotoxin (VacA), cytotoxin-associated antigen A (CagA), duodenal ulcer promoting gene A protein (DupA), outer inflammatory protein (OipA) and gamma-glutamyl transpeptidase (GGT) and genetic substrates of the host [*e.g.*, IL1B gene cluster and tumor necrosis factor-α (TNFα) gene polymorphism] play an important role [16–20] shown in **Figure 1**. During the course of infection host immune system play a very pivotal role shown in **Figure 1**. Flagella-mediated motility is used by *H. pylori* for movement toward the epithelial cells of stomachs and penetrating the mucus lining [21]. With all the suitable conditions, organism crosses the acidic environment. At the mucus layer, the coccoid form enabled its colonization [22, 23]. Attachment to the host epithelial cells is through the production of an adhesin [21, 24]. So far colonization of *H. pylori* could be negatively and positively associated with the induction and progression of several diseases [23, 25, 26]. It has been reported to be linked to gastric and duodenal ulcers, gastric carcinoma, and gastric mucosa-associated lymphoid tissue (MALT) lymphoma [6, 27, 28]. Several other studies are also directing a positive correlation between gastrointestinal diseases and *H. pylori*. Many research shows a positive association between *H. pylori*, duodenal ulcer and gastric ulcer [29], gastritis [30], and esophageal cancer [31]. Moreover, evidence shows a positive

#### **Figure 1.**

*Representation of characteristics of* H. pylori *infection.*

Helicobacter pylori *Gastric Infection: Pathogenesis and Clinical Management DOI: http://dx.doi.org/10.5772/intechopen.106783*

association between *H. pylori* and non-gastrointestinal diseases such as diabetes mellitus [32], coronary artery disease [33], and anemia [34].

#### **2. Clinical manifestations and diagnosis**

The discovery of *H. pylori* in the early 1980s caused peptic ulcer diseases [35]. By International Agency for Research on Cancer in 1994 H. pylori was first classified as a carcinogen [36]. In 2001, an epidemiological study stated that patients with H. pylori were nearly six times more potent to develop gastric cancer compared with uninfected people [36]. In 2015, a community of gastroenterologists meticulously recognized *H. pylori* gastritis as an infectious disease and recommended its eradication [37]. This recommendation has repeatedly been confirmed by more recent consensus statements [35, 38, 39]. The most recent consensus conferences on the proactive testing and eradication of *H. pylori* infection [35, 38, 39]. Patients with uninvestigated dyspepsia, having a history of past or current gastric or duodenal ulcer, with a diagnosis of gastric mucosa-associated lymphoid tissue lymphoma, having a family history with peptic ulcer or gastric cancer, and a person with constant use of non-steroidal anti-inflammatory drugs should be recommended for *H. pylori* testing [35, 38]. The strengths and weaknesses of endoscopic and noninvasive tests are shown in **Table 1**.

First-generation immigrants from high-prevalence countries and potential highrisk populations were targeted for testing. Once the presence of the infection has been diagnosed and documented outreach to family members is suggested because transmission from person to person occurs within families [40]. Testing and treating of *H. pylori-*infected individuals can protect other members from infection as well as re-infection from its related diseases [41]. This approach may engage those who test positive to concur with the eradication treatment [41, 42]. To detect *H. pylori* infection a wide variety of methods is available [43]. Because the organism is trophic for gastric epithelium, *H. pylori* are primarily found in the stomach which causes an acute-on-chronic inflammation [44]. Using special stains, organisms can be detected the most accurate and popularly used is immunohistochemistry with *H. pylori-*specific antibodies [45, 46]. Wide range of other tests such as serologic tests for anti–*H. pylori* IgG antibodies and by using molecular testing such as next-generation sequencing [47]. Other tests are noninvasive while some require endoscopy to sample gastric contents, amongst them noninvasive testing is more preferred [48, 49].

The diagnostic strategy utilized clinical indication as well as the local availability and costs of the different tests followed by patient preferences [35]. The presence of the infection gives rise to a serum immune response. Recently, the most commonly used diagnostic test was serology [38]. By Medicare serology is generally neither recommended currently. Tests for the detection of *H. pylori* infection are shown in **Table 1**. IgA and IgM anti–*H. pylori* tests available in some laboratories are not recommended or trusted because of their low specificity and sensitivity generally not approved by the US Food and Drug Administration (FDA). Another important diagnostic method for *H. pylori* is the rapid urease test (RUT). RUT detects an increase in pH of the reagent after the addition of a biopsy specimen that contains *H. pylori* to the reagent [35, 38]. The sort of pH variation is caused by the transformation of the urea test reagent into ammonia. As compared to other tests, RUT is quick, cheap, easy, and specific and is a widely available test [50]. The urea


#### **Table 1.**

*Strengths and weakness of endoscopic and noninvasive tests for the detection of* H. pylori *infection.*

Helicobacter pylori *Gastric Infection: Pathogenesis and Clinical Management DOI: http://dx.doi.org/10.5772/intechopen.106783*

breadth test (UBT) and the stool antigen test (SAT) are the main non-invasive tests for the diagnosis of active infection [51, 52]. UBT is based on the mechanism of degradation of 13C or 14C-labeled urea into CO2 that can be measured by an infrared spectrometer [38, 52]. The false positive tests are commonly associated with serology but can occur in the UBT. For example presence of achlorhydria promotes excessive growth of non–*H. pylori* organisms that produce urease result in false positive UBTs. The apparent failure of repeated treatment is the main cause of false positive tests [38, 50, 51]. The apparent failure of repeated treatment results in False positive tests. When false positive tests are suspected, a less expensive option for UBT is with a stool antigen test or endoscopy for the diagnosis of *H. pylori* [51, 53]. For the diagnosis of *H. pylori* infection urine test has been a new promising non-invasive largely recommended as an alternative [51, 54].

A meta-analysis reported that testing for antibodies from urine samples might be a good diagnostic option [54, 55]. For the confirmation of the accuracy of this method, further studies are necessary. Through the discovery of specific serological markers for the diagnosis of *H. pylori*, the infection has been developed. A recent study confirmed the accuracy of the "hook-associated protein 2 homologs", FliD, as a marker of the diagnosis of *H. pylori* infection [54]. The use of Flid ELISA method for the detection of *H. pylori* infection provides up to 99% high specificity and 97% of sensibility at a low cost [35, 41, 51, 56].

#### **3. Pathogenesis**

#### **3.1 Colonization**

A special mechanism is required by *H. pylori* for successful colonization in the gastric environment. After entering the gastric environment *H. pylori* uses crucial flagellar motility for swimming in gastric content which allows the bacteria to get into the gastric mucus layer [38, 40, 51]. Flagella movements are differ in different media "spreading" in solid media and "swarming" movements, or "swimming motility" in liquid media [57]. Various mutations in genes that encode specific flagellar proteins such as fliD, FlaA, and FlaB disrupts the motility of *H. pylori* resulting in reduce colonization in the gastric mucosal layer [58]. Apart from flagella, the mobility of *H. pylori* lies in the chemotaxis actions of various molecules like mucin, urea, sodium bicarbonate, sodium chloride, and specific amino acids [59]. In recent years various colonization factors like urease, GGT, Flolitin-like protein (FLOT), and RhpA [60]. Several *H. pylori* chemoreceptors like T1pA, B, C, and D, CheA kinase, and various coupling proteins are all important for bacterium colonization [61].

Apart from them, various transition metals are crucial for living organisms, as they serve as cofactors for enzymatic reactions that enhanced the rate of reaction which carries out genetic material replication, transcription, attenuation of oxidative stress, and cellular energy production [54]. In bacteria for survival and successful infection, these metals are crucial [62]. Nickel is an essential metal for *H. pylori* and cofactors for two important enzymes like urease and hydrogenase, both enzymes play a vital role in the process of infection [14]. *H. pylori* urease catalyzes the hydrolysis of urea to ammonia and carbon dioxide which acts as a buffer medium that diminished the acidity of the stomach [63, 64]. Hydrogenase is a signaling cascade that allows Hydrogen as a source of energy for metabolism

to be used by *H. pylori* [65]. In the interaction between bacteria and host Adhesion molecules and surface receptors of gastric cells play a very important role [14, 65]. The well-characterized molecule is blood group antigen binding adhesin A (BabA) that carries specific binding to b and H-1 Lewis antigens from the surface of epithelial cells of gastric [66, 67]. The adhesion of the outer membrane Hp HopQ depicts the bacterial-host interaction. These adhesins bind to the cell adhesion molecules related to the carcinoembryonic antigen 1,3,5 and 6 (CEACAMs which give rise to cell signaling mediated by the HopQ-CEACAM interaction that allows the translocation of CagA which is the most crucial and virulence factor of *H. pylori* that increase pro-inflammatory mediators [63, 64, 68–70]. 64 outer membrane proteins (OMPs) of *H. pylori* are grouped into five gene families. *Hop* and *hor* genes are part of family 1, which encodes BabA/B/C, SabA/B, and AlpA/B [64]. In the virulence of *H. pylori,* various OMPs have been identified [64].

#### **3.2 Cytotoxin-associated gene product (CagA)**

Cytotoxin-associated gene product (CagA) is one of the most important and studied virulence factors of *H. pylori*. Expression of cagA is always induced whenever the pathogen adhered to the epithelial cells [71]. The cag-pathogenicity island (*cag*PAI) is approximately 40kb that encodes CagA [72], type (IV) secretion system (T4SS) [73], and oncoproteins [74]. CagPA1 is a 40kb chromosomal DNA region of which 31 genes form a type IV secretion system (T4SS) [65, 73]. Seven different secretion systems from I-VII are present, amongst them penetration in the plasma membrane and delivery of bacterial molecules directly to the cytoplasm of the target cells is done by Type III and IV. Flagellum-like tube to translocate effector proteins into eukaryotic host cells performed by type III secretion system (T3SS) whereas a pilus-based structure to mediate the delivery of DNA or proteins into target cells employed by type IV secretion system (T4SS). Cytotoxic effect on the host cell, induced by oncoprotein that is injected into the cell via a pilus formed by the T4SS [74, 75]. This results in the induction of cellular alterations like cellular proliferation, impairing cell motility, apoptosis, and change in the pattern of the cytoskeleton [76].

Transport of CagA protein from gastric mucosal surface to endothelial cells for the tyrosine phosphorylation, carried out by T4SS which directly induces an immune response [75, 77]. The specific interaction between the *H. pylori* HopQ adhesin and the CEACAM (a cellular adhesion molecule) is used for translocating CagA into gastric epithelial cells [77]*.* Some studies showed this interaction using CEACAM-humanized (hCEACAM) mouse PMNs and humans resulting that *H. pylori* Hop Q-dependent interaction greatly eases the translocation and phosphorylation of CagA. The PMNs positively enhanced the expression of pro-inflammatory chemokines MIP-1-alpha whereas chronic mouse model infection showed downregulation of hCEACAM and -6 receptors on neutrophils [38, 78, 79]. Once CagA, the effector protein of *H. pylori* outreach the host cell it interacts with a diversity of SH2 domains where tyrosine phosphorylation took place (**Table 2**). Site of phosphorylation in *H. pylori* coerce with Glu-Pro-Ile-Tyr-Ala (EPIYA) sequence simultaneously or with closely related sequence located at the N-terminal region and a C-terminal tail [87]. The classification of different subtypes of CagA such as CagA-AB, CagA-ABC, CagA-ABD, or CagA-BD totally based on the composition of the EPIYA-A, EPIYA-B, EPIYA-C, and EPIYA-D motifs [89]. Binding of the host SH2 domain with different EPIYA segments also differs, Among all, the D segment is more harmonious than the C segment and releases the maximum amount of IL-8. [77, 89]. The cytotoxin-associated gene A (*cagA*)-positive


#### **Table 2.**

*Important virulence factors in* H. pylori*.*

and *cagA*-negative are the two subclasses of *H. pylori* [88]*.* The *cagA*-positive is more motile as compared to *cagA* negative [88]. A more severe clinical outcome of *H. pylori* infection, associated with mucosal inflammation is due to the presence of two segments *cag* I and *cag* II [87]. The level of expression of *cagA* differs in *H. pylori* strains. Yeh *et al,* 2019 demonstrate that the *H. pylori* strains which possess Y58/E59 polymorphism in the *cagL* are at higher risk of facilitating gastric cancer [87, 88]. Mutations in genes present in the *cag*PAI totally influence virulence [87].

#### *3.2.1 Non-CagA virulence factors*

Impairing gastric homeostasis is the main capacity by other various virulence factors. Vacuolating cytotoxins (VacA) protein and its genes are presents in almost all the strains, promotes pathogenicity of *H. pylori* (**Table 2**)*.* Vacuolation is known to be the creation of vacuoles on a host cell which promotes its pathogenicity by inducing cytotoxicity and apoptosis [90]. It promotes endocytic trafficking disruption, perturbations in mitochondrial, depolarization in plasma membrane potential and various ions like chloride, bicarbonate and urea efflux, and results in the activation of MAP kinases [91, 92]. The activation and suppression of the immune response is prompted by VacA that induce immune tolerance through T cells and antigen-presenting cells. Moreover, this protein also enhances the activation and suppression of the immune response resulting in immune tolerance and persistent infection through its activities

on T-cells and antigen-presenting cells [93]. The 140 kDa precursor is produced by VacA which undergoes proteolytic process to produce a toxin of 88 kDa in mass [90]. VacA bind to the epithelial cells with the help of receptor-like protein tyrosine phosphatase alpha and beta (RPTP-α, RPTP-β), sphingomyelin, and density lipoprotein receptor-related protein-1 (LRP-1) [90, 94] also binds to β2 integrin (CD18) receptors [90]. The VacA toxins in amino-terminal is 33KDa and carboxy-terminal 55 kDa that transport into extracellular space by type V secretion pathway, subsequently internalized into endosomal compartments [90, 93, 94]. Several clinical outcomes are due to the different polymorphic forms [94].

The virulence factor promotes gastritis, ulcer, and prolonged infection lead to the cancer development [17, 92]. Duodenal ulcer-promoting gene (DupA) gives a higher acid resistance to the bacterium which promote increase in the production of IL-8 in the gastric mucosa [95]. DupA belongs to the T4SS which integrate conjugative element (ICEHptfs4). VirB4 ATPase homolog is encoded by *dupA ,*linked with gastric ulceration [90, 93] *.*Pro-inflammatory cytokine secreted by mononuclear cells are induced by *dupA* [96]. The secretions of IL-8 and IL-12 are induced by DupA in the gastric mucosa by gastric epithelial cells in vitro [97]. The biomarkers for peptic ulcers disease is due to *dupA* [98]. Recently a study didn't show any positive correlation between *dupA* and peptic ulcer disease [99]. The increased development of peptic ulcers and gastric cancer totally correlated with the discovery of OipA [96]. OipA is one of the important factor in the outcome of the infection is regulated by "slipped strand mispairing", that depends on the quantity of CT dinucleotide repeats in the5' region of *oip*A [100]. This process determines the functionality and nonfunctionality of OipA that enhance the gastric pathogenicity [100]. OipA change the signaling of β-catenin, proliferation of the cell and decreased the cell-cell junctions [100, 101]. *H. pylori* produce the enzyme GGT which catalyzes the conversion of glutamine into glutamate and finally to ammonia; glutathione into glutamate and cysteinylglycine [102]. It lead to the production of reactive oxygen species (ROS) that induce apoptosis and necrosis [20, 21]. The enzyme inhibits T cell proliferation and dendritic cell differentiation [25, 51, 52]. Patients with peptic ulcers have high GGT activity as compared to the other gastroduodenal disease [90, 96]. Other important virulence factors in *H. pylori* shown in **Table 2**.

#### **3.3 Treatment**

No universal regimen for the treatment of *H. pylori* infection. Mostly target the regressing symptomatology and mucosa healing [102]. Since 1997 Maarstricht consensus, proton pump inhibitors (PPI) as standard triple therapy by using a standard dose of 500 mg of clarithromycin and 1g of amoxicillin twice for 7 days as a first-line regimen for the eradication of *H. pylori*. Triple therapy is still recommended as the first line of treatment for *H. pylori* infection in areas with a low rate of clarithromycin according to the European Helicobacter and Microbiota Study Group (EHMSG) [49]. A high dose of clarithromycin resistance lowers the rate for eradication rate of clarithromycin-containing triple therapy like 75% cure rate in Argentina is estimated [103]. A recent study showed that in type 2 diabetic patients the rate of infection eradication is up to 74% [103]. The PPIs, bismuth salt, tetracycline, and metronidazole are complex regimens of Bismuth quadruple therapy, recommended as the second-line or even first-line [104]. According to some previous studies it is stated that the multicenter randomized controlled trials (RCTs) rate of curing of bismuth quadruple therapy is notably high in the standard triple therapy from 90.4% Helicobacter pylori *Gastric Infection: Pathogenesis and Clinical Management DOI: http://dx.doi.org/10.5772/intechopen.106783*

#### **Figure 2.**

*Treatment regimens of* H. pylori *infection.*

to 83.7% for 14 days [103, 104]. In a meta-analysis study, nine RCTs were evaluated and the eradication of infection by bismuth quadruple therapy was the same as those who had received clarithromycin triple therapy [104, 105]. The bismuth quadruple and Levofloxacin triple therapy are the two best therapeutic against infection of *H. pylori* [103]. Levofloxacin regime contains PPIs plus levofloxacin and amoxicillin [104]. Eradication rate of levofloxacin triple therapy (74.5%) and bismuth quadruple therapy (78%) [102, 105]. The third-line therapy is prescribed by using antibiotic susceptibility testing (AST) and prescribed only when the first and second lines of treatment failed [70]. Therapeutic protocols like bismuth-based levofloxacin quadruple therapy or rifabutin triple therapy are used [106]. All three treatment lines are summarized in **Figure 2**.

Probiotics are ―live microorganisms that, when administered in adequate amounts, confer health benefits on the host and they favorably alter the balance in intestinal microflora [107]. Probiotics prevent the adhesion of pathogens by competing for the binding site on intestinal epithelial cells, reducing the colonization of pathogens and thereby preventing the onset of infection. The probiotic's clinical benefits are widely accepted such as diarrhea, antibiotic-associated diarrhea, functional

**Figure 3.**

*Mechanism of probiotics against H. pylori infection.*

digestive involvements, inflammatory bowel disease, cardiovascular diseases, allergic reactions, and cancer [104, 107]. Anti -*H. pylori* properties proved by spp. of *Lactobacillus* [108]. *Lactobacillus* strains prevent the colonization of *H. pylori* due to their specific adhesins [109] shown in **Figure 3**. The adjuvant therapies with probiotics cure infections caused by *H. pylori* according to the European Helicobacter Pylori Study Group (EHPSG) [104, 105]. *Lactobacillus* spp. and *Bifidobacterium* spp are used more in clinical trials than other probiotics [110]. Studies showed that the yogurt containing bacteria could improve the eradication rate of *H. pylori* infection in the fifth week of treatment [107, 110]. Probiotics act as antibiotic-producing bacteria as they produce antimicrobial substances that inhibit the growth of *H. pylori* [87]. Probiotics' short-chain fatty acids products such as acetic acid, propionic acid, and lactic acid lower the pH of the environment totally unfavorable conditions for the survival of *H. pylori* [111]. Bacteriocins produced by probiotics showed antagonistic activity against *H. pylori* [112]. *Lactobacillus acidophilus* significantly reduced the viability of *H. pylori* [112]. Inhibition of *H. pylori* is due to the antimicrobial Nisin A [113]. The heterogeneous group of antimicrobial proteins is mostly produced by all LAB lactic acid bacteria [114]. Inducing pores in the membrane, activating autolytic enzymes, and downregulating the expression of *vacA*, *cagA*, *luxS*, and *flaA* genes are several mechanisms by bacteriocin to inhibit the growth of *H. pylori* [112, 114].

### **Author details**

Neha Bisht and Amar P. Garg\* Shobhit Institute of Engineering and Technology, Deemed to-be-University, Meerut, India

\*Address all correspondence to: amarprakashgarg@yahoo.com

© 2022 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.

Helicobacter pylori *Gastric Infection: Pathogenesis and Clinical Management DOI: http://dx.doi.org/10.5772/intechopen.106783*

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#### **Chapter 2**

## Alpha-Glutamyl-Tryptophan in the Treatment of Chronic Atrophic Gastritis, Associated with *Helicobacter pylori*

*Yury P. Uspensky, Natalia V. Baryshnikova, Yulia A. Fominykh, Alexey A. Krasnov, Sergey V. Petlenko and Vera A. Apryatina*

#### **Abstract**

To evaluate the effectiveness of alpha-glutamyl-tryptophan as a cytoprotector in comparison with the control group (placebo) as part of the complex therapy of chronic atrophic *H. pylori* (HP)-associated gastritis. A total of 121 patients with chronic atrophic HP-associated gastritis were observed in 3 research centers. Before and after treatment blood test "Gastropanel", stomach endoscopy with biopsies of atrophied mucosa for histological examination, rapid urease test for *H. pylori* detection, and daily pH-metry were performed. After HP eradication, according to randomization, the study drug (n = 61) or placebo (n = 60) was administered twice a day, in the morning 20–30 minutes before meals and in the evening before bedtime for 28 days. Alpha-glutamyl-tryptophan intake is associated with a statistically significant increase in acidity index according to pH-metry (p = 0.001), an increase in the ratio of pepsinogen I/pepsinogen II (p = 0.003), decrease in the level of gastrin-17 (p = 0.005), increase in the number of glands per 1 mm2 of the gastric mucosa (р = 0.028). Alpha-glutamyl-tryptophan in the treatment of chronic atrophic HP-associated gastritis has a superior regenerative effect compared with placebo, and promotes the restoration of acid-forming and pepsin-forming functions of the stomach.

**Keywords:** chronic atrophic gastritis, *Helicobacter pylori*, alpha-glutamyl-tryptophan, atrophy, stomach

#### **1. Introduction**

In accordance with the current standards for the treatment of chronic gastritis, eradication of *Helicobacter pylori* is an effective strategy to reduce the risk of developing stomach cancer [1–4]. However, a large percentage of *H. pylori*-infected patients get to the primary doctor's appointment already at the stage of not superficial active gastritis, but at the stage of atrophic gastritis, when the risk of cancer becomes higher [5–8]. Data on the possibility of reverse development of atrophy and intestinal metaplasia after eradication of infection are contradictory [1, 9]. Even if the pathogen is successfully

eradicated in patients with chronic atrophic gastritis, regression of atrophy does not always take place. Already the Maastricht Consensus III introduced the term "point of no return", after which *H. pylori* eradication no longer gives a significant preventive effect on the development of stomach cancer [10]. This "point of no return" is considered to be the presence of severe atrophy and intestinal metaplasia. Thus, in a meta-analysis of 12 studies involving 2658 patients conducted by J. Wang et al., it was shown that *H. pylori* eradication reduces atrophy in the stomach body (p = 0.006), but not in its antrum (p = 0.06), and does not affect intestinal metaplasia in these departments (respectively, p = 0.42 and p = 0.76) [11]. Consequently, the changes described in the Correa cascade can progress even in the absence of a microorganism, which once again emphasizes the need for additional measures to preserve the structure and function of the gastric mucosa at the stage of atrophy development. Therefore, it is extremely important to look for ways of primary cancer prevention by including in the complex therapy of this category of patients drugs for the restoration of the gastric mucosa, i.e., having a regenerative effect [12]. One of such medicine is alpha-glutamyl-tryptophan. The pharmacological properties of alpha-glutamyl-tryptophan revealed during experimental [13] and clinical [14] studies indicate the effect of this peptide on the unified pathogenetic mechanisms of inflammatory diseases of the gastrointestinal tract: it is effective against chronic gastritis accompanied by atrophic processes of the gastric mucosa [15].

The aim is to evaluate the effectiveness of alpha-glutamyl-tryptophan as a cytoprotector in comparison with the control group (placebo) as part of the complex therapy of chronic atrophic *H. pylori-*associated gastritis.

#### **2. Materials and methods**

#### **2.1 Patients population**

We included in the study 152 adult patients with a history of diagnosis of "chronic atrophic gastritis" in three research centers. A total of 121 patients met all inclusion criteria: signed informed consent (before the start of the study procedures); men and women aged 40–70 years; previously diagnosed chronic atrophic gastritis; the presence of complaints and symptoms characteristic of chronic atrophic gastritis; confirmed diagnosis of atrophic gastritis associated with *H. pylori* infection by endoscopic and histological examination; hypo- or anacidity according to pH-metry (pH greater than 5.0); negative pregnancy test; use of any methods of contraception during the entire time of participation in the study. Four weeks before participation in the study some drugs are prohibited to use: cytostatic, immunosuppressive, hormonal (hormone-like), antimicrobial or sedative effects, as well as drugs or biologically active additives for the treatment of inflammatory diseases of the stomach, duodenum (bismuth-containing drugs, proton pump inhibitors, antacids, gastric secretion or motility stimulants, antiemetics, laxatives, etc.), liver and pancreas (hepato-pancreatoprotectors, enzymes, choleretics, cholekinetics, etc.), nonsteroidal anti-inflammatory drugs (NSAIDs).

#### **2.2 Diagnostic methods**

Before and after treatment complex diagnostic examination was performed for all patients.

*Alpha-Glutamyl-Tryptophan in the Treatment of Chronic Atrophic Gastritis, Associated… DOI: http://dx.doi.org/10.5772/intechopen.108346*

*Evaluation of the results of daily pH-metry.* In the course of the study, the data of the daily pH-metry of the stomach was analyzed twice (before the appointment of the studied drug during the screening period and after taking the course of the studied drug). The analysis included an assessment of the parameters: the minimum pH value, the average pH value, the aggressiveness index, and the acidity index.

*Evaluation of the results of histological examination.* Morphological (morphometric) analysis of the biopsy data of the gastric mucosa taken from the center of the atrophy zone twice (before the appointment of the test drug during the screening period and after taking the course of the study drug/placebo). The analysis included an assessment of such parameters as the number of glands per 1 mm2 of the gastric mucosa, the depth of the glands of the gastric mucosa, and the number of lining cells per 100 epithelial cells of the gastric mucosa.

*Evaluation of the dynamics of laboratory parameters.* "Gastropanel" is a comprehensive study with the determination of a number of biochemical markers associated with gastric secretion and regenerative processes in the gastric mucosa, as well as antibodies to *H. pylori*. The "Gastropanel" complex was performed according to the standard protocol of the manufacturer (BioHit, Finland) and included an assessment of the level of pepsinogen I (PG I), pepsinogen II (PG II), gastrin-17, and the IgG titer to *H. pylori*. In addition to analyzing data on the content of the listed compounds, the PG I/PG II ratio was calculated and analyzed to assess the degree of atrophy. The study was conducted twice (before the appointment of the study drug during the screening period and after the end of the course of taking the study drug/placebo). The ratio of PG1/PG2 decreases linearly with increasing severity of atrophic gastritis.

*Verification of the presence of H. pylori infection* was made using several methods:


#### **2.3 Treatment**

The order of randomization: patients who met the inclusion criteria and did not have non-inclusion criteria were randomized into two groups: the main and control in a ratio of 1:1. Then performing the randomization procedure, the random number method was used. A double-blind method was used: neither the patients nor the research doctor knew which drug alpha-glutamyl-tryptophan or placebo the study participant received. These measures made it possible to minimize the influence of the human factor and contributed to obtaining more reliable data on the safety and effectiveness of the drug. The study drug and placebo were identical in packaging, labeling, and appearance.

The therapy in the study consisted of two stages:

1.A standard course of eradication therapy with Omeprazole 20 mg two times a day 10 days; amoxicillin 1000 mg two times a day for the first 5 days; clarithromycin 500 mg two times a day for next 5 days.

2.After *H. pylori* eradication, according to randomization, the study drug (n = 61) or placebo (n = 60) was administered twice a day, in the morning 20–30 minutes before meals and in the evening before bedtime for 28 days.

In the patients included in the study, the use of other medications and non-drug treatments other than the use of eradication therapy and the study drug/placebo was not allowed for the treatment of the underlying disease (atrophic gastritis).

During the study, all possible adverse events were recorded.

#### **3. Statistical data processing**

The statistical software package "Statistica 12.0 for Windows" was used for statistical analysis. The value p<0.05 is taken as the level of statistical significance. The data, the distribution of which corresponded to normal, were presented in the form of arithmetic averages indicating standard square deviations (M ± σ). The data, the distribution of which differed from the normal, were presented in the form of median and quartile intervals (Mediana: [25 quartile; 75% quartile]). The Lillefors criterion was used to determine the degree of difference between the distribution and the normal one.

Due to the small sample size, nonparametric criteria were used in most cases to assess the dynamics of indicators between visits. The dynamics of the indicators were evaluated using the Wilcoxon criterion, as well as the McNemar criterion. If necessary, Bonferroni's correction for the multiplicity of comparison was used. The reliability of the differences between the indicators of dependent groups for parametric data with a normal distribution was evaluated using the Student's t-test for dependent samples.

The results of each assessment were considered as statistical indicators of the effect. In the future, the difference in the proportion of patients with a positive effect was calculated according to the primary (main variable) and secondary efficiency parameters, and a two-sided 95% confidence interval was built for this difference. To assess the effectiveness of the studied drug, a statistical analysis of the population according to the protocol (PP) was used.

The study was conducted in strict accordance with the ethical principles of the Helsinki Declaration of the World Medical Association of 1964, as amended in 2013, in accordance with the international standards of the Guidelines for Good Clinical Practice (ICH GCP R2) and other necessary regulatory documents in force on the territory of the Russian Federation.

#### **4. Results**

#### **4.1 Data of histological examination**

One of the main morphological signs of atrophic gastritis is a decrease in the number of glands of the gastric mucosa, as well as a violation of their histological structure. Therefore, an important indicator for assessing the regenerative effect of alpha-glutamyl-tryptophan can be considered an increase of 26.1% in the number of glands per 1 mm2 while taking the study drug (**Figure 1**).

*Alpha-Glutamyl-Tryptophan in the Treatment of Chronic Atrophic Gastritis, Associated… DOI: http://dx.doi.org/10.5772/intechopen.108346*

#### **Figure 1.**

*Diagram of the scale of the dynamics of the number of glands per 1 mm2 of the gastric mucosa during the administration of the alpha-glutamyl-tryptophan and placebo.*

The medians, 25 and 75% quartiles, outliers of values, and minimum and maximum values of the indicator are presented

Along the abscissa axis of the treatment group:

1. results of alpha-glutamyl-tryptophan group before treatment

2. results of alpha-glutamyl-tryptophan group after treatment

3. results of placebo group before treatment

4. results of placebo group after treatment

On the ordinate axis: the number of glands per 1 mm2 of the gastric mucosa in the atrophy zone

The diagram shows that taking of alpha-glutamyl-tryptophan leads to the statistically significant (p = 0.028) increase in the number of glands per 1 mm2 of the gastric mucosa in comparison with the initial screening indicators. In the group of patients taking placebo, on the contrary, there was a decrease in the number of glands per 1 mm2 of the gastric mucosa after the end of treatment in comparison with screening indicators, which had no statistical significance of differences. Intergroup comparison of the final treatment parameters showed that after a course of therapy in patients taking the alpha-glutamyl-tryptophan, the number of glands per 1 mm2 of the gastric mucosa was statistically significantly higher compared with the results in the placebo group (p = 0.013).

#### **4.2 Data of daily pH-metry**

The average pH value after taking of study drug was shift in the acidic side by 1.59 times compared to the initial values from 4.3 [2.6; 6.1] to 2.7 [1.6; 4.7] (p = 0.001). No statistically significant dynamics of the mean pH was obtained in placebo group: from 4.35 [2.4; 6.1] to 3.6 [1.8; 5.0].

The value of the acidity index increased statistically significantly after taking the study drug as compared with the initial values by 5.44 times (from 8.95 [0; 50.33] to 48.70 [0; 110.90]), (p = 0.001), and in comparison with the placebo group by 2.94 times (from 22.80 [0; 63.62] to 16.55 [0; 77.68]), (p = 0.034) (**Figure 2**). In the placebo group, a decrease in the acidity index was noted, which indicates the absence of regression of atrophy even against the background of successful eradication of *H. pylori*.

#### **Figure 2.**

*Diagram of the magnitude of changes in the acidity index of gastric juice during the administration of alphaglutamyl-tryptophan and placebo.*

The medians, 25 and 75% quartiles, outliers of values, and minimum and maximum values of the indicator are presented

Along the abscissa axis of the treatment group:


On the ordinate axis: stomach acidity index, units

A statistically significant increase in the aggressiveness index by 1.48 times was revealed after taking the study drug when comparing the results before and after treatment (from 4.8 [3.1; 6.2] to 3.25 [1.7; 5.0]), (p < 0.001). For the placebo group, the same indicator was 1.18 times (parameter change from 4.9 [2.7; 6.2] to 4.15 [2.0; 5.5]). The effect of the studied drug on the value of the aggressiveness index was more pronounced and stable than that of placebo.

*Alpha-Glutamyl-Tryptophan in the Treatment of Chronic Atrophic Gastritis, Associated… DOI: http://dx.doi.org/10.5772/intechopen.108346*

There were no statistically significant changes in the minimum pH of gastric juice during the administration of both the study drug and placebo.

The results obtained indicate that alpha-glutamyl-tryptophan has a clinically significant moderate positive effect on increasing the acidity of gastric juice, i.e. restoring the functional activity of the glandular apparatus of the gastric mucosa in patients with chronic atrophic gastritis, associated with *H. pylori*. These changes in acid secretion can be regarded as an effect that occurs indirectly due to the restoration of the morphological structure of the gastric mucosa. It should be understood that a relatively short course of the drug was used in the study, which, nevertheless, revealed a statistically significant positive effect on the indicators of acid secretion in this category of patients.

#### **4.3 "Gastropanel" data**

When evaluating the results of the Gastropanel complex of laboratory examinations, we saw a statistically significant (p = 0.003) 1.45-fold increase in the ratio of pepsinogen I /pepsinogen II (PG I/PG II): 9.33 [5.5; 12.2] was revealed in comparison with the initial data (6.43 [4.17; 9.6]) in alpha-glutamyl-tryptophan group and the absence of similar differences in the placebo group (before taking placebo: 7.01 [4.55; 10.9], after taking placebo: 8.03 [4.8; 11.6]) (**Figure 3**).

#### **Figure 3.**

*Diagram of the range of values of the PGI/PGII coefficient in the process of taking alpha-glutamyl-tryptophan and placebo.*

The medians, 25 and 75% quartiles, outliers of values, and minimum and maximum values of the indicator are presented

Along the abscissa axis of the treatment group:


On the ordinate axis: values of the PGI / PGII coefficient, units

The restoration of the normal PGI / PGII ratio indirectly indicates the restoration of pepsin-forming function of the stomach and is an important point in the pathogenetic treatment of chronic atrophic gastritis, since such an effect can be classified as anti-oncogenic.

We found a statistically significant (p = 0.005) 1.75-fold decrease in the level of gastrin-17 in the blood (pmol/L) (2.9 [1.4; 8.6]) in comparison with the initial data (5.1 [1.85; 14.0]) after taking the alpha-glutamyl-tryptophan and the absence of similar differences in the placebo group (before taking placebo: 5.13 [1.38; 16.9]; after taking placebo: 3.14 [1.28; 15.1]) (**Figure** 4). This indicates a decrease in inflammation associated with *H. pylori* invasion. That is, it can be a manifestation of both regenerative and anti-inflammatory effects of alpha-glutamyl-tryptophan.

#### **Figure 4.**

*Diagram of the range of gastrin-17 levels in venous blood (pmol/l) in the process of taking alpha-glutamyltryptophan and placebo.*

The medians, 25 and 75% quartiles, outliers of values, and minimum and maximum values of the indicator are presented

Along the abscissa axis of the treatment group:

1. results of alpha-glutamyl-tryptophan group before treatment

*Alpha-Glutamyl-Tryptophan in the Treatment of Chronic Atrophic Gastritis, Associated… DOI: http://dx.doi.org/10.5772/intechopen.108346*

2. results of alpha-glutamyl-tryptophan group after treatment

3. results of placebo group before treatment

4. results of placebo group after treatment

On the ordinate axis: gastrin-17 level in venous blood, pmol/l

#### **4.4 Estimation of adverse events**

In the study, 45 adverse events (AE) were registered. Of these, 20 were on the background of taking the study drug, 12 were on the background of taking a placebo, 13 occurred before the taking of the study drug/placebo. An intergroup comparison of the number of AE detected during the period of taking the study drug and placebo revealed no statistically significant differences (χ2 = 1.55; p = 0.213) in the amount of AE in the study groups. No any serious AE was detected in the study.

#### **5. Conclusion**

According to the results of the study, it can be concluded that the study drug alpha-glutamyl-tryptophan, in comparison with placebo, has superior regenerative efficiency (an increase in the number of glands per 1 mm2 of the gastric mucosa, an increase in the acidity index and a shift in the average pH value to the acidic side according to the daily pH-metry, an increase in the ratio of PG I / PG II and a decrease in the level of gastrin-17 in the blood according to the Gastropanel complex). The study drug promotes the restoration of acid-forming and pepsin-forming functions of the stomach in the treatment of chronic atrophic gastritis in patients aged 40–70 years. It can be assumed that the study drug, due to the restoration of anatomical and functional parameters of the gastric mucosa, also decreases the pro-oncogenic processes associated with the development of atrophy.

Therefore, it can be recommended to include alpha-glutamyl-tryptophan in the complex therapy of chronic atrophic gastritis, associated with *H. pylori* and for primary prophylaxis of gastric cancer. In the future, it is important to conduct studies with the estimation of alpha-glutamyl-tryptophan efficacy in the treatment of chronic atrophic gastritis not associated with *H. pylori*, peptic ulcer disease (*H. pylori*associated and not associated), chronic non-atrophic gastritis (*H. pylori*-associated and not associated) for improving regeneration of gastric mucosa.

### **Author details**

Yury P. Uspensky1,2, Natalia V. Baryshnikova1,2,3\*, Yulia A. Fominykh1,2, Alexey A. Krasnov4 , Sergey V. Petlenko5 and Vera A. Apryatina6

1 St. Petersburg State Pediatric Medical University, St. Petersburg, Russia

2 Pavlov First St. Petersburg State Medical University, St. Petersburg, Russia

3 Institute of experimental Medicine, St. Petersburg, Russia

4 The Herzen State Pedagogical University of Russia, St. Petersburg, Russia

5 Golikov Research Clinical Center of Toxicology under the Federal Medical-Biological Agency, St. Petersburg, Russia

6 Saint Petersburg State University, Institute of translational biomedicine, Universitetskaya Embankment, St. Petersburg, Russia

\*Address all correspondence to: baryshnikova\_nv@mail.ru

© 2022 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.

*Alpha-Glutamyl-Tryptophan in the Treatment of Chronic Atrophic Gastritis, Associated… DOI: http://dx.doi.org/10.5772/intechopen.108346*

#### **References**

[1] Malfertheiner P, Megraud F, O'Morain CA, Gisbert JP, Kuipers EJ, et al. Management of *Helicobacter pylori* infection—the Maastricht V/Florence Consensus Report. Gut. 2017;**66**:6-30

[2] Sugano K, Tack J, Kuipers EJ, Graham DY, El-Omar EM, Miura S, et al. Faculty members of Kyoto Global Consensus Conference. Kyoto global consensus report on *Helicobacter pylori* gastritis. Gut. 2015;**64**(9):1353-1367

[3] Waldum H, Fossmark R. Gastritis, gastric polyps and gastric cancer. International Journal of Molecular Science. 2021;**22**(12):6548

[4] Ansari S, Yamaoka Y. *Helicobacter pylori* virulence factors exploiting gastric colonization and its pathogenicity. Toxins (Basel). 2019;**11**(11):677

[5] Correa P. *Helicobacter pylori* and gastric carcinogenesis. American Journal of Surgery Pathology. 1995;**19**(Suppl. 1): S37-S43

[6] Correa P. Gastric cancer: Overview. Gastroenterological Clinical North America. 2013;**42**(2):211-217

[7] Kishikawa H, Ojiro K, Nakamura K, Katayama T, Arahata K, Takarabe S, et al. Previous Helicobacter pylori infection-induced atrophic gastritis: A distinct disease entity in an understudied population without a history of eradication. Helicobacter. 2020;**25**(1):e12669

[8] Shichijo S, Hirata Y. Characteristics and predictors of gastric cancer after *Helicobacter pylori* eradication. World Journal of Gastroenterology. 2018;**24**(20):2163-2172

[9] Watari J, Chen N, Amenta PS, Fukui H, Oshima T, Tomita T, et al. Helicobacter pylori associated chronic gastritis, clinical syndromes, precancerous lesions, and pathogenesis of gastric cancer development. World Journal of Gastroenterology. 2014;**20**(18):5461-5473

[10] Malfertheiner P, Megraud F, O'Morain C, Bazzoli F, El-Omar E, Graham D, et al. Current concepts in the management of *Helicobacter pylori* infection: The Maastricht III Consensus Report. Gut. Jun 2007;**56**(6):772-781

[11] Wang J, Xu L, Shi R, Huang X, Li SW, Huang Z, et al. Gastric atrophy and intestinal metaplasia before and after *Helicobacter pylori* eradication: A metaanalysis. Digestion. 2011;**83**(4):253-260

[12] Lahner E, Carabotti M, Annibale B. Treatment of *Helicobacter pylori* infection in atrophic gastritis. World Journal of Gastroenterology. 2018;**24**(22):2373-2380

[13] Shevtsov MA, Smagina LV, Kudriavtceva TA, Petlenko SV, Voronkina IV. Glu-Trp-ONa or its acylated analogue (R-Glu-Trp-ONa) administration enhances the wound healing in the model of chronic skin wounds in rabbits. Drug Design and Developmental Therapy. 2015;**9**:1717-1727

[14] Kasimova AR, Petlenko IS, Bozhkova SA. Dynamics of postsurgical wound local changes and healing rate during the use of alpha-glutamyltryptophan in combination therapy of patients with skin and soft-tissue infections. Siberian Scientific Medical Journal. 2020;**40**(5):98-105

[15] Petlenko IS, Egorova TY, Petlenko SV, et al. Experimental study of the specific activity of L-Glutamyl- L-Tryptophan. Modern Problems of Science and Education. 2019;**3**:199

### **Chapter 3**

*Helicobacter pylori*: A Bacterium Influencing and Causing Most of the Diseases in the Upper Gastrointestinal Tract – An Overview with Respect to Pathogenesis and Treatment Based on Basic Physiology

*Helge L. Waldum*

#### **Abstract**

The discovery that *Helicobacter pylori* was the dominating cause of gastritis is among the most important findings in the last century. It gave rise to the understanding and treatment of serious and common diseases, such as peptic ulcer disease and gastric cancer. The gastric hormone gastrin is involved in the pathogenesis of both duodenal ulcer and gastric cancer, whereas reduction in the defense mechanism (mucus and bicarbonate) by the inflammation itself predisposes to gastric ulcer. The search for carcinogenic *H. pylori* factors has been unsuccessful and based upon the fact that *H. pylori* predispose to gastric cancer only after having induced oxyntic atrophy is an important argument in favor of a central role of gastrin increase secondary to reduced acidity. The only cell with an undisputed gastrin receptor is the enterochromaffin-like cell where gastrin has a trophic effect leading to hyperplasia, neuroendocrine tumor (NET), and long-term carcinoma of diffuse type. *H. pylori* may be eradicated by a combination of antibiotics with a potent inhibitor of acid secretion. *H. pylori* is dependent on acid surrounding to thrive, and therefore anacidity due to complete oxyntic atrophy or profound inhibition of acid secretion by drugs will promote its disappearance.

**Keywords:** *Helicobacter pylori*, duodenal ulcer, gastric peptic ulcer, gastric cancer, gastrin, enterochromaffin-like cell

#### **1. Introduction**

Diseases of the upper gastrointestinal tract, such as peptic ulcer and gastric cancer, were previously very prevalent. Moreover, gastric cancer has high mortality, and

peptic ulcer was an important disabling disease. With different types of surgical interventions on the regulation of acid secretion, such as removal of the gastrin-producing antrum or cutting of the vagal nerves, the prognosis of severe peptic ulcer disease improved but not seldom with serious postoperative complaints. With the description of the histamine 2(H2) receptor and the development of the first H2 receptor antagonist, cimetidine, by Black and coworkers [1], peptic ulcer disease became available for drug treatment. Later the more efficient inhibitor of acid secretion, omeprazole, was described and found to inhibit the final step in acid secretion, the proton pump (PPI) [2, 3]. Drugs inhibiting gastric acid secretion when dosed sufficiently made virtually every peptic ulcer heal but had to be continued indefinitely to prevent relapses. At the same time period, it was realized that peptic ulcer disease was associated with gastritis [4, 5].

Similarly, gastritis was recognized as a factor in gastric carcinogenesis [6, 7] in the 1950s, while a role of gastric hypoacidity was described the decade before [8, 9]. Gastritis was, thus, established as central in diseases of the upper gastrointestinal tract. The etiology of gastritis was unknown, but based upon distribution, two types of gastritis were described as type A only affecting the oxyntic mucosa and type B affecting the antral mucosa and gradually spreading to the oxyntic mucosa [10]. Thus, there was apparent that gastritis was very important in upper gastrointestinal pathology and that there existed two types of gastritis with presumed different etiology before Marshall and Warren made their description of *H. pylori* (*H. pylori*) [11], which subsequently has been shown to be the major cause of peptic ulcer [12], as well as gastric cancer [13].

#### **2.** *H. pylori*

Around nineteen hundred "spirochete" resembling organisms were recognized in the gastric mucosa [14] in gastric tissue taken from stomachs with gastric cancer [15]. Similarly, epidemic gastritis with hypochlorhydria was reported in the fifties [16] and in the late seventies, the occurrence of gastritis leading to hypoacidity was described as to result of contaminated gastric tubes [17]. Likewise, a gastric urease had been described, which subsequently was shown to be of bacterial origin since tetracycline treatment changed gastric juice nitrogen from ammonium to urea [18]. The indications for an infectious agent causing gastritis accumulated during the nearly hundred years period ahead of the culture of the organism now known as *H. pylori* [11] are excellently summarized by Marshall himself [18]. *H. pylori* produces many factors that make the bacterium able to live in the gastric mucus, as well as to induce damage and inflammation in the epithelial cells. The urease is essential for its ability to survive in the highly acidic stomach, whereas the cytotoxin-associated gene A (Gag A) probably is most important in inducing inflammation, damage to the gastric mucosa, and diseases [19].

#### **2.1 Urease**

The high production of urease by *H. pylori* is a central trait for thriving in the gastric mucus [20] and is also the basis for the rapid urease test to diagnose gastric infection with *H. pylori* [21]. In the eradication cures of *H. pylori*, potent inhibition of acid secretion is combined with high doses of antibiotics, and it is probable that the reduction in acidity of the mucus contributes to the killing of the bacterium. Potassium-competitive acid blockers (P-CABs) are even more effective than proton Helicobacter pylori*: A Bacterium Influencing and Causing Most of the Diseases in the Upper… DOI: http://dx.doi.org/10.5772/intechopen.108494*

pump inhibitors (PPIs) in inhibiting acid secretion. In combination with amoxicillin and clarithromycin, vonoprazan (a P-CAB) induced the same degree of *H. pylori* eradication after one-week therapy as with the same antibiotics at the same doses together with PPIs for 2 weeks [22].

#### **2.2 Blood group antigen binding adhesin A (Bab A)**

Urease activity of *H. pylori* is necessary for both establishing and persistence of infection [20]. The initial binding of *H. pylori* to the gastric mucosal cells depends on adhesins. Among them, Bab A has been considered particularly important, although the clinical implications of the different expressions seem marginal [23].

#### **2.3 Cytotoxin-associated gene A (Cag A)**

Among the virulence factors in *H. pylori*, Cag A is probably the most important. Cag A gene is part of the cytotoxin-associated gene pathogenicity island (cagPAI), which also contains the bacterial type IV secretion system (T4SS) whereby Cag A enters the gastric mucosal cells [24]. The presence of cagPAI seems to be associated with more severe gastric pathology, including gastric cancer [19], and some polymorphisms may also have a higher risk [25]. After having penetrated the epithelial cell membrane, Cag A is phosphorylated, and phosphorylated Cag A then interacts with different proteins causing damage to the infected cell [19]. However, any direct mechanism for the pathogenetic effect of Cag A or *H. pylori* itself is still missing.

#### **2.4 Vacuolating cytotoxin A (Vac A)**

Vac A is a pore-forming protein that binds to some receptors and enters the cell interior by endocytosis [26]. After having entered the cell, Vac A induces large vacuoles [27] and cell death possibly by affecting mitochondrial function [28].

The pathogenetic role of the different factors of *H. pylori* has been discussed in depth in different recent reviews [19, 29], but the exact mechanism for the carcinogenic effect has not been disclosed. Already, in 2000, Graham and Yamaoka wrote a review with the title: Disease-specific *H. pylori* virulence factors: the unfilled promise [30]. They concluded that only the cag pathogenicity island had passed the tests of biological plausibility with respect to increased inflammation. Subsequently, I will describe the course of *H. pylori* infection and afterward return to the question of the pathogenesis of gastric cancer due to *H. pylori*.

#### **2.5 Course of** *H. pylori* **infection**

The symptoms of acute *H. pylori* infection are probably best described by the two known voluntary infections [31, 32]. As early as 3 days after ingestion of *H. pylori* epigastric pains were noticed and mild symptoms persisted for 14 days. Normal gastric acidity before infection was changed to anacidity on day 8 after infection [32]. Interestingly, these two voluntary infections were successful only after giving an inhibitor of gastric acid secretion suggesting that gastric acidity protects to some degree against initial infection. In this context, it shall also be mentioned the outbreak of gastritis due to contamination of the equipment in a study of gastric secretion described in 1979 [17]. The healthy subjects were tested multiple times and developed epigastric symptoms, gastritis, and hypoacidity. In retrospect, this outbreak of

hypo-acidic gastritis has been attributed to contamination with *H. pylori*. It should be noticed that also in these subjects *H. pylori* most probably was introduced into the stomach with hypoacidity since the gastric juice was continuously aspirated [33]. What about the role of gastric acidity in real-life initial steps of infection?

It is well-known that *H. pylori* infection occurs mainly in childhood both in developed and developing countries [34, 35]. Although gastric acidity is lower during the first year of life compared with healthy individuals later in life [36], a difference in gastric acidity cannot explain the different susceptibility for *H. pylori* infection in childhood. The habit of small children putting so many things into their mouths may perhaps contribute. The present prevalent use of profound inhibitors of acid secretion in adults seen during the last decades has not resulted in any increased tendency to new *H. pylori* infections in grown-ups, indicating that hypoacidity is not as important for establishing *H. pylori* infection as the two voluntary studies [31, 32] suggested. On the other hand, in those studies acid secretion was inhibited by a histamine blocker, thus only moderate reduction in gastric acidity compared with PPIs. It is possible that profound acid inhibition could reduce the susceptibility for *H. pylori* infection due to a reduction in acidity in gastric mucous. In contrast, PPI treatment has been reported to increase the proximal spread of *H. pylori* gastritis [37] possibly by reducing mucous acidity reflecting that *H. pylori* require some acidity, but not too high acidity as patients with gastrinoma generally have a low frequency of *H. pylori* infection [38].

The mechanism for the initial inhibition of acid secretion is not completely elucidated, but hypoacidity may persist for weeks or even months [17]. After ingestion, *H. pylori* first infects the antral mucosa but after days spreads to the oxyntic mucosa as well [31, 32]. Properties both by *H. pylori* itself, and the inflammation provoked have been implicated [33, 39]. For some reason or the other, the transition from acute to chronic gastritis is accompanied by resolution of the inflammation in the oxyntic mucosa, whereas it persists in the antral mucosa. Concomitant with the healing of the oxyntic mucosa, gastric acidity is normalized [17, 32]. The general belief is that when first infected, *H. pylori* infection will persist until eventual eradication or reaching complete anacidity secondary to atrophic oxyntic atrophy. In some patients, *H. pylori* gastritis remain confined to the antral mucosa for years, whereas in others *H. pylori* and accompanying gastritis early spread in the oral direction. The reason for this difference is not known, but the fact that inhibition of gastric acid secretion promotes the distribution of gastritis orally [40] and may suggest that acidity plays a role [33].

The development of the *H. pylori* gastritis has a dual effect on gastric acid secretion. When the infection is confined to the antral mucosa, gastric acid secretion is increased due to elevated gastrin release [41], whereas gastric acid secretion is impaired when oxyntic gastritis with damage to the parietal cells has occurred. It is probable that the increase in gastrin release, in relation to gastric acidity (inappropriate gastrin release), is due to an effect on gastrin release by NH3 produced by *H. pylori* urease. Studies to examine whether NH3 could be the causative factor for this effect on gastrin release have been ambivalent, but in a careful evaluation of the data related to this question, we concluded that *H. pylori*-induced NH3 was the cause of inappropriate gastrin release and thus hypersecretion of acid [33].

Subsequently, the inflammation in most patients spreads to the oxyntic mucosa. Why some patients are more resistant to oxyntic affection is not known. Similarly, the reason why the oxyntic mucosa is apparently less susceptible to *H. pylori* gastritis than the antral mucosa is also unknown. However, it is thought that higher acidity could play a role. Nevertheless, the oxyntic glands empty their contents into the lumen through transient openings and not by diffusion through the mucous layer. Anyhow,

Helicobacter pylori*: A Bacterium Influencing and Causing Most of the Diseases in the Upper… DOI: http://dx.doi.org/10.5772/intechopen.108494*

the luminal acidity is slightly higher in the oxyntic area, and this could play a role in the relative resistance. The oxyntic *H. pylori* gastritis starts as superficial gastritis, which gradually affects the deeper layers of the mucosa including the glands finally destroying them and leading to reduced acid production by the disappearance of the parietal cells and other specialized cells, such as the chief cells. All the specialized cells of the oxyntic mucosa are killed during this process except the target cell of gastrin, the enterochromaffin-like (ECL) cell [42]. With time, all the oxyntic mucosa is destroyed leading to anacidity and disappearance of the *H. pylori* infection [43] since the bacterium depends on some acidity in the surroundings to neutralize the NH3 production caused by the urease. The complete atrophy of the oxyntic mucosa naturally leads to hypergastrinemia [44].

#### **2.6 Consequences of** *H. pylori* **infection**

#### *2.6.1 Gastritis*

The acute infection causes acute gastritis, which subsides within a week or two. Chronic uncomplicated phase of gastritis does not cause any symptoms, which is exemplified by the previous belief that gastritis could be regarded as a normal phenomenon of older age. However, chronic *H. pylori* gastritis is complicated with many serious upper gastrointestinal diseases; in fact, most of the diseases in the upper gastrointestinal tract are influenced or caused by this infection.

#### *2.6.2 Peptic ulcer disease*

Peptic ulcer disease consists of two subgroups: duodenal and gastric ulcers. At both locations, the ulcer is caused by the digestion of the mucosa by the acidic and proteolytic gastric juice. In duodenal ulcer, the aggressive forces are increased as shown by the increased acid secretion [45], whereas in gastric ulcers, a reduction in defense (bicarbonate and mucous production by superficial cells) is probably the mechanism. *H. pylori* gastritis has been shown to inhibit mucin synthesis [46]. Generally, the more oral a gastric ulcer is localized, the lower is the capacity to produce acid [45]. Also, reflux oesophagitis is ultimately due to the erosive activity of gastric juice. The roles of acid versus pepsin in tissue damage in all these conditions are difficult to differentiate since the regulations of pepsinogen, and acid secretions in many ways are similar. Furthermore, acid is required for the autocatalytic activation of pepsinogen into the active form pepsin [47]. The most important factor in the pathogenesis of reflux oesophagitis is insufficiency of the functional gastro-esophageal valve, whereas *H. pylori* is the dominating cause of both duodenal and gastric ulcers. *H. pylori* gastritis influences the risk and severity of gastro-esophageal reflux through the reduction of gastric acid secretion due to oxyntic atrophy [33].

#### *2.6.3 Duodenal ulcer*

Duodenal ulcer has for long been known to be associated with increased gastric acid secretion [45]. Concomitant with the description that *H. pylori* was the dominating cause of gastritis, it was also shown that most patients with peptic ulcer, being duodenal or gastric, also were infected [11]. Initially, it was thought that duodenal ulcers occurred at islands of gastric metaplasia in the duodenum. This has not been substantiated [48, 49], and the focus has been directed toward the elevation of

gastric acid secretion. It was detected that patients with antral gastritis had a slight elevation of gastrin in the blood causing an increase in gastric acid secretion [33, 41]. The pathogenesis of duodenal ulcer is, thus, most likely the increase in gastric acid secretion due to *H. pylori* infection of the antrum. An increase in gastric acid secretion is alone sufficient to induce peptic ulcer as shown in non-infected patients with gastrinoma [38]. Moreover, the lower frequency of *H. pylori* in gastrinoma patients compared with age-matched controls suggests that high acidity can eradicate *H. pylori* since infection with *H. pylori* most often occurs in childhood, and gastrinoma seldom manifests itself before adulthood [33]. *H. pylori* eradication reduces gastrin and gastric acid secretion and prevents new ulcers, in other words, cures duodenal ulcer disease [41, 50].

#### *2.6.4 Gastric peptic ulcer*

In gastric peptic ulcers, it is the defense mechanisms (bicarbonate and mucous) that are reduced and not an increase in aggressive factors that cause the ulcers. The decline in the defense factors is caused by *H. pylori* gastritis [46] in most instances but may also be due to other factors with intake of nonsteroidal anti-inflammatory drugs (NSAIDs) as the most important one. The effect of NSAIDs on the gastric mucosa is related to their ability to inhibit prostaglandin synthesis [51]. Prostaglandin treatment may prevent development or heal gastric ulcers [52]. The distribution between *H. pylori* and NSAIDs use as the cause of peptic gastric ulcer depends on the time for the study, the age of the patients, as well as their country, because the prevalence of *H. pylori* in many populations is rapidly declining and shows great variability between countries. Of course, whenever *H. pylori* is found in a patient with upper gastrointestinal disease, it should be eradicated. The treatment of NSAID- induced gastric ulcers is termination of NSAID use when possible, or otherwise add an inhibitor of gastric acid secretion or possibly a prostaglandin analog.

#### *2.6.5 Gastro-esophageal reflux disease*

Patients with duodenal ulcer have increased gastric acid secretion, which can induce reflux symptoms as exemplified in patients with gastrinoma [53]. Such symptoms may occur in patients with duodenal ulcer, but the increase in gastric acid secretion due to antral *H. pylori* gastritis seldom leads to reflux oesophagitis, possibly due to maintained regulation of gastrin release, and thus only a marginal increase in gastrin. On the other hand, *H. pylori* gastritis leading to oxyntic atrophy may reduce the occurrence of gastrointestinal reflux due to impaired gastric acid secretion [54]. Thus, *H. pylori* may induce gastro-esophageal symptoms or at another phase of gastritis reduce such symptoms. Generally, it may be stated that *H. pylori* does not play any central role in gastro-esophageal reflux disease.

#### *2.6.6 Gastric cancer*

An old slogan was "no acid, no peptic ulcer." Similarly, with some limitations, it may be said: "no gastritis, no gastric cancer" [6]. After the recognition that *H. pylori* was the major cause of gastritis [11], it was logical that *H. pylori* also was an important contributor to gastric cancer [13]. This induced a search for the carcinogenic factor in *H. pylori*, the first bacterium to be accepted to be carcinogenic. Despite intense work by many groups for many years, the mechanism has not been disclosed leading to the

#### Helicobacter pylori*: A Bacterium Influencing and Causing Most of the Diseases in the Upper… DOI: http://dx.doi.org/10.5772/intechopen.108494*

paper containing: "unfulfilled promise" in the title [30]. However, major progress was done by the recognition that *H. pylori* did not cause gastric cancer before having induced oxyntic atrophy [55]. Moreover, even after the disappearance of *H. pylori* either due to eradication therapy or complete oxyntic atrophy leading to anacidity, patients having been infected for years have an increased risk for gastric cancer for decades after the loss of the bacterium [56]. Also, when the infection was confined to the antral mucosa, the patients were not predisposed to gastric cancer. On the contrary, patients with a duodenal ulcer, which has mainly antral gastritis, have lower cancer risk than controls [57]. Altogether, these data do not support a direct carcinogen effect of *H. pylori*. In any way, carcinogenesis is connected to induced gastritis in the oxyntic mucosa. Among the *H. pylori* factors, Cag A seems to be the most important in the pathogenesis of gastritis, although its direct role in gastric carcinogenesis beyond driving the inflammation is still not disclosed [19]. The *H. pylori* infection goes through stages from superficial to atrophic gastritis, and the latter may be complicated by intestinal metaplasia [58]. Intestinal metaplasia has been regarded as a very important step and according to Correa [59], being a precursor to gastric cancer of the intestinal type (Lauren [60]). However, the importance of intestinal metaplasia in carcinogenesis has been questioned [61, 62], and intestinal metaplasia may only be a marker of long-standing oxyntic atrophy [63]. It, thus, seems that atrophic gastritis is central in gastric carcinogenesis, a condition that leads to reduced killing of swallowed micro-organisms, as well as hypergastrinemia. If changes in microbiological milieu secondary to impaired gastric acid secretion are the mechanism, it is peculiar that patients with autoimmune gastritis do develop cancers only in the oxyntic mucosa, and not the whole stomach [64]. Therefore, hypergastrinemia may be the factor mediating the cancers induced by *H. pylori* [63]. This concept is compatible with no increase or lower incidence of gastric cancers in patients with duodenal ulcers [57], as well as the continuous predisposition decades after eradication of the bacterium [56]. This view has implications for the treatment with *H. pylori* eradication in those still being infected, and the use of a gastrin analog such as netazepide [65] in those having oxyntic atrophy and hypergastrinemia but having lost the bacterium.

*H. pylori* gastritis also predisposes to gastric lymphoma so-called mucosaassociated lymphoid tumor (MALT). In contrast to gastric carcinomas, these tumors develop because of the continuous and chronic inflammation itself and are independent of gastric atrophy [66]. Many of the gastric MALT-lymphomas associated with *H. pylori* may be cured by *H. pylori* eradication [67].

#### *2.6.7* H. pylori *eradication: When and how*

*H. pylori* is an important cause of serious diseases. The eradication of *H. pylori* in peptic ulcer diseases cures the diseases, which previously were rather frequent and could have grave consequences. Gastric cancer was among the most common cancers and had and still has a high mortality. During the last fifty years, there has been a remarkable decline in occurrence of gastric cancer [68], most probably due to a decline in infection with *H. pylori*, especially in the Western world. However, still, a proportion of the population is infected, and in non-Western countries, the percentage infected is even today high [69]. The spontaneous reduction in infection rate seen during the last decades is attributed to improved hygienic conditions. Most of the infections occur in childhood and even above the age of five years, reinfection is seldom [70]. After infection, chronic gastritis develops spreading slowly to include the oxyntic mucosa and gradually destroying the specialized cells leading to atrophy.

Atrophy usually precedes development of intestinal metaplasia [71]. Uemura and coworkers showed that *H. pylori* infection predisposed to gastric cancer first after having induced oxyntic atrophy [55], and a separate role of intestinal metaplasia in gastric carcinogenesis as suggested by Correa [59] is not ambiguously accepted [61, 62]. Alternatively, intestinal metaplasia could just be a consequence of long-standing atrophy [63]. Anyhow, to prevent common and serious diseases, such as peptic ulcer disease and gastric cancer, *H. pylori* should be eradicated before irreversible atrophic gastritis has developed. Since *H. pylori* infection occurs in childhood and the actual diseases, as well as atrophic gastritis seldom, occurs in young people, the natural conclusion is that all should be tested for *H. pylori* infection around the age of twenty years, and those positive should have *H. pylori* eradicated at that age. Eradication of *H. pylori* has traditionally been achieved by a combination of two or more antibiotics and rather early together with an inhibitor of acid secretion. Bismuth salts were among the first to show efficacy in *H. pylori* eradication [72]. Antibiotic resistance has been a problem in the eradication of *H. pylori* [73]. The initial argument for adding an inhibitor of acid secretion was to prevent destruction of the antibiotics in the stomach, thus prolonging their local effect. To achieve acceptable *H. pylori* eradication, cures of two weeks duration were most often required. Recently, the potassium-competitive acid blocker (P-CAB) vonoprazan in combination with amoxicillin, and clarithromycin for 1 week was as efficient in eradicating *H. pylori* compared to the same antibiotics in combination with PPIs for 2 weeks [22], indicating that even more complete acid inhibition further improved the efficacy of the treatment cure. In other words, the more efficient inhibition of gastric acid secretion, the more likely *H. pylori* will not survive reflecting the self-toxicity by NH3 produced by its urease. It is conceivable that high doses of P-CABs will totally remove gastric acidity, and thus be suitable for *H. pylori* eradication alone. The reported bactericide effect on *H. pylori* by high doses of PPIs most probably is caused by the dependence of some acidity in the surrounding of *H. pylori* [74]. Of course, such treatment will naturally induce marked hypergastrinemia, which could make harm even during a short period but could be prevented by a gastrin antagonist. Marked oxyntic atrophy after *H. pylori* eradication and termination of inflammation nevertheless predisposes to gastric cancer, which probably is caused by the corresponding hypergastrinemia. Thus, such patients will most likely also profit from treatment with a gastrin antagonist [75].

#### **3. Conclusion**

The description of *H. pylori* as the main cause of gastritis leading to peptic ulcer disease, and gastric cancer is among the most important achievement in medicine in the last century. This allows prevention of such important diseases and opens up for an understanding of new mechanisms in diseases, including cancer. Together with the hormone gastrin, *H. pylori* may explain most aspects of diseases of the upper gastrointestinal tract. It is probable that a similar cause/mechanism also is found in other organs, but it is not surprising that it is first disclosed in the stomach, an organ ideal for studying biological mechanisms.

#### **Conflict of interest**

The authors declare no conflict of interest.

Helicobacter pylori*: A Bacterium Influencing and Causing Most of the Diseases in the Upper… DOI: http://dx.doi.org/10.5772/intechopen.108494*

#### **Author details**

Helge L. Waldum Faculty of Medicine and Health Sciences, Department of Clinical and Molecular Medicine, Norwegian University of Science and Technology, Trondheim, Norway

\*Address all correspondence to: helge.waldum@ntnu.no

© 2022 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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### Section 2
