**2. Epidemiology of** *H. pylori* **infection**

The *H. pylori* infection has emerged as one of the most common chronic bacterial infections worldwide and affects more than half of the world's population, with clinical signs of infection only manifesting in <20% of these individuals [21].

*H. pylori* is thought to be indigenous to the human population and is well adapted to existing in the human stomach for the lifetime of its host [22] unless eradication using appropriate chemotherapeutic agents is successful. Lifelong colonization seems to be due to the ability of some strains of *H. pylori* to both adapt to the host's immunological responses and to also withstand the constantly changing gastric environment [23].

The rate of *H. pylori* infection differs among groups as well as within the population. Strains from different geographical areas exhibit phylogeographic features [24–26]. The genomic patters of *H. pylori* have been shown to be extremely diverse, and gastric mucosa may be colonized by strains with small differences in the genomic patterns suggesting subtype variation [27].

The prevalence of *H. pylori* infection varies widely by geographic area, age, race, and socioeconomic status. While the infection is on a fast decline in the most of the Western countries, mainly due to the success of therapeutic regimens and improved personal and community hygiene that prevents reinfection, in developing countries, the prevalence rates can reach 90% and is higher among individuals belonging to low socioeconomic status group [28, 29]. It occurs especially due to failure of treatment and emergence of drug resistance [25, 30].

Most studies suggest that males and females are infected at approximately the same rates [31–33]. In spite of it, a meta-analysis population-based study reported a male predominance of *H. pylori*-related diseases in adults but not in children [34].

The infection probably occurs in the childhood, and children are often infected by a strain with a genetic fingerprint identical to that of their parents [35]. Besides, local prevalence of *H. pylori* within a country also should be considered, and there are estimates that infection is more common in rural developing areas than in urban developed ones [36].

Moreover, differences by ethnic and racial groups are evident [31, 32, 37]. In addition, the main risk factors of *H. pylori* infection, especially if present during childhood, have been associated with socioeconomic status. Malaty and Graham [38] demonstrated that there is probably an inverse correlation between prevalence and socioeconomic status. It has also been reported that overcrowding, such as living in a crowded environment, sibship size, number of persons or children in the home, number of persons per room, crowding index, and living in an institutionalized population, is a situation consistently related to *H. pylori* positivity [39–42].

Finally, it is important to consider that the pathogenetic role of *H. pylori* in gastroduodenal pathologies has been elucidated and confirmed in the past 30 years [43] redirecting the scientific and medical understanding of great part of gastrointestinal diseases. The development of effective therapies against *H. pylori* infection has progressed, and its successful eradication leads to healing of chronic active gastritis and reverses inflammation of the mucosa. In spite of it, the challenge nowadays is gastric cancer and the understanding of gastric carcinogenesis, almost always associated with *H. pylori* long-term infection [44].

#### **3. Transmission pathways**

Although *H. pylori* is primarily responsible for the upper gastrointestinal diseases, only 10% of people colonized with this bacterium portray disease symptoms. It suggests that host and bacterial factors also contributed to differences in *H. pylori* pathogenicity [10, 11]. For instance, the risk of developing gastric cancer is also related to genetic characteristics of the host and environmental factors, which, associated with specific bacterial strain characteristics, influ-

*H. pylori* is perhaps the most ubiquitous and successful human pathogen, since it colonizes the stomach of more than 50% of the world population [14, 15]. It has been demonstrated that *H. pylori* has a long period of coevolution with humans, going back at least since human migration out of Africa about 60,000 years ago [16, 17]. There are very well-characterized mechanisms of adaptation which was developed by ancestral *H. pylori* over the time. Through selection and coevolution, this bacterium established measures which actively and passively

*H. pylori* infection results in recruitment of neutrophils, lymphocytes, and macrophages into the gastric mucosa through the induction of several cytokines such as TNF-α, IL-6, and IL-8 [19, 20]. It is believed that the immune response during infection plays an important role in the pathogenesis. *H. pylori* successfully establishes a chronic infection by achieving a delicate balance between inducing immune response and surviving in the inflammatory milieu by

*H. pylori* presents important virulence factors which are essential both for bacterium colonization and maintenance in the human stomach (such as urease and flagella) and for the interaction with the gastric epithelial cells, the bacterial adhesins (blood group antigen-binding adhesion (BabA), sialic acid-binding adhesion (SabA), AlpA and AlpB, HopZ, and OipA). Besides, virulence factors involved in gastric inflammation are important for the development of chronic infection and clinical symptoms of gastrointestinal diseases (the principal are cytotoxin-associated gene-pathogenicity island (cagPAI), vacuolating cytotoxin A (VacA), and

The *H. pylori* infection has emerged as one of the most common chronic bacterial infections worldwide and affects more than half of the world's population, with clinical signs of infec-

*H. pylori* is thought to be indigenous to the human population and is well adapted to existing in the human stomach for the lifetime of its host [22] unless eradication using appropriate chemotherapeutic agents is successful. Lifelong colonization seems to be due to the ability of some strains of *H. pylori* to both adapt to the host's immunological responses and to also

The rate of *H. pylori* infection differs among groups as well as within the population. Strains from different geographical areas exhibit phylogeographic features [24–26]. The genomic

ence the severity of the chronic inflammatory response [12, 13].

4 Helicobacter Pylori - New Approaches of an Old Human Microorganism

avoid the human immune response [18].

duodenal ulcer promoting gene (dupA)).

**2. Epidemiology of** *H. pylori* **infection**

tion only manifesting in <20% of these individuals [21].

withstand the constantly changing gastric environment [23].

using an array of important virulence factors [15].

Although the natural niche for *H. pylori* is the human stomach, some questions about other possible reservoirs for bacterium have been appearing in the last years. Nevertheless, most part of the questions about the transmission of *H. pylori* remains unclear, and, because of it, the possible modes of transmission are still unknown. Consequently, the routes of transmission of *H. pylori* are supposed to occur via an array of different pathways.

Some important studies have reported and highlighted the importance of *H. pylori* biofilms, the presence of coccoid forms within the biofilm, and resistance, providing insight into the prevalence of coccoid forms in the gastric mucosa. These reports are very important because these can bring a better understanding about the mechanisms behind recalcitrant coccoid states and how they can phenotypically shift into more virulent spiral forms [21, 45–47].

to 14 days. In spite of it, there is no treatment regimen which guarantees cure of *H. pylori* infection in 100% of patients. Individuals should be asked about any previous antibiotic uses, information that has to be taken into consideration when choosing an *H. pylori* treatment regimen.

Introductory Chapter: *Helicobacter pylori* - An Overview of an Old Human Microorganism

http://dx.doi.org/10.5772/intechopen.88806

Clarithromycin triple therapy consisting of a PPI, clarithromycin, and amoxicillin or metronidazole for 14 days remains a recommended treatment option in regions where *H. pylori* clarithromycin resistance is known to be <15% and in patients with no previous history of macrolide exposure for any reason. Bismuth quadruple therapy consisting of a PPI, bismuth, tetracycline, and a nitroimidazole for 10–14 days is a recommended first-line treatment option. Concomitant therapy consisting of a PPI, clarithromycin, amoxicillin, and nitroimidazole for 10–14 days is a recommended first-line treatment option. Levofloxacin triple therapy consisting of a PPI, levofloxacin, and amoxicillin for 10–14 days is a suggested first-line treatment option. Finally, fluoroquinolone sequential therapy consisting of a PPI and amoxicillin for 5–7 days followed by a PPI, fluoroqui-

nolone, and nitroimidazole for 5–7 days is a suggested first-line treatment option [60–62].

clinical symptoms and disease in only a small part of the infected individuals.

Address all correspondence to: roeslerbruna@gmail.com

tritis and peptic ulceration. Lancet. 1984;**1**:1311-1315

*pylori* flagella. Journal of Clinical Microbiology. 1989;**27**:436-441

FEMS Immunology and Medical Microbiology. 2009;**56**:112-115

peptic ulcer. The Journal of Infectious Diseases. 1986;**153**:664-669

Campinas, Campinas, São Paulo, Brazil

**Author details**

Bruna Maria Roesler

**References**

This book comprehends important chapters that will certainly clarify the understanding of this microorganism infection, which affects half of the world population, despite promoting

Center of Diagnosis of Digestive Diseases, School of Medical Sciences, State University of

[1] Marshall BJ, Warren JR. Unidentified curved bacilli in the stomach of patients with gas-

[2] Goodwin CS et al. Transfer of *Campylobacter pylori* and *Campylobacter mustelae* to *Helicobacter* gen. nov. as *Helicobacter pylori* comb. nov. and *Helicobacter mustelae* comb. nov., respectively. International Journal of Systematic Bacteriology. 1989;**39**:397-405 [3] Geis G, Leying H, Suerbaum S, et al. Ultrastructure and chemical analysis of *Campylobacter* 

[4] Andersen LP, Rasmussen L. *Helicobacter pylori*-coccoid forms and biofilm formation.

[5] Buck GE, Gourley WK, Lee WK, et al. Relation of *Campylobacter pyloridis* to gastritis and

The infection is typically acquired in early childhood and once established commonly persists throughout life unless treated. Person-to-person transmission within the family appears to be the predominant mode of transmission, particularly from mothers to children and among siblings, indicating that intimate contact is important [29, 48–50]. The route of transmission is uncertain, but the gastro-oral, oral-oral, and fecal-oral routes are likely possibilities.

The community and environment may play additional roles for *H. pylori* transmission in some settings. Molecular analyses show that the microorganism is also present in various aquatic environments suggesting that human-fecal-contaminated water sources could be a plausible reservoir of the pathogen. The persistence of the environment virulent *H. pylori* strain in a clustered state, such as the biofilm, suggests a long-term survival of the bacterial community outside the host, enabling bacterial transmission with important clinical repercussions [21, 46]. In addition, zoonotic transmission by houseflies [51–53] and some domestic animals such as dogs, cats, and sheep [54–56], as well as iatrogenic transmission [57, 58], have been proposed. Besides, there can be factors both from host and bacterium which may modify the acquisition and persistence of *H. pylori* infection.

Another possibility of *H. pylori* transmission which has been extensively reported is the water. The contamination of drinking water by human feces has been suggested as one of the possible routes of *H. pylori* transmission, and it has been demonstrated that the microorganism is present in the so-called viable but nonculturable state in this unsuitable environment, meaning that their role in fecal-oral transmission via contaminated water sources cannot be disregarded [47, 59]. The first evidences of water transmission route were obtained in studies developed in some Latin American countries—Peru, Colombia, Chile, and Venezuela—and since then *H. pylori* has been detected in several water sources, including lakes, rivers, tap water, well water, irrigation water, and sea water, and also in water distribution systems. Consequently, it can be hypothesized that drinking water could be the pathway for returning to humans [14]. Consequently, it can be suggested that water can serve as an intermediate source in the fecal-oral transmission of *H. pylori*, acting as a reservoir in which this pathogen can survive for long periods.

#### **4.** *H. pylori* **eradication therapies**

The principal cases in which *H. pylori* have to be eradicated have been discussed in several guidelines worldwide, also considering that this microorganism is sensitive to only a few medications, and their widespread use in other kind of infections has led to a reduction in their effectiveness against the bacterium.

The infection is typically treated with combinations of two to three antibiotics along with a proton pump inhibitor (PPI), taken concomitantly or sequentially for periods ranging from 3 to 14 days. In spite of it, there is no treatment regimen which guarantees cure of *H. pylori* infection in 100% of patients. Individuals should be asked about any previous antibiotic uses, information that has to be taken into consideration when choosing an *H. pylori* treatment regimen.

Clarithromycin triple therapy consisting of a PPI, clarithromycin, and amoxicillin or metronidazole for 14 days remains a recommended treatment option in regions where *H. pylori* clarithromycin resistance is known to be <15% and in patients with no previous history of macrolide exposure for any reason. Bismuth quadruple therapy consisting of a PPI, bismuth, tetracycline, and a nitroimidazole for 10–14 days is a recommended first-line treatment option. Concomitant therapy consisting of a PPI, clarithromycin, amoxicillin, and nitroimidazole for 10–14 days is a recommended first-line treatment option. Levofloxacin triple therapy consisting of a PPI, levofloxacin, and amoxicillin for 10–14 days is a suggested first-line treatment option. Finally, fluoroquinolone sequential therapy consisting of a PPI and amoxicillin for 5–7 days followed by a PPI, fluoroquinolone, and nitroimidazole for 5–7 days is a suggested first-line treatment option [60–62].

This book comprehends important chapters that will certainly clarify the understanding of this microorganism infection, which affects half of the world population, despite promoting clinical symptoms and disease in only a small part of the infected individuals.

### **Author details**

Some important studies have reported and highlighted the importance of *H. pylori* biofilms, the presence of coccoid forms within the biofilm, and resistance, providing insight into the prevalence of coccoid forms in the gastric mucosa. These reports are very important because these can bring a better understanding about the mechanisms behind recalcitrant coccoid states and how they can phenotypically shift into more virulent spiral forms [21, 45–47].

The infection is typically acquired in early childhood and once established commonly persists throughout life unless treated. Person-to-person transmission within the family appears to be the predominant mode of transmission, particularly from mothers to children and among siblings, indicating that intimate contact is important [29, 48–50]. The route of transmission is

The community and environment may play additional roles for *H. pylori* transmission in some settings. Molecular analyses show that the microorganism is also present in various aquatic environments suggesting that human-fecal-contaminated water sources could be a plausible reservoir of the pathogen. The persistence of the environment virulent *H. pylori* strain in a clustered state, such as the biofilm, suggests a long-term survival of the bacterial community outside the host, enabling bacterial transmission with important clinical repercussions [21, 46]. In addition, zoonotic transmission by houseflies [51–53] and some domestic animals such as dogs, cats, and sheep [54–56], as well as iatrogenic transmission [57, 58], have been proposed. Besides, there can be factors both from host and bacterium which may modify the

Another possibility of *H. pylori* transmission which has been extensively reported is the water. The contamination of drinking water by human feces has been suggested as one of the possible routes of *H. pylori* transmission, and it has been demonstrated that the microorganism is present in the so-called viable but nonculturable state in this unsuitable environment, meaning that their role in fecal-oral transmission via contaminated water sources cannot be disregarded [47, 59]. The first evidences of water transmission route were obtained in studies developed in some Latin American countries—Peru, Colombia, Chile, and Venezuela—and since then *H. pylori* has been detected in several water sources, including lakes, rivers, tap water, well water, irrigation water, and sea water, and also in water distribution systems. Consequently, it can be hypothesized that drinking water could be the pathway for returning to humans [14]. Consequently, it can be suggested that water can serve as an intermediate source in the fecal-oral transmission of *H. pylori*,

The principal cases in which *H. pylori* have to be eradicated have been discussed in several guidelines worldwide, also considering that this microorganism is sensitive to only a few medications, and their widespread use in other kind of infections has led to a reduction in

The infection is typically treated with combinations of two to three antibiotics along with a proton pump inhibitor (PPI), taken concomitantly or sequentially for periods ranging from 3

acting as a reservoir in which this pathogen can survive for long periods.

uncertain, but the gastro-oral, oral-oral, and fecal-oral routes are likely possibilities.

acquisition and persistence of *H. pylori* infection.

6 Helicobacter Pylori - New Approaches of an Old Human Microorganism

**4.** *H. pylori* **eradication therapies**

their effectiveness against the bacterium.

Bruna Maria Roesler

Address all correspondence to: roeslerbruna@gmail.com

Center of Diagnosis of Digestive Diseases, School of Medical Sciences, State University of Campinas, Campinas, São Paulo, Brazil

#### **References**


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**Chapter 2**

**Provisional chapter**

**Clinical Manifestations of the** *Epsilonproteobacteria*

*Epsilonproteobacteria* is a large group of Gram-negative curved or spiral microaerophilic rods, of which many are difficult to culture. Because this group of bacteria is not very well investigated, our knowledge about them is limited, and a great amount of research is still needed. At least two species are well-established human pathogens: *Campylobacter jejuni/coli* causing gastroenteritis and *Helicobacter pylori* causing gastric and extra-gastric manifestations. It is well accepted that *H. pylori* causes a chronic inflammation in the stomach and thereby causes *H. pylori-*associated gastritis, which may or may not be symptomatic. The association between *H. pylori* and peptic ulcers, MALT lymphomas, gastric cancer, idiopathic thrombocytopenic purpura, and unexplained iron-deficiency anemia (IDA) is strongly evidence based. On the other hand, pernicious (vitamin B12 deficiency) anemia, neuromyelitis optica, asthma, and Graves' disease are less evidence based. *H. pylori* may also be associated with cardiovascular disease, pancreatitis, pancreatic cancer, obesity, diabetes mellitus type 2, Parkinson's disease, liver diseases, and preeclampsia. *H. pylori* is thus involved in many gastric and extra-gastric manifestations either directly or indirectly by several proposed mechanisms including

**Keywords:** *Helicobacter pylori*, infection, mimicry, gastritis, anemia, thrombocytopenic

**Clinical Manifestations of the** *Epsilonproteobacteria*

© 2016 The Author(s). Licensee InTech. 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.

© 2018 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.

DOI: 10.5772/intechopen.80331

**(***Helicobacter pylori***)**

**(***Helicobacter pylori***)**

Leif Percival Andersen

**Abstract**

antigenic mimicry.

purpura, gastric cancer

Rie Louise Møller Nordestgaard,

Rie Louise Møller Nordestgaard, Malene Roed Spiegelhauer,

http://dx.doi.org/10.5772/intechopen.80331

Caroline Gren, Agnes Tving Stauning and

Tove Havnhøj Frandsen, Caroline Gren,

Additional information is available at the end of the chapter

Additional information is available at the end of the chapter

Malene Roed Spiegelhauer, Tove Havnhøj Frandsen,

Agnes Tving Stauning and Leif Percival Andersen

#### **Clinical Manifestations of the** *Epsilonproteobacteria* **(***Helicobacter pylori***) Clinical Manifestations of the** *Epsilonproteobacteria* **(***Helicobacter pylori***)**

DOI: 10.5772/intechopen.80331

Rie Louise Møller Nordestgaard, Malene Roed Spiegelhauer, Tove Havnhøj Frandsen, Caroline Gren, Agnes Tving Stauning and Leif Percival Andersen Rie Louise Møller Nordestgaard, Malene Roed Spiegelhauer, Tove Havnhøj Frandsen, Caroline Gren, Agnes Tving Stauning and Leif Percival Andersen

Additional information is available at the end of the chapter Additional information is available at the end of the chapter

http://dx.doi.org/10.5772/intechopen.80331

#### **Abstract**

*Epsilonproteobacteria* is a large group of Gram-negative curved or spiral microaerophilic rods, of which many are difficult to culture. Because this group of bacteria is not very well investigated, our knowledge about them is limited, and a great amount of research is still needed. At least two species are well-established human pathogens: *Campylobacter jejuni/coli* causing gastroenteritis and *Helicobacter pylori* causing gastric and extra-gastric manifestations. It is well accepted that *H. pylori* causes a chronic inflammation in the stomach and thereby causes *H. pylori-*associated gastritis, which may or may not be symptomatic. The association between *H. pylori* and peptic ulcers, MALT lymphomas, gastric cancer, idiopathic thrombocytopenic purpura, and unexplained iron-deficiency anemia (IDA) is strongly evidence based. On the other hand, pernicious (vitamin B12 deficiency) anemia, neuromyelitis optica, asthma, and Graves' disease are less evidence based. *H. pylori* may also be associated with cardiovascular disease, pancreatitis, pancreatic cancer, obesity, diabetes mellitus type 2, Parkinson's disease, liver diseases, and preeclampsia. *H. pylori* is thus involved in many gastric and extra-gastric manifestations either directly or indirectly by several proposed mechanisms including antigenic mimicry.

**Keywords:** *Helicobacter pylori*, infection, mimicry, gastritis, anemia, thrombocytopenic purpura, gastric cancer

© 2016 The Author(s). Licensee InTech. 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. © 2018 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.

#### **1. Introduction**

*Epsilonproteobacteria* is a large group of Gram-negative curved or spiral rods which include the genera *Campylobacter* spp., *Helicobacter* spp., *Arcobacter* spp., and *Wolinella* spp. (**Table 1**) [1]. The bacteria have microaerobic or anaerobic growth requirements, and many of these are difficult to culture from clinical samples [2]. Recent studies with identification of *Epsilonproteobacteria* by PCR have shown that these bacteria cause infections in humans more commonly than previously thought [3, 4]. The most well-known species are *Campylobacter jejuni/coli* causing gastroenteritis [2] and *Helicobacter pylori* causing gastric and extra-gastric manifestations [5].

*H. pylori* may either cause direct or indirect damage to the stomach: direct damage where *H. pylori* infections disintegrate gastric mucosa and cause apoptosis through cytotoxinassociated gene A (CagA) and vacuolating toxin (VacA) or indirect damage where *H. pylori* induces a strong and chronic immune response by activating B and T lymphocytes, macrophages, neutrophilic lymphocytes, and probably also eosinophil leukocytes. T cell-activated B lymphocytes, regulatory T cells (Treg), and T helper 17 cells (Th17) are some of the B and T lymphocytes that are important in *H. pylori* infections. T cell-activated B lymphocytes are responsible for a strong humoral immune response primarily toward *H. pylori* urease, flagella, CagA, and VacA. These activated B and T lymphocytes release a large range of cytokines of which IL1-β, TNF-α, INF-γ, IL6, IL-8, IL-10, IL-17, and cyclooxygenase-2 (COX-2) are the most

Clinical Manifestations of the *Epsilonproteobacteria* (*Helicobacter pylori*)

http://dx.doi.org/10.5772/intechopen.80331

Many microorganisms can cause autoimmune diseases. The mechanisms involved include molecular mimicry (when bacterial antigens cross-react with human tissue), epitope spreading, bystander effect, microbial superantigens, immune complex formation, MHC class II expression on nonimmune cells, and high levels of pro-inflammatory cytokines [14–17]. *H. pylori* has been implicated in both organ-specific and non-organ-specific autoimmune diseases and has been investigated sporadically or systematically in 95 autoimmune-related diseases [18]. Many mechanisms underlying the antigenic mimicry between *H. pylori* and the host have been proposed. Efforts have been made to identify homologous sequences between *H. pylori* and host polypeptides. H+/K + −adenosine triphosphatase, Lewis antigens, and lipopolysaccharide seem to be autoantigens in autoimmune gastritis. Glycoproteins and Lewis antigens may be autoantigens directed against platelets in idiopathic thrombocytopenic purpura (ITP). Lewis antigens, heat shock protein 60 (HSP60), and 160/180 kDa antigens appear to be autoantigens to the endothelium, while alpha-carbon anhydrase and plasminogen-binding

All in all, *H. pylori* can cause both gastric and extra-gastric diseases through a complex mecha-

Whenever *H. pylori* is found in the human stomach, there is never just a simple colonization. Instead, there is always a cellular and humoral immune response confirming that *H. pylori* causes infection [10, 19, 20]. Thus, patients with gastritis and *H. pylori* have *H. pylori*-related gastritis. However, if there is no *H. pylori* infection, patients may have functional gastritis but no inflammation. *H. pylori*-related gastritis may benefit from antibiotic treatment, whereas

Peptic ulcers occur in about 10% of patients infected with *H. pylori* where most (80%) are duodenal ulcers [19]. More than 90% of duodenal ulcers are caused by *H. pylori* [19]. The pathogenesis of these ulcers is not clear, but they often occur in the part of the duodenum where the flow from the stomach content is the highest. Duodenal ulcers may be caused by a combination of physical, physiological, and immunologic effects as well as *H. pylori*. Patients with duodenal ulcers almost always benefit from antibiotic treatment. More than 60% of gastric

there is no indication for antibiotic treatment for functional gastritis [21].

important cytokines in severe *H. pylori* infections [12, 13].

proteins could to be autoantigens in the pancreas [13].

nism involving both host and bacterial factors.

**2. Gastritis and peptic ulcer**

This chapter will focus on *Helicobacter* spp. and mainly on *H. pylori*. *Helicobacter* spp. can be divided into three groups: (1) gastric *Helicobacter* spp., (2) intestinal *Helicobacter* spp., and (3) hepatobiliary *Helicobacter* spp. [6]. The knowledge about intestinal *Helicobacter* spp. in human diseases is very limited mainly because they are very difficult to culture. In contrast to the intestinal and hepatobiliary *Helicobacter* spp., the gastric *Helicobacter* spp. produce a great amount of urease, which is important for its survival in the stomach by neutralizing acid, thereby creating a neutral microenvironment [7]. Urease is also crucial for the bacteria's survival through antigenic shedding where urease captures human antibodies [8]. The human gastric *Helicobacter* sp., *H. pylori*, is the most intensively investigated *Helicobacter* sp., but gastric *Helicobacter* spp. from animals (*Helicobacter heilmannii*, *Helicobacter bizzozeronii*, *Helicobacter suis*, etc.) have also been found in the human stomach [9]. These bacteria colonize the stomach in very different ways. *H. pylori* colonizes the antrum part of the stomach on the surface between epithelial cells and can actively move down between the epithelial cells [10]. On the other hand, *Helicobacter* sp. from animals colonizes the parietal cell glands in the corpus/fundus part of the stomach which may contribute to other manifestations than those caused by *H. pylori* [11]. Usually, a stronger cellular immune response is seen in *H. pylori* in comparison to the animal-associated *Helicobacter* spp. [11].


**Table 1.** The species belonging to the four largest groups of *Epsilonproteobacteria* [102].

*H. pylori* may either cause direct or indirect damage to the stomach: direct damage where *H. pylori* infections disintegrate gastric mucosa and cause apoptosis through cytotoxinassociated gene A (CagA) and vacuolating toxin (VacA) or indirect damage where *H. pylori* induces a strong and chronic immune response by activating B and T lymphocytes, macrophages, neutrophilic lymphocytes, and probably also eosinophil leukocytes. T cell-activated B lymphocytes, regulatory T cells (Treg), and T helper 17 cells (Th17) are some of the B and T lymphocytes that are important in *H. pylori* infections. T cell-activated B lymphocytes are responsible for a strong humoral immune response primarily toward *H. pylori* urease, flagella, CagA, and VacA. These activated B and T lymphocytes release a large range of cytokines of which IL1-β, TNF-α, INF-γ, IL6, IL-8, IL-10, IL-17, and cyclooxygenase-2 (COX-2) are the most important cytokines in severe *H. pylori* infections [12, 13].

Many microorganisms can cause autoimmune diseases. The mechanisms involved include molecular mimicry (when bacterial antigens cross-react with human tissue), epitope spreading, bystander effect, microbial superantigens, immune complex formation, MHC class II expression on nonimmune cells, and high levels of pro-inflammatory cytokines [14–17]. *H. pylori* has been implicated in both organ-specific and non-organ-specific autoimmune diseases and has been investigated sporadically or systematically in 95 autoimmune-related diseases [18]. Many mechanisms underlying the antigenic mimicry between *H. pylori* and the host have been proposed. Efforts have been made to identify homologous sequences between *H. pylori* and host polypeptides. H+/K + −adenosine triphosphatase, Lewis antigens, and lipopolysaccharide seem to be autoantigens in autoimmune gastritis. Glycoproteins and Lewis antigens may be autoantigens directed against platelets in idiopathic thrombocytopenic purpura (ITP). Lewis antigens, heat shock protein 60 (HSP60), and 160/180 kDa antigens appear to be autoantigens to the endothelium, while alpha-carbon anhydrase and plasminogen-binding proteins could to be autoantigens in the pancreas [13].

All in all, *H. pylori* can cause both gastric and extra-gastric diseases through a complex mechanism involving both host and bacterial factors.
