A Systematic Review and Meta-Analysis of the Association between Helicobacterpylori Infection and Dementia - IOS Press

A positive association between Helicobacter pylori infection and dementia has been reported, yet findings are inconsistent.

Objective:To examine the association between H. pylori infection and dementia. Methods:A literature search was performed using the databases OVID-Medline, Institute of Scientific Information Web of Science, and EMBASE. The meta-analysis was conducted using the random effects model. The primary analysis included studies in which the exposure variable was presence of H. pylori infection (yes versus no) and the outcome was incident dementia (yes versus no), which was pre-selected as the end-result of gradual cognitive decline overtime. Publication bias was explored using funnel plot and the Egger regression intercept.

Results:A total of 260 records were identified; 13 addressed cognition and/or dementia in relation to H. pylori infection, of which only seven were included in the meta-analysis. The primary analysis showed a significant positive association between H. pylori infection and dementia; pooled odds ratio 1.71 (95% CI 1.17–2.49) (pv = 0.01). No significant evidence of publication bias was found. Conclusions:H. pylori may play a role in the etiology of dementia. Identification of the biological mechanisms of such association is needed, as well as assessment of the impact of H. pylori therapy on the risk and progression of dementia."



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Common mechanisms involved in Alzheimer's disease and type 2 diabetes: a key role of chronic bacterial infection and inflammation. - PubMed - NCBI

Strong epidemiologic evidence and common molecular mechanisms support an association betweenAlzheimer's disease (AD) and type 2-diabetes. Local inflammation and amyloidosis occur in both diseases and are associated with periodontitis and various infectious agents. This article reviews the evidence for the presence of local inflammation and bacteria in type 2 diabetes and discusses host pathogen interactions in chronic inflammatory disorders. Chlamydophyla pneumoniae, Helicobacter pylori and spirochetes are demonstrated in association with dementia and brain lesions in AD and islet lesions in type 2 diabetes. The presence of pathogens in host tissues activates immune responses through Toll-like receptor signaling pathways. Evasion of pathogens from complement-mediated attack results in persistent infection, inflammation and amyloidosis. Amyloid beta and the pancreatic amyloid called amylin bind to lipid bilayers and produce Ca(2+) influx and bacteriolysis. Similarly to AD, accumulation of amylin deposits in type 2 diabetes may result from an innate immune response to chronic bacterial infections, which are known to be associated with amyloidosis. Further research based on an infectious origin of both AD and type 2 diabetes may lead to novel treatment strategies.

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Herpes Simplex Virus Type 1 and Other Pathogens are Key Causative Factors in Sporadic Alzheimer’s Disease - IOS Press

This review focuses on research in epidemiology, neuropathology, molecular biology, and genetics regarding the hypothesis that pathogens interact with susceptibility genes and are causative in sporadic Alzheimer’s disease (AD). Sporadic AD is a complex multifactorial neurodegenerative disease with evidence indicating coexisting multi-pathogen and inflammatory etiologies. There are significant associations between AD and various pathogens, including Herpes simplex virus type 1 (HSV-1), Cytomegalovirus, and other Herpesviridae, Chlamydophila pneumoniae, spirochetes, Helicobacter pylori, and various periodontal pathogens. These pathogens are able to evade destruction by the host immune system, leading to persistent infection. Bacterial and viral DNA and RNA and bacterial ligands increase the expression of pro-inflammatory molecules and activate the innate and adaptive immune systems. Evidence demonstrates that pathogens directly and indirectly induce AD pathology, including amyloid-β (Aβ) accumulation, phosphorylation of tau protein, neuronal injury, and apoptosis. Chronic brain infection with HSV-1, Chlamydophila pneumoniae, and spirochetes results in complex processes that interact to cause a vicious cycle of uncontrolled neuroinflammation and neurodegeneration. Infections such as Cytomegalovirus, Helicobacter pylori, and periodontal pathogens induce production of systemic pro-inflammatory cytokines that may cross the blood-brain barrier to promote neurodegeneration. Pathogen-induced inflammation and central nervous system accumulation of Aβ damages the blood-brain barrier, which contributes to the pathophysiology of AD. Apolipoprotein E4 (ApoE4) enhances brain infiltration by pathogens including HSV-1 and Chlamydophila pneumoniae. ApoE4 is also associated with an increased pro-inflammatory response by the immune system. Potential antimicrobial treatments for AD are discussed, including the rationale for antiviral and antibiotic clinical trials.

Helicobacter pylori infection as a protective factor against multiple sclerosis risk in females.

In recent years, a relationship between Helicobacter pylori and many disease conditions has been reported, however, studies in its relationship with multiple sclerosis (MS) have had contradictory results.

OBJECTIVE:

To determine the association between the H. pylori infection and MS.

METHODS:

550 patients with MS were included in the study and were matched by gender and year of birth to 299 controls. Patients were assessed for clinical and demographic parameters. An enzyme immunoassay was used to detect the presence of specific IgG antibodies against H. pylori in the serum sample of both groups.

RESULTS:

H. pylori seropositivity was found to be lower in the patients with MS than in controls (16% vs 21%) with the decrease pertaining to females (14% vs 22%, p=0.027) but not males (19% vs 20%, p=1.0). When adjusted for age at onset, year of birth and disease duration, H. pylori seropositive females presented with a lower disability score than seronegative females (p=0.049), while among males the reverse was true (p=0.025). There was no significant association between H. pylori seropositivity and relapse rate.

CONCLUSIONS:

Our results could reflect a protective role of H. pylori in the disease development. However, it may be that H. pylori infection is a surrogate marker for the 'hygiene hypothesis', a theory which postulates that early life infections are essential to prime the immune system and thus prevent allergic and autoimmune conditions later in life. The fact that the association between H. pylori seropositivity and MS risk was seen almost exclusively in females requires further investigation.

A common gut bacterium (Helicobacter pylori) may protect women against MS, study finds - Medical News Today

For comparison, the authors looked at the presence of H. pylori antibodies among 299 age- and sex-matched healthy individuals without MS, drawn from the Busselton Community Health Study.

The results of the analysis revealed that women who did not have MS were significantly more likely to be infected with H. pylori than women with MS, suggesting the bacterium may have a protective effect against the condition.

This association, however, was not found in men. In fact, men infected with the bacterium were more likely to have MS.

Explaining the possible reasons behind the protective effect of H. pylori found in women, the researchers say the bacterium may move the immune system into a less inflammatory state, which may reduce its sensitivity and lower the risk of autoimmune disorders like MS.

The team, however, says they are unable to explain why H. pylori did not appear to protect men against MS, and that this is something that needs to be investigated in future research.

A study on the association between infectious burden and Alzheimer's disease.

BACKGROUND AND PURPOSE:

Previous studies suggested that the overall burden of prior infections contributes to cardiovascular
diseases and stroke. In the present study, the association between
infectious burden (IB) and Alzheimer's disease (AD) was examined.

METHODS:

Antibody titers to common infectious pathogens including cytomegalovirus (CMV),
herpes simplex virus type 1 (HSV-1), Borrelia burgdorferi, Chlamydophila
pneumoniae and Helicobacter pylori were measured by enzyme-linked
immunosorbent assay in 128 AD patients and 135 healthy controls. IB was
defined as a composite serological measure of exposure to these common
pathogens.

RESULTS:

Seropositivities toward zero-two, three and four-five of these pathogens were found in 44%, 40% and 16% of healthy controls but in 20%, 44% and 36% of AD patients, respectively. IB, bacterial burden and viral burden were independently associated with AD after adjusting for age, gender, education, APOE genotype and various comorbidities. Mini-Mental State Examination scores were negatively correlated with IB in all cases. Serum beta-amyloid protein (Aβ) levels (i.e. Aβ40, Aβ42 and total Aβ) and inflammatory cytokines (i.e. interferon-γ, tumor necrosis factor α, interleukin-1β and interleukin-6) in individuals exposed to four-five infectious pathogens were significantly higher than those exposed to zero-two or three pathogens.

CONCLUSIONS:

IB consisting of CMV, HSV-1, B. burgdorferi, C. pneumoniae and H. pylori is associated with AD. This study supports the role of infection/inflammation in the etiopathogenesis of AD.

Eradication of Helicobacter pylori Is Associated with the Progression of Dementia: A Population-Based Study

Objective. To evaluate the effect of eradication of Helicobacter pylori (H. pylori) on the progression of dementia in Alzheimer’s disease (AD) patients with peptic ulcer. Methods. Participants with the diagnosis of AD and peptic ulcer were recruited between 2001 and 2008. We examined the association between eradication of H. pylori and the progression of AD using the multiple regression models. Medication shift from Donepezil, Rivastgmine, and Galantamine to Mematine is defined as progression of dementia according to the insurance of National Health Insurance (NHI) under expert review. Results. Among the 30142 AD patients with peptic ulcers, the ratio of medication shift in AD patients with peptic ulcers is 79.95%. There were significant lower incidence comorbidities (diabetes mellitus, hypertension, cerebrovascular disease, coronary artery disease, congestive heart failure and hyperlipidemia) in patients with H. pylori eradication as compared with no H. pylori eradication. Eradication of H. pylori was associated with a decreased risk of AD progression (odds ratio [OR] 0.35 [0.23–0.52]) as compared with no H. pylori eradication, which was not modified by comorbidities. Conclusions. Eradication of H. pylori was associated with a decreased progression of dementia as compared to no eradication of H. pylori in AD patients with peptic ulcers.

Helicobacter pylori filtrate impairs spatial learning and memory in rats and increases β-amyloid by enhancing expression of presenilin-2 | Frontiers in Aging Neuroscience

Helicobacter pylori (H. pylori) infection is related with a high risk of Alzheimer's disease (AD), but the intrinsic link between H. pylori infection and AD development is still missing. In the present study, we explored the effect of H. pylori infection on cognitive function and β-amyloid production in rats. We found that intraperitoneal injection of H. pylori filtrate induced spatial learning and memory deficit in rats with a simultaneous retarded dendritic spine maturation in hippocampus. Injection of H. pylori filtrate significantly increased Aβ₄₂ both in the hippocampus and cortex, together with an increased level of presenilin-2 (PS-2), one key component of γ-secretase involved in Aβ production. Incubation of H. pylori filtrate with N2a cells which over-express amyloid precursor protein (APP) also resulted in increased PS-2 expression and Aβ₄₂ overproduction. Injection of Escherichia coli (E.coli) filtrate, another common intestinal bacterium, had no effect on cognitive function in rats and Aβ production in rats and cells. These data suggest a specific effect of H. pylori on cognition and Aβ production. We conclude that soluble surface fractions of H. pylori may promote Aβ₄₂ formation by enhancing the activity of γ-secretase, thus induce cognitive impairment through interrupting the synaptic function.

DNA methylation in gastric cancer, related to Helicobacter pylori and Epstein-Barr virus.

Gastric cancer is a leading cause of cancer death worldwide, and
significant effort has been focused on clarifying the pathology of
gastric cancer. In particular, the development of genome-wide analysis
tools has enabled the detection of genetic and epigenetic alterations in
gastric cancer; for example, aberrant DNA methylation in gene promoter
regions is thought to play a crucial role in gastric carcinogenesis. The
etiological viewpoint is also essential for the study of gastric
cancers, and two distinct pathogens, Helicobacter pylori (H. pylori)
and Epstein-Barr virus (EBV), are known to participate in gastric
carcinogenesis. Chronic inflammation of the gastric epithelium due to H. pylori
infection induces aberrant polyclonal methylation that may lead to an
increased risk of gastric cancer. In addition, EBV infection is known to
cause extensive methylation, and EBV-positive gastric cancers display a
high methylation epigenotype, in which aberrant methylation extends to
not only Polycomb repressive complex (PRC)-target genes in embryonic
stem cells but also non-PRC-target genes. Here, we review aberrant DNA
methylation in gastric cancer and the association between methylation
and infection with H. pylori and EBV.

Human and Helicobacter pylori coevolution shapes the risk of gastric disease

Helicobacter pylori is the principal cause of gastric cancer, the second leading cause of cancer mortality worldwide. However, H. pylori prevalence generally does not predict cancer incidence. To determine whether coevolution between host and pathogen influences disease risk, we examined the association between the severity of gastric lesions and patterns of genomic variation in matched human and H. pylori samples. Patients were recruited from two geographically distinct Colombian populations with significantly different incidences of gastric cancer, but virtually identical prevalence of H. pylori infection. All H. pylori isolates contained the genetic signatures of multiple ancestries, with an ancestral African cluster predominating in a low-risk, coastal population and a European cluster in a high-risk, mountain population. The human ancestry of the biopsied individuals also varied with geography, with mostly African ancestry in the coastal region (58%), and mostly Amerindian ancestry in the mountain region (67%). The interaction between the host and pathogen ancestries completely accounted for the difference in the severity of gastric lesions in the two regions of Colombia. In particular, African H. pylori ancestry was relatively benign in humans of African ancestry but was deleterious in individuals with substantial Amerindian ancestry. Thus, coevolution likely modulated disease risk, and the disruption of coevolved human and H. pylori genomes can explain the high incidence of gastric disease in the mountain population.

Helicobacter pylori Infection Synergizes with Three Inflammation-Related Genetic Variants in the GWASs to Increase Risk of Gastric Cancer in a Chinese Population.

Three recent genome-wide association studies (GWASs) have reported that three SNPs (rs4072037, rs13361707 and rs2274223) located on genes related to host inflammatory response are significantly associated with susceptibility to gastric cancer (GC) in Chinese populations. Helicobacter pylori infection is also an important risk factor for GC through causing inflammatory response in the gastric mucosa. However, no study has established whether there are potential gene-environment interactions between these genetic variants and H. pylori infection to the risk of GC.

METHODS:

We genotyped three polymorphisms (rs4072037 at 1q22, rs13361707 at 5p13, and rs2274223 at 10q23) in 335 Chinese gastric adenocarcinoma patients and 334 controls. H. pylori serology was examined by enzyme-linked immunosorbent assay. Multivariable logistic regression models were used to evaluate the association between the variables and GC risk.

RESULTS:

We confirmed that the three SNPs (rs4072037, rs13361707 and rs2274223) were significantly associated with GC susceptibility. H. pylori infection also significantly increased the risk of GC. Furthermore, there were joint effects between H. pylori infection and the three SNPs on the risk of GC. The most elevated risk of GC was found in subjects with H. pylori seropositivity and AA genotypes for rs4072037 [odds ratio (OR), 3.95; 95% confidence interval (CI), 2.29-6.79], H. pylori seropositivity and CT/CC genotypes for rs13361707 (OR, 2.68; 95% CI, 1.62-4.43), H. pylori seropositivity and AG/GG genotypes for rs2274223 (OR, 2.45; 95% CI, 1.55-3.88) compared with those with H. pylori seronegativity and other genotypes of each SNP. Significant interactions were observed between H. pylori seropositivity and the three SNPs (all P G× E <0.05) to the risk of GC.

CONCLUSION:

These findings indicate that the three SNPs (rs4072037, rs13361707 and rs2274223) identified in the GWASs may interact with H. pylori infection to increase the risk of GC.

Stomach bacteria switch off human immune defences to cause disease

 : "Researchers from the University of Nottingham have shown that Helicobacter pylori is able to supress the body's normal production of 'human beta defensin 1' (DEFB1), an antimicrobial factor present in the stomach lining that helps prevent bacterial infection. By collecting stomach tissue biopsies from 54 patients at the Queens Medical Centre, Nottingham, the team showed that patients infected with H. pylori had ten times less DEFB1 than uninfected patients. Those with the lowest amount of DEFB1 had the most bacteria present in their stomach lining."
H.Pylori has been linked to gastritis, peptic ulcers and gastric cancer.

Presence of different genotypes of Helicobacter pylori in patients with chronic tonsillitis and sleep apnoea syndrome.

 Helicobacter pylori, a well-known gastric pathogen, has been detected in the oral cavity and oropharynx in tonsillar tissue. In our study, the presence of H. pylori in the tonsillar tissue of patients with chronic tonsillitis and sleep apnoea syndrome (SAS) was investigated. The aim was to detect and genotype H. pylori for a collection of data supporting the possible role of H. pylori in the aetiology of chronic tonsillitis and SAS. Helicobacter pylori was detected by real-time polymerase chain reaction (rt-PCR). 89 patients, 60 with a diagnosis of chronic tonsillitis and 29 with SAS, were tested. In the chronic tonsillitis group, Helicobacter was detected in 48 (80 %) specimens, cagA gene was detected in 12 samples (25 %) and 12 samples were negative. In SAS group, Helicobacter was found in 24 samples (82.76 %), cagA gene was detected in 5 (20.83 %) and 5 samples (17.24 %) were negative. Helicobacter pylori-specific immunoglobulins were tested by ELISA in the serum of 57 patients only with 41 (71.93 %) showing positive. Our results on H. pylori DNA detection and H. pylori seropositivity show 26.32 % discrepancy, slightly in favour of rt-PCR (15.79 % compared to 10.53 %). The H. pylori presence in tonsillar tissue does not depend on the type of oropharyngeal disease (p = 0.756). This study shows that oropharynx constitutes an extragastric reservoir of H. pylori infection which could serve as an aetiopathogenetic factor for chronic tonsillitis and tonsillar hyperplasia by SAS. No conclusion has yet been drawn about the mechanism of the process.

Genetic variations associated with susceptibility to bacteria linked to stomach disorders

 "Two genome-wide association studies and a subsequent meta-analysis have found that certain genetic variations are associated with susceptibility to Helicobacter pylori, a bacteria that is a major cause of gastritis and stomach ulcers and is linked to stomach cancer, findings that may help explain some of the observed variation in individual risk for H pylori infection, according to a study in the May 8 issue of JAMA."

High-salt diet and ulcer bug combine to increase risk of cancer

 "Numerous epidemiologic studies have shown that a diet high in salt is associated with an increased risk of gastric cancer. Now Timothy L. Cover and colleagues of Vanderbilt University show that high dietary salt combined with infection by the ulcer-causing bacterium Helicobacter pylori greatly increases the risk of cancer. The study was published ahead of print in the journal Infection and Immunity."

Other stomach microbiota modulate resistance to H. pylori-driven ulcers

 "Mice with different naturally occurring stomach bacteria have distinct susceptibilities to disease caused by Helicobacter pylori, the well-known cause of ulcers in humans, according to a study published online ahead of print in the journal Infection and Immunity. This is the first study to document (in mice) that the presence of certain bacteria in the stomach microbiota can prevent pathology from H. pylori."

Could that cold sore and other infections increase your risk of memory problems?

"The virus that causes cold sores, along with other viral or bacterial infections, may be associated with cognitive problems, according to a new study published in the March 26, 2013, print issue of Neurology."For the study, researchers tested thinking and memory in 1,625 people with an average age of 69 from northern Manhattan in New York. Participants gave blood samples that were tested for five common low grade infections: three viruses (herpes simplex type 1 (oral) and type 2 (genital), and cytomegalovirus), chlamydia pneumoniae (a common respiratory infection) and Helicobacter pylori (a bacteria found in the stomach).

The landscape of host transcriptional response programs commonly perturbed by bacterial pathogens: towards host-oriented broad-spectrum drug targets.

The emergence of drug-resistant pathogen strains and new infectious agents pose major challenges to public health. A promising approach to combat these problems is to target the host's genes or proteins, especially to discover targets that are effective against multiple pathogens, i.e., host-oriented broad-spectrum (HOBS) drug targets. An important first step in the discovery of such drug targets is the identification of host responses that are commonly perturbed by multiple pathogens.

RESULTS:

In this paper, we present a methodology to identify common host responses elicited by multiple pathogens. First, we identified host responses perturbed by each pathogen using a gene set enrichment analysis of publicly available genome-wide transcriptional datasets. Then, we used biclustering to identify groups of host pathways and biological processes that were perturbed only by a subset of the analyzed pathogens. Finally, we tested the enrichment of each bicluster in human genes that are known drug targets, on the basis of which we elicited putative HOBS targets for specific groups of bacterial pathogens. We identified 84 up-regulated and three down-regulated statistically significant biclusters. Each bicluster contained a group of pathogens that commonly dysregulated a group of biological processes. We validated our approach by checking whether these biclusters correspond to known hallmarks of bacterial infection. Indeed, these biclusters contained biological process such as inflammation, activation of dendritic cells, pro- and anti- apoptotic responses and other innate immune responses. Next, we identified biclusters containing pathogens that infected the same tissue. After a literature-based analysis of the drug targets contained in these biclusters, we suggested new uses of the drugs Anakinra, Etanercept, and Infliximab for gastrointestinal pathogens Yersinia enterocolitica, Helicobacter pylori kx2 strain, and enterohemorrhagic Escherichia coli and the drug Simvastatin for hematopoietic pathogen Ehrlichia chaffeensis.

CONCLUSIONS:

Using a combination of automated analysis of host-response gene expression data and manual study of the literature, we have been able to suggest host-oriented treatments for specific bacterial infections. The analyses and suggestions made in this study may be utilized to generate concrete hypothesis on which gene sets to probe further in the quest for HOBS drug targets for bacterial infections. All our results are available at the following supplementary website: http://bioinformatics.cs.vt.edu/murali/supplements/2013-kidane-plos-one.

Some bacteria may protect against disease caused by H.Pylori stomach infection

: "Half of the world's human population is infected with the stomach bacteria called Helicobacter pylori, yet it causes disease in only about 10 percent of those infected. Other bacteria living in the stomach may be a key factor in whether or not H. pylori causes disease, according to a new study led by scientists at the University of California, Santa Cruz."

Serum markers of infections in patients with primary biliary cirrhosis: evidence of infection burden.

Currently not much is known regarding the environmental factors involved in primary biliary cirrhosis (PBC). It is even more unclear which factors may determine the subgroup (i.e., AMA status) of patients with PBC. We thus tested AMA+and AMA- PBC patients' sera for antibodies (Abs) against multiple infectious agents.

METHODS:

Sera from 69 patients with PBC (49 AMA+and 20 AMA-) and 100 matched controls were screened for IgG-Abs against Toxoplasma gondii, Helicobacter pylori, Epstein-Barr virus (EBV), cytomegalovirus (CMV), hepatitis B, and hepatitis C utilizing the BioPlex 2200 and ELISA kits (Bio-Rad Laboratories, USA).

RESULTS:

The prevalence of four anti-infectious agents Abs was significantly elevated among PBC patients when compared with controls, namely anti-T. gondii (ATxA; 71% vs. 40%, p<0.0001), EBV early antigen (EA; 44% vs. 12%, p<0.0001), H. pylori (54% vs. 31%, p<0.01), and CMV (90% vs. 75%, p<0.05) Abs, respectively. The co-occurrence of these four anti-infectious agents Abs was highly common in PBC, whereas this infection burden was rare in healthy subjects (20% vs. 3% respectively, p<0.0001). Furthermore, specific infections interactions possibly increasing PBC risk were noted as well. Seropositivity of ATxA was inversely associated with cirrhosis among PBC patients (p<0.05). Finally, no differences were observed between AMA- sera and their AMA+counterparts with regard to seroprevalence of any of the investigated infectious agents.

CONCLUSIONS:

We note the association of ATxA and PBC, with the possibility of a milder disease manifestation. We also suggest that multiple exposures to infectious agents may contribute to PBC risk.