**12. Neuromyelitis optica**

Several studies have shown a correlation between *H. pylori* and neuromyelitis optica (NMO) [18]. NMO is a disease where antibodies attack aquaporin-4 on astrocytes in the central nervous system [80]. There is a close relationship between *H. pylori* and antibodies to aquaporin-4, and thus molecular mimicry could play a role [18].

#### **13. Asthma**

stomach. The interaction leading to pancreatic cancer is unknown, but *H. pylori* infection in the antral part of the stomach decreases the production of somatostatin. This increases pancreatic bicarbonate and secretin which stimulates ductal epithelial cell proliferation [64]. In addition, studies indicate that *H. pylori* increases the risk of autoimmune pancreatitis through molecular mimicry and thereby increases the risk for pancreatic cancer [13, 60, 63–65]. These

Obesity is becoming a worldwide problem, and population studies have shown that in the same areas where the prevalence of *H. pylori* is decreasing, the prevalence of obesity is increasing [21, 66]. An implication of obesity could be diabetes mellitus type 2. A possible mechanism in which *H. pylori* affects obesity and thereby also affects type 2 diabetes is persistent damage of gastric mucosa, e.g., chronic gastritis. This might affect ghrelin production, thereby chang-

Ghrelin is a hormone mainly produced by endocrine cells in the gastrointestinal mucosa and is released to the surroundings. This molecule is important for stimulating food intake and weight gain [69]. The damages that *H. pylori* introduce on gastric mucosa reduce the number of ghrelin-producing cells and decrease plasma ghrelin concentrations significantly, thereby

Ghrelin also seems to play a role in fat metabolism and glucose homeostasis, which can lead to a cross-reaction between lipid and glucose metabolisms that may result in insulin resistance [71]. However, one thing is clear, diabetes mellitus type 2 is a multifactorial disease, and *H. pylori* is only one of the many risk factors. *H. pylori* may also act on leptin or by activating

Although many studies have shown that there could be a correlation between *H. pylori* and obesity and diabetes mellitus type 2, other studies have shown that there are none and the

Numerous studies indicate that *H. pylori* infection is associated with a more rapid development of cognitive and functional deterioration. Furthermore, eradication of *H. pylori* could give an improved disease severity [75–78]. Also, a study by Weller et al. showed that the presence of CagA antibodies is associated with a poorer Parkinson's prognosis [79]. It is proposed that *H. pylori* initiates the destruction of mitochondria and together with antigenic mimicry stimulates Parkinson's disease [72]. Only few studies focus on *H. pylori* and Alzheimer's disease, and they are too preliminary to show a causal or therapeutic

findings are of great interest and need further intensive research.

reducing the feeling of satiety which can lead to obesity [67, 68, 70].

cytokines that together can have an effect on insulin secretion [72, 73].

**10. Obesity and diabetes mellitus type 2**

20 Helicobacter Pylori - New Approaches of an Old Human Microorganism

ing food intake and increasing body weight [67, 68].

correlation is still uncertain [66, 74].

association [72, 75].

**11. Parkinson's and Alzheimer's diseases**

The prevalence of asthma is increasing in areas where the prevalence of *H. pylori* is decreasing [81]. Meta-analyses have found an inverse correlation between *H. pylori* and asthma, but the mechanism is unclear [72, 82, 83]. CagA-positive *H. pylori* strains especially have been found to have a greater inverse relationship with asthma than those without *H. pylori* [81]. The longestablished hygiene hypothesis, where a lack of exposure to infectious agents leads to an increased risk for allergens, has been proposed as one way in which an absence of *H. pylori* causes asthma [82]. Th2-mediated immune responses drive allergies, while Th1-mediated immune responses inhibit these reactions. *H. pylori* appears to stimulate Th1-mediated immune responses but inhibit Th2-mediated immune responses through neutrophil-activating protein (HP-NAP), thereby inhibiting asthma development [84]. Another possible mechanism of *H. pylori* is upregulation of Treg cells which can control Th2-mediated immune responses [82]. A mouse study by Arnold et al. proved that *H. pylori* infection protected mice against asthma and an upregulation of Treg cells was found in mice infected with *H. pylori* [85]. Thus, *H. pylori* could inhibit asthma in a multitude of ways.

#### **14. Hepatobiliary diseases**

Non-pylori *Helicobacter* species have been isolated from the liver of a variety of animals. *H. hepaticus*, *H. bilis*, and *H. cholecystus* are involved in the pathogenesis of chronic liver diseases and liver carcinomas [86–88]. *H. pylori*, *H. hepaticus*, *H. bilis*, and *H. cholecystus* have been detected in the human hepatobiliary tissue mainly by PCR [89–91]. Several studies have shown an increased prevalence of *H. pylori* in patients with hepatocellular carcinomas (HCC), liver encephalopathy (HE), liver fibrosis, cholangiocarcinoma (CCA), primary biliary cirrhosis (PBC), and primary sclerosing cholangitis [92]. Much interest has been linked to HCC and CCA which histologically is characterized as adenocarcinomas. The pathogenesis has been proposed to follow the same pattern as in stomach cancer: hyperplasia, metaplasia, dysplasia, and lastly cancer [92]. Inflammatory cytokines and chemokines may play an important role in the pathogenesis. HE is a frequent complication to liver cirrhosis with a wide variety of neuropsychiatric symptoms, and high levels of ammonia play an important role in the pathogenesis [93]. *H. pylori* produces urease which reacts to ammonium, which might explain a possible mechanism in HE development. Liver fibrosis, among other ways, may be caused by *H. pylori* stimulating hepatocytes and results in accumulation of collagen, thereby causing fibrosis [63]. Some of the risk factors for these cancers are population genetics, geographical and environmental factors, cholelithiasis, obesity, chronic inflammation, and obstruction of the bile duct [92, 94].

**17. Discussion**

*H. pylori* can induce many pathogenic reactions in infected individuals. There are mainly three different ways *H. pylori* acts. (1) The bacteria have several virulence factors (Cag PAI, Vac A, etc.) that can cause direct damage and apoptosis of epithelial cells in the stomach and can stimulate mast cells to liberate PAF which affects the angiogenesis in the stomach. This may be some of the main actions on gastric diseases such as peptic ulcers and gastric cancer (**Figure 1**). (2) There is a strong cellular and humoral immune response to *H. pylori* with the release of different cytokines and chemokines. Cytokines and chemokines subsequently react both in the stomach and in extra-gastric organs (**Figure 2**). In addition, several *H. pylori* antigens are structurally like antigens of the human body and therefore may cause cross-reactions (antigenic mimicry) (**Figure 3**). All these pathogenic mechanisms of *H. pylori* may result in

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

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

The role of *H. pylori* in relation to gastritis, peptic ulcers, MALT lymphomas, and gastric cancer is well known and established. However, there is confusion about the difference between

**Figure 1.** The roles of the main virulence factors in pathogenesis of *Helicobacter pylori* infection [6]. Adherence of *Helicobacter pylori* to gastric epithelial cells is mediated by BabA and SabA binding Leb and Lewis x/a, respectively. CagA is translocated into epithelial cells through T4SS and then tyrosine-phosphorylated at EPIYA sites by Src and Abl kinases. CagA contributes to alteration of myriad signaling transduction, which affects host cell physiology with disruption of intercellular junctions, loss of cell polarity, promotion of inflammation, dysregulation of cellular apoptosis,

and proliferation. VacA inducts cytoplasmic vacuolation, apoptosis, and immune suppression [6, 103].

different diseases both in the stomach and in extra-gastric organs.

#### **15. Autoimmune thyroid diseases**

Both Graves' disease and Hashimoto's thyroiditis are autoimmune diseases in the thyroid. Graves' disease is characterized by hyperthyroidism and an enlarged gland, while Hashimoto's thyroiditis is characterized by hypothyroidism and the destruction of thyroid tissue. There is an association between Graves' disease and *H. pylori*, where CagA is most likely an important virulence factor [95]. A study by Bassi et al. showed that 82% (43/52) of patients with Graves' disease were positive for *H. pylori*, where 84% (36/43) of *H. pylori*-positive Graves' disease patients were positive for CagA antigens. Also, a different study by Bertalot et al. showed a reduction in thyroid autoantibodies following *H. pylori* eradication [96]. Amino acid sequences of thyroid peroxidase and CagA are very similar, and cross-reactivity is a possible mechanism by which *H. pylori* increases the risk of developing Graves' disease [18, 95]. In addition, Graves' disease is often found with other autoimmune diseases which may reflect the ability of *H. pylori* to induce multiple autoimmune diseases simultaneously [97]. However, the same cannot be said about Hashimoto's thyroiditis where a significant association between Hashimoto's thyroiditis and *H. pylori* was not found by Bassi et al. [95].

#### **16. Preeclampsia**

The first study investigating the association between *H. pylori* infection and preeclampsia (PE) was conducted in Italy and published in 2006 [98]. It was found that 32% of women with a normal pregnancy harbored anti-*H. pylori* antibodies compared to 51% of preeclamptic women. The difference was even bigger when looking at the presence of anti-CagA antibodies: 15 vs. 81% in women with a normal pregnancy vs. preeclamptic women. The authors concluded that the increased inflammatory activity in *H. pylori*-infected patients may contribute to the development of PE, especially in CagA strains. Interestingly, no *H. pylori* DNA was present in the placentas that were studied, and therefore the inflammation is probably not locally induced.

A review from 2014 concluded that there is evidence indicating that *H. pylori* negatively influences human reproductivity, including PE [99]. This is probably due to both increased inflammatory activity and antigenic mimicry with CagA-positive strains appearing to be the most important culprits [99]. A recent meta-analysis of observational studies with 9787 women (879 preeclamptic) confirmed these theories, with an OR of 2.32 for anti-*H. pylori* antibodies in cases compared to controls and an OR of 3.97 for having anti-CagA antibodies in preeclamptic patients [100]. A review on the topic of infections and the risk of PE mentions *H. pylori* as a possible cause of PE and recommends that screening (and treatment) of known infectious organisms causing PE should be included in antenatal programs [101]. However, as mentioned by Bellos et al., it is yet unknown if *H. pylori* predisposes to mild or severe PE, at which gestational age optimal screening should be conducted, and most importantly how effective eradiation is in terms of reducing the incidence and severity of PE [100].
