Iranian Journal of Medical Microbiology

The present study aimed to assess the relationship of H. pylori with extra-gastrointestinal infections by classifying the subjects researched from 1980 to 2019. This evaluation was conducted in 2020 and databases including PubMed, Medline, Cochran Library, WHO, and Iranmedex were used to obtain the desired articles. Aiming to collect data on the relationship of H. pylori with extra-gastrointestinal infections, the keywords such as “gastrointestinal diseases”, “Helicobacter pylori”, “extra-gastrointestinal diseases”, and “pathogenic factors” were used. Finally, out of 210 retrieved papers, 51 papers were identified as appropriate and examined in terms of subject, content structure, and relevance.

An Overview of H. Pylori Infection and Pathogenic Factors

Figure 1. Schematic diagram of pathogenesis and infection of H. pylori. (Kao et al. 2016)

Epidemiology and Natural History

A steady decrease has been noticed in the prevalence of H. pylori infection and gastric cancer among most populations, especially in affluent Western societies in recent decades. Dominant bacterial genotypes also vary in different societies. Communities with higher risk of gastric cancer have higher pathogenicity strains (14). In some populations, more than one strain with different pathogenicity is located in the gastric mucosa. In these societies, along with the reduction of cancer rates and the spread of infection, great changes have taken place, including economic development; the most important changes include improving the health status of homes, reducing family population, changing eating habits (e.g., consuming less salt and more fresh vegetables and fruits), improving cooling equipment, and controlling infectious diseases. Excessive consumption of antibiotics to deal other infectious disorders may have adverse effects on the prevalence of H. pylori infection (12, 15).
Clinically, H. pylori infection has variable course and is affected by the host and microbial agents. The gastritis distribution and pattern is highly correlated with the risk of several clinical disorders including as mucosal atrophy, duodenal and gastric ulcers, gastric lymphoma, and gastric cancer (16). Antral-predominant gastritis is the most prevalent type of H. pylori gastritis and patients with this type of gastritis are more prone to duodenal ulcers. However, patients with multifocal atrophic and corpus predominant gastritis are at higher risk to develop ulcers, intestinal metaplasia, gastric atrophy, and eventually gastric cancer. Gastric adenocarcinoma caused by H. pylori infection starts with gastritis and results in atrophy followed by intestinal dysplasia, metaplasia, and gastric cancer, respectively. H. pylori contributes to most types of gastric and duodenal ulcers. The prevalence of gastric ulcer in a person affected by H. pylori infection varies from 3% in the USA to 25% in Japan. Gastric cancer is considered as the 2^th leading reason of death from cancer. The relation of H. pylori with the increased risk of gastric cancer is confirmed in various research, so that in 1994 it was definitively classified as type 1 carcinogen (8, 12, 15, 17).

 

Figure 2. Outbreak of gastric cancer in 2012 (O'connor et al., 2017)

Studies have shown that almost all patients with MALT lymphoma are effected by H. pylori infection, i.e. H. pylori infection significantly elevate the risk of developing MALT lymphoma. Patients who are in the primary stages of the disease are more likely to recover completely with antibiotic treatment, but people with progressed stages of the disease (wounds, submucosal lesion, wall attack, or lymphadenopathy) are more likely in need of lymphoma treatment. Patients with intestinal metaplasia should be tested for H. pylori infection, as intestinal metaplasia is an autonomous risk factor of gastric malignancy. After eradication of the bacterium, the probability of gastric lymphoma (MALT) recurrence is about 70-80% (5, 8, 12, 15).

 

Figure 3. The natural course of H. pylori infection (Suerbaum and Suerbaum, 2002)

It is estimated that about 5% of people with dyspepsia (most of them functional) were due to H. pylori infections. Patients with H. pylori may have symptoms of dyspepsia without the presence of macroscopic lesions in the gastroduodenal mucosa. This is known as dyspepsia and various pathogenic mechanisms are involved in it. The results of various experiments and data from several extensive studies have noted that eradicating H. pylori to improve dyspepsia symptoms is more cost-effective statistically, and has a better effect on the natural history of functional dysplasia compared with placebo. The reasons for the recurrence of dyspeptic symptoms in some patients following elimination of H. pylori have not been fully elucidated yet (12, 15, 18).
Gastroesophageal reflux disease (GERD) is referred to a multifactorial disorder which causes the gastric acid to reflux into the esophagus, resulting tissue injury and certain symptoms such as burning and vomiting. Increased prevalence of GERD symptoms indicates decreased prevalence of peptic ulcer and H. pylori. The exact link among H. pylori infection and GERD seems complex. However, current evidence does not support a definitive conclusion as to whether patients infected by H. pylori have the same GRED symptoms as non-infected patients (19, 20). Studies to date have noted that the treating infection caused by H. pylori leads to worsening of GERD. According to a theory that suggests an exact link between H. pylori infection and GERD, because the induction of gastric atrophy by bacteria and the resulting lack of stomach acid, the development of GERD in individuals is reduced, which is a potential risk for Barrett's esophagus and esophageal adenocarcinoma. Therefore, the concern is that eradication may cause the spread of GERD symptoms and lead to the spread of esophageal adenocarcinoma worldwide (15, 21).
In recent years, many scientists around the world have studied the association between extra-gastrointestinal diseases and H. pylori infection. In fact, H. pylori possibly is associated with a variety of biological procedures both outside and inside the gastrointestinal tract and is likely to determine and affect the incidence of many extragastrointestinal disorders. However, the association of H. pylori with sideropenic anemia and idiopathic thrombocytopenic purpura has already been identified. Recent evidence shown that H. pylori is related with increased risk of acute coronary syndrome, insulin resistance, neurogenic and respiratory diseases, and other disorders. Various pathogenic mechanisms such as the induce of low-grade chronic inflammation and the incidence of molecular mimicry mechanisms have been proposed in this field (11, 22).
 

Extragastric Diseases

 Cardiovascular Diseases

Wang et al. (2018) studied the relationship between the infection by H. pylori and the risk of coronary heart disease (CHD). They designed a comprehensive cohort study using Taiwan's National Health Database and compared 3,713 patients with peptic ulcer disorder treated by anti H. pylori medicine with available data of untreated patients. The results of this study showed that mortality was reduced in patients affected by H. pylori infection who underwent eradication therapy (23). In their cohort study, Lai et al. (2015) found a direct relationship between H. pylori infection and increased prevalence of acute coronary syndrome, even following the elimination of pathogens, and it increases with aging (24). The results of the study conducted by Hughes (2014) on a military group born in the 1930s showed a decrease in the simultaneous heart attack and duodenal ulcers. Hughes concluded that duodenal ulcer is highly associated with the infection with H. pylori and one of the reasons for the reduction in heart attacks is the eradication of H. pylori (25). Since inflammation has a major role in atherosclerotic plaque rupture, high levels of serum IL-6 appear to be significantly related to H. pylori infection and may actively contribute in ischemic heart disease. Other studies have reported a high level of B-type natriuretic peptide and IL-6 (biomarkers of heart failure) in the body of patients suffering from coronary artery disorder infected with CagA-positive strains (11).

Diabetes and Insulin Resistance

Insulin resistance (IR) is among the main pathogens of type 2 diabetes (1). The relationship among H. pylori and diabetes was first studied in 1989, and it was found that the rate of infected cases with H. pylori was higher in diabetic patients compared the control (62% vs. 21%). A systematic review (2011) reported a very significant score in the hemostatic model for assessing insulin resistance in individuals infected with H. pylori in comparison with non-infected individuals in seven cross-sectional analyses (26). Yang et al. (2014) study also showed a meaningful correlation among diabetics and H. pylori infection by studying 1,285 subjects (age range: 19-85 years), and in line with these researchers, similar results were reported by Indian researchers (27). Diabetic patients infected with H. pylori have poorer glycemic control than non-infected cases. In addition, other researchers identified higher diabetes rates of prevalence in H. pylori infected patients and there is a positive relationship between IR and H. pylori infection (11, 28). The potential mechanism proposed is that H. pylori lipopolysaccharides activate Toll-like receptors, which are often expressed in macrophages and dendritic cells, causing energy absorbing, fat accumulating and eventually IR. In severe inflammation, cytokines inhibit the insulin to affect its receptor via phosphorylation of residual serine in the receptor, leading to IR (1).
Despite the significant correlation between diabetes and H. pylori infection, the issue is still under debate among researchers. The reason for this disagreement is different results in comparing the levels of diabetes pre and after the H. pylori eradication in several experiments. Most of the experiments have reported the favorable effects of H. pylori eradication in reducing diabetes, but other reports indicate a lack of correlation between IR level and diabetes before and after the eradication (1, 11, 29). Numerous studies have shown that diabetics are more susceptible to infection. Diabetes-induced humoral and cellular immune disorders may increase a person's susceptibility to H. pylori infection. On the other side, diabetes reduces the rate of acid secretion and gastrointestinal motility, which may contribute to H. pylori colonization and gastrointestinal infection. Alterations in glucose metabolism may also lead to chemical changes in gastric mucus, which in turn promotes H. pylori colonization. In addition, people with diabetes are more exposed to pathogens in the hospital environment than other individuals (30).

Metabolic Syndrome (MetS)

MetS refers to a set of metabolic disorders which are considered as a risk factor for various gastrointestinal diseases as well as cardiovascular diseases. MetS, known as syndrome x and IR syndrome, has been steadily increasing worldwide and has placed a significant burden on public health (31-33). MetS is so closely related to IR that it is known as one of the mechanisms of MetS expression. H. pylori is also regarded as a mechanism involved in the development of MetS. There are multitude studies indicating the global spread of MetS and H. pylori infection, and growing evidence exists regarding the possible link of H. pylori infection with both IR and MetS. Evidence suggests that these syndromes are associated with diseases like cardiovascular disease, diabetes mellitus type 2, abdominal obesity, dyslipidemia, hypertension, and non-alcoholic fatty liver disease (NAFLD).
Nabiour et al. (2006) was the first study that assessed the correlation between H. pylori infection and MetS and reported that H. pylori infected cases was 1.5 times more prone to MetS compared to healthy individuals (34). Using histological diagnosis of H. pylori and urea breath test, Chen et al. (2015) concluded that MetS prevalence in patients with H. pylori infection was higher compared to non-infected cases in both males and females (35). A same association between IR and H. pylori has also been noted in a systematic review by Polyzos et al. (2011) (36). The relationship of H. pylori eradication with MetS recurrence was investigated to assess the impact of H. pylori infection on MetS pathogenicity among black populations. The results of this study showed improvement in three components including plasma glucose, HDL-cholesterol, and systolic and diastolic blood pressure compared to base values following 3 weeks of H. pylory eradication (1).
A review article titled "The Possible Role of Helicobacter pylori Infection in Non-alcoholic Fatty Liver Disease" by Cheng et al. (2017) is a good illustration of the mechanism by which H. pylori infection affect the development of NAFLD disease. IR is considered as an important part of the development of NAFLD disease and many studies have confirmed the important role of H. pylori infection on IR development. Infection by H. pylori can increase low-grade chronic inflammation and levels of anti-inflammatory factors, including TNF- α and IL-6, and subsequently activate IKK/NF-κB, causing IR. Inhibiting leptin release by white adipose tissue is another possible effect of H. pylori infection, which causes an increase in the activity of desaturase CoA stearoyl (SCDI) in the liver, thereby accelerating the deposition of fat and VLDL-C in the liver tissues (Figure 4). Regarding the interaction between intestines and stomach, H. pylori infection may cause other gastrointestinal diseases [37]. Chen et al. (2019) also stated that people infected with H. pylori are more susceptible to NAFLD than those not infected by H. pylori (38).
 

Figure 4. Possible relationship between NAFLD and H. pylori infection (Cheng et al., 2017)

Neurogenic Diseases

The relationship between neurodegenerative diseases and neuroinflammation can potentially be triggered by environmental conditions and disruption of the blood-brain barrier. Recent studies outlined that various pathogens (including H. pylori) may reach the central nervous system (CNS) via blood flow, gastrointestinal tract, and olfactory tract. Thus, H. pylori is able to induce cellular and humoral immune responses and also, interact with CNS components through sharing homologous epitopes, thereby causing damage to nerve tissue. Hence, one could associate H. pylori with several CNS-related degenerative and autoimmune diseases (39-42).

Figure 5. Schematic representation of three theories that mechanically explain the possibility of H. pylori entering the CNS (Doulberis et al., 2018)

Parkinson's Disease

Parkinson's disease (PD) ranked in the 2^th place among neurological disorder worldwide. The disease has been specified as accumulating cytoplasmic proteins, including α-synuclein, causing gradual degeneration of dopaminergic neurons (43). Degeneration leads to tremors, stiffness, and difficulty with movement as symptoms of PD. The risk of PD may increase in the presence of H. pylori infection. L-3, 4-Dihydroxyphenyl alanine (L-dopa), a dopamine precursor, is prescribed to treat PD. The accessibility of L-DOPA may be affected by H. pylori infection via disrupting the duodenal mucosa in which initial L-DOPA uptake occurs. Recent studies have argued that H. pylori eradication improves L-DOPA accessibility and reduces motor instabilities in PD patients. Parkinsonism is also a neurological disease with same symptoms as PD. If anti-inflammatory cytokines such as IL-1β, TNF-α, and IL-8 are presented in the bloodstream, the immune response induces a blood-brain barrier disorder and ultimately causes neurotoxicity and neuroinflammation. Researchers have found that infection by H. pylori provides the necessary basis for autoimmune disease, which in turn leads to nerve damage and eventually Parkinsonism (41, 44, 45).
 

Alzheimer's Disease (AD)

Alzheimer's disease (AD) is regarded as the most prevalent form of dementia, especially in industrialized countries, affecting approximately 20 million people worldwide [40]. AD is a progressive neurogenic disorder specified by nerve death and synaptic loss due to intra- and extra-cellular accumulation of neurofibrillary tangles and beta-amyloid deposits in those brain areas that are involved in cognitive and memory processes The inflammatory reaction has an significant role in the pathophysiology of AD. Given the H. pylori-induced inflammatory reactions and high levels of H. pylori, TNF-α, IL-8, and IgG in the cerebrospinal fluid (CSF) of H. pylori-infected patients suffering AD, it could be concluded that H. pylori may contribute in AD. This confirms the results of the studies that noticed an improvement in cognitive status, functional parameters, and survival of AD patients after H. pylori eradication (41). Chronic atrophic gastritis caused by H. pylori reduces the concentration of B vitamins in the serum and thus increases the concentration of homocysteine; concentration of homocysteine in serum​​ corresponds with the intensity of dementia. Oxidative damage may be induced by homocysteine in the brains of patients with mild cognitive disorder is possible. The information suggests that oxidative damage may be considered as one of the first events occurs at the onset and development of AD (41, 44).
 

Multiple Sclerosis

Multiple sclerosis (MS) is a complex multifactorial and autoimmune disease, which causes demyelinating inflamed lesions in the CNS system. The etiology of MS is not yet fully understood. Several environmental factors, including microbial agents, are known to cause the disease. Among microbial agents, H. pylori has been considered as a microbial agent of the disease. This hypothesis is confirmed by the high prevalence and occurrence of gastrointestinal symptoms in MS (44, 46, 47). H. pylori infections are known as important risk factors in the progression of anti-aquaporin 4 (AQP4) and the results of some studies confirm the improvement of patients after H. pylori eradication. Neuromyelitis optica (NMO) is an inflammatory disorder that electively influences the spinal cord and optic nerve. Optic neuromyelitis development may be affected by chronic infection via molecular mimicry existed between bacterial AQP4 and human AQP4. Moreover, the protein responsible for activating H. pylori neutrophil is involved in pathogenesis by inducing activation and migration of neutrophils (42, 44).
 

Ischemic Stroke

Studies indicate that some infectious agents have a role in the progression of neurological disorders like ischemic stroke. There are a positive relationship between H. pylori infection and the occurrence of stroke. The pathophysiological mechanism of most strokes is cerebrovascular and carotid occlusion [48]. The presence of CagA-positive strains and H. pylori-chronic infection are two main risk factors for stroke. Likewise, there are a clear relationship between CagA-positive strains of H. pylori and higher risk of atherosclerotic strokes in patients with active infection. The underlying mechanism through which chronic H. pylori infection augments the risk of ischemic stroke is not yet wholly known. H. pylori is thought to affect coagulation by activating platelets. According to the results of various studies, the levels of plasma and LDL cholesterols, IL-8, and fibrinogen were significantly decreased following six months of H. pylori infection eradication compared to the control group and patients infected with H. pylori suffering from stroke (44, 48, 49).
 

Hematological Diseases

Iron Deficiency Anemia (IDA)

There are a large body of studies examining the relation between IDA and H. pylori infection. Blaser et al. (1991) described the relationship between hemorrhagic gastric and infection by H. pylori, and also suggested a possible association between IDA and H. pylori infection (7, 51). The same association has been confirmed in children and adults in several studies [50-53]; however, few studies did not confirm this association. A meta-analysis consisting 15 case-control studies was conducted by Qu et al. (2010) in order to examine the association between IDA and H. pylori infection. In 5 studies, the diagnosis of the infection was successfully done using endoscopy and histological tests, which did not include gastric ulcer and gastric cancer cases. In 10 other studies, H. pylori infection was identified using serological tests and urea breath test; the data showed with high reliability the association between H. pylori infection and higher risk of IDA in these people (54). A recent study also confirmed the relationship between IDA and H. pylori infection (55). Improvement of IDA patients following H. pylori eradication in the absent of iron supplementation has also been confirmed in other studies (51).
H. pylori can result in IDA through certain mechanisms. First, iron loss may increase because of peptic ulcer disorder, hemorrhagic gastritis, and gastric adenocarcinoma. Secondly, the role of H. pylori CagA protein has been confirmed in the absorption of iron from interstitial holotransferrin. The rate of iron uptake by H. pylori increases during bacterial development. In summary, the relationship between IDA and H. pylori has been established in various research, and currently national and international instructions suggest H. pylori infection eradication in IDA patients (51, 52).
 

Immune Thrombocytopenic Purpura (ITP)

ITP, formerly known as autoimmune- and idiopathic-thrombocytopenic purpura, refers to an autoimmune disruption specified by isolated thrombocytopenia when other causes are absent. In 1999, the first relation of ITP with H. pylori infection was explained in Spain. In addition to this association, several researchers have also reported a significant increase in the number of platelets due to H. pylori eradication from 32% to 100% in Italy and 26% to 100% in other parts of the world (50, 56).
H. pylori affects ITP through several mechanisms. An interesting hypothesis about molecular mimicry outlines that antibodies with cross-reactivity can react with platelet surface antigens as well as H. pylori. By washing the platelets of H. pylori-infected ITP patients, the researchers identified the CagA protein in the immunoblots, whereas it was not detected in H. pylori-infected patients who were free from ITP. Other researchers have outlined that the reaction of H. pylori urease with GP IIb/IIIa expressed on platelet surface resulted in monoclonal antibodies. Although these results represent a molecular mimicry between platelet surface antigens and H. pylori components, the pathogenic role of these cross-reactive antibodies is still unclear [57 Other possible mechanisms may be due to the destabilizing impact of H. pylori infection on the balance of Fcγ receptor of monocytes/macrophages, resulting the formation of autoantibodies. Based on a recent study, the expression of FcγR II B in circulating monocytes was reduced in patients infected by H. pylori who had IPT. Thus, H. pylori may change the balance of Fcγ receptor of monocytes/macrophages by reductive regulation (51).
 

Vitamin B12 Deficiency

There are several major enzymatic reactions inside the body, in which vitamin B12 acts as the coenzyme, thereby results in DNA synthesis. Lahner et al. (2012) performed a systematic review of 17 studies including a total of 2,454 patients and found a direct association between H. pylori infection and low levels of serum vitamin B12 Homocysteine is an important ingredient of the vitamin B12 metabolism pathway, and many researchers have reported a positive association between H. pylori infection and both high serum homocysteine levels and low serum vitamin B12 levels. Reduced homocysteine and increased vitamin B12 serum levels after H. pylori eradication have also been reported (50, 58, 59).
As described in the previous sections, H. pylori infection is strongly related with chronic gastritis and disrupts gastric acid and pepsin secretion. Thus, H. pylori is associated with incomplete absorption of vitamin B12 in food, however, the underlying pathophysiological metabolism is still unknown. Pangastritis related with H. pylori infection leads to the destruction of gastric parietal cells, which in turn reduces the level of endogenous factors and leads to a decrease in the absorption of vitamin B12 [50, 60]. The possible mechanisms that lead to the association between IDA, ITP, and vitamin B12 shortage with H. pylori infection are summarized in Figure 6.


 

Figure 6. Possible mechanisms leading to the connection between hematologic diseases and the infection by H. pylori (Gravina et al., 2018)

Conclusion

The results of various studies over the years indicate the involvement and impact of H. pylori infection on many biological processes associated with gastrointestinal and extra-gastrointestinal diseases. H. pylori contribute in several gastrointestinal disorders including peptic and duodenal ulcer, gastritis dyspepsia, gastric adenocarcinoma, and MALT lymphoma. The pathogenic mechanism of these diseases is not fully known yet. The bacterium also causes many extra-gastrointestinal diseases, including cardiovascular disease, diabetes, IR, MetS, PD, AD, MS, ischemic stroke, IDA, ITP, and deficiency of vitamin B12. The likely mechanism of H. pylori leading to these diseases has also been investigated in the last few years.