Helicobacters and Extragastric Diseases

For two decades, Helicobacter pylori has been considered as the culprit in many extragastric manifestations. However, for several of these supposed associations the hypothesis of an etiological role has not yet been fully investigated. This may be due to a series of factors linked to the epidemiological features of the studies and to the diseases investigated. This review attempts to highlight the main reported associations of H. pylori with extragastric manifestations during the last year. The most convincing data arise in the field of idiopathic thrombocytopenic purpura (ITP) and sideropenic anemia. Long-term follow-up studies have shown that 50% of subjects with ITP maintain a hematological response after H. pylori eradication. There is also growing evidence of the role of H. pylori in other diseases, including ischemic heart disease even though results are not conclusive.     

A review of the postulated mechanisms concerning the association of Helicobacter pylori with ischemic heart disease

Since its discovery, Helicobacter pylori has been implicated in the pathogenesis of several diseases, both digestive and extradigestive. Interestingly, the majority of the extradigestive-related literature is focused on two vascular manifestations: stroke and ischemic heart disease. Potential mechanisms for the establishment of a H. pylori-induced ischemic heart disease have been proposed with regard to chronic inflammation, molecular mimicry, oxidative modifications, endothelial dysfunction, direct effect of the microorganism on atherosclerotic plaques as well as changes regarding traditional or novel risk factors for ischemic heart disease or even platelet-H. pylori interactions. A positive link between H. pylori infection and ischemic heart disease has been suggested by a series of studies focusing on epidemiologic evidence, dyslipidemic alterations, upregulation of inflammatory markers or homocysteine levels, induction of hypercoagulability, oxidation of low-density lipoprotein, causation of impaired endothelial function, detection of H. pylori DNA in atherosclerotic plaques, and participation of certain antigens and antibodies in a cross-reactivity model. There are studies, however, which investigated the relationship between H. pylori and ischemic heart disease with regard to the same parameters and failed to confirm the suggested positive association. Further studies in the direction of interaction between H. pylori and the host's genotype as well as a quest for evidence towards novel risk factors for ischemic heart disease such as oxidative stress, vascular remodeling, vascular calcification, or vasomotor activity, may reveal a field of great interest, thus contributing to the determination of new potential mechanisms.     

Eradication of Helicobacter pylori infection in the management of patients with dyspepsia and non-ulcer dyspepsia.

Although H. pylori infection has been recognized as a major etiological agent for the development of chronic active gastritis, duodenal ulcer and benign non-NSAID related gastric ulcer, its role in the development of symptoms in patients with dyspepsia remains uncertain. Results from population-based epidemiological studies have been conflicting regarding a causal link between H. pylori infection and dyspepsia. Abnormalities in gastric acid secretion may exist in some dyspeptic patients. Whether disordered gastric motility seen in dyspeptic patients is related to the infection is not clear based on the results in the literature. Numerous clinical trials have been undertaken to eradicate H. pylori infection and improve the symptoms in dyspeptic patients; however, the results have been discrepant between studies. Many published studies suffer from methodological problems that have made interpretation difficult. Large, well-conducted, randomized, placebo-controlled, clinical trials with long-term follow-up are needed to justify the beneficial effect of H. pylori eradication treatment in dyspeptic patients seen in some small studies. H. pylori eradication therapy is cost-effective in H. pylori-infected dyspeptic patients although this benefit may take a long time to accrue, especially in younger patients.     

幽门螺杆菌Ⅳ型分泌系统(T4SS)研究进展

Ⅳ型分泌系统(T4SS)广泛存在于革兰阴性菌中,细菌可通过该系统将生物大分子或毒力因子等运输至靶细胞中并发挥相应功能。目前在H.pylori中已发现了至少三种T4SS,其中研究较为透彻的是cag致病岛(cagPAI)编码的cagT4SS系统,此外可塑区编码的tfs3系统和comB系统也有相关的报道。H.pylori的T4SS作为其与致病相关的重要结构已受到很多学者关注,对该菌T4SS系统的研究有助于进一步明确H.pylori的致病机制,并为临床诊断和治疗相关胃十二指肠疾病提供新的靶点。本文将对H.pylori的T4SS相关研究进展作一简要综述。     

Neurovascular and Cognitive failure in Alzheimer’s Disease: Benefits of Cardiovascular Therapy

Alzheimer’s disease (AD) is a multifactorial and multifaceted disease for which we currently have very little to offer since there is no curative therapy, with only limited disease-modifying drugs. Recent studies in AD mouse models that recapitulate the amyloid-β (Aβ) pathology converge to demonstrate that it is possible to salvage cerebrovascular function with a variety of drugs and, particularly, therapies used to treat cardiovascular diseases such as hypercholesterolemia and hypertension. These drugs can reestablish dilatory function mediated by various endothelial and smooth muscle ion channels as well as nitric oxide availability, benefits that result in normalized brain perfusion. These cerebrovascular benefits would favor brain perfusion, which may help maintain neuronal function and, possibly, delay cognitive failure. However, restoring cerebrovascular function in AD mouse models was not necessarily accompanied by rescue of cognitive deficits related to spatial learning and memory. The results with cardiovascular therapies rather suggest that drugs originally designed to treat cardiovascular diseases that concurrently restore cerebrovascular and cognitive function do so through their pleiotropic effects. Specifically, recent findings suggest that these drugs act directly on brain cells and neuronal pathways involved in memory formation, hence, working simultaneously albeit independently on neuronal and vascular targets. These findings may help select medications for patients with cardiovascular diseases at risk of developing AD with increasing age. Further, they may identify molecular targets for recovering memory pathways that bear potential for new therapeutic avenues.     

Helicobacter pylori infection and skin diseases.

There is increasing evidence for systemic effects of gastric H. pylori infection which may result in extragastrointestinal disorders. This review summarizes the available medical literature up to September 1999, identified through a MEDLINE research including own studies, regarding H. pylori and skin diseases. Due to current knowledge best evidence for a potential link of H. pylori infection exists for chronic urticaria although the data are still conflicting. Thus, the search for H. pylori should be included in the diagnostic management of chronic urticaria. With regard to other skin diseases such as rosacea, hereditary or acquired angioedema due to C1-esterase inhibitor deficiency, systemic sclerosis, Sch?nlein-Henoch purpura, Sj?gren's syndrome, sweet's syndrome, and atopic dermatitis only single of few cases have been reported so far. Thus, we clearly need further randomized, double-blind and placebo-controlled studies including adequate diagnostic schedules, sufficient eradication treatment protocols, confirmation of eradication, and adequate control groups to establish a role of H. pylori in skin diseases. Caution must be taken not to accuse H. pylori as the infectious agent responsible for every disease, particularly since H. pylori infection is very common. Although from an epidemiological and morphological view the skin diseases to which H. pylori has been linked seem to be completely different it is striking that in most of them an autoimmune pathogenesis is suspected or considerable vascular impairment can be found.     

Cardiovascular disease mortality in Canada.

During the past two decades approximately one half of all deaths in Canada were due to cardiovascular diseases. Ischemic heart disease and cerebrovascular disease caused more than 60% and 20% of those deaths respectively. The mortality rates for ischemic heart disease in males increased slightly until 1965 and then dropped substantially, whereas the rates for females, which were declining at least since the early 1960s, accelerated in their decline. As a consequence, the rates for males remain almost twice as high as those for females. The reductions were initially observed in males 25 to 34 years old and in all age groups of females, but became apparent in a wider range of ages in the second period reviewed (1969 through 1977). The mortality of cerebrovascular disease has gradually diminished for both sexes since the 1950s, but the decline has been more pronounced among females, who originally had the higher rate. Marked geographic differences in mortality rates still exist in Canada despite the decline in death rates for both ischemic heart disease and cerebrovascular disease in all regions of the country. Surprising regional differences in times of onset of these declines have been demonstrated. For ischemic heart disease Ontario maintains the highest and the Prairies the lowest mortality rates. Quebec, despite a sustained decline, still ranks third, while the Pacific region shows the second-lowest rates in the country. The Atlantic region showed the lowest rates of decline in the period reviewed. The reduction in the mortality of ischemic heart disease in Canada (16.4% between 1969 and 1977) must be considered real for a variety of reasons. Direct evidence is not available to elucidate whether the reduction is the consequence of reduced incidence, increased survival or a combination of the two factors. The potential role of various factors that may have contributed to this decline is briefly discussed in this article.     

High prevalence of Cag-A positive H. pylori strains in ischemic stroke: a primary care multicenter study

Background: Previous studies suggested an association between CagA-positive H. pylori strains and ischemic stroke. The aim of the present study was to assess the prevalence of Helicobacter pylori infection and CagA status in patients with atherosclerotic stroke in the primary care setting.
Materials and methods: A total of 106 consecutive patients (age 76.6 ± 8 years; males 52%) with well-documented history of atherosclerotic stroke and 106 sex–age- (age 76.5 ± 9 years; males 52%) and social background-matched controls without relevant vascular diseases. Risk factors for ischemic stroke were recorded in all subjects. H. pylori infection was assessed by[13]C-urea breath test. A serologic assay for specific IgG against CagA was performed in infected subjects.
Results: A trend toward a higher prevalence of H. pylori was observed in cases (63%) with respect to controls (54%) without reaching a statistical significance. CagA positivity was associated to a higher risk of atherosclerotic stroke (adjusted odds ratio 2.69, 95% confidence interval 1.37–5.30).
Conclusions: Our findings suggest that CagA-positive strains of H. pylori are significantly associated to atherosclerotic stroke. This is not a merely confirmative study since it has been performed for the first time in the primary care setting and included only subjects with an active infection.     

Extragastric manifestations of Helicobacter pylori infection -- other Helicobacters

Today there is evidence that Helicobacter pylori has a critical role in different extragastric diseases. The discovery of a number of other novel Helicobacter species has stimulated the research in different extragastric diseases, in which an infectious hypothesis is plausible. Enterohepatic Helicobacter species have been hypothesized to play a role in different disorders, including hepatocellular carcinoma, gallstones formation and cholangiocellular carcinoma, as well as enteric diseases and inflammatory bowel diseases. Concerning the extragastric manifestations of H. pylori infection, idiopathic thrombocytopenic purpura, and sideropenic anemia represent, based on the current data, the diseases in which the pathogenic link appears to be strongest. There is also an increasing evidence for a possible association of H. pylori with cardiovascular disease.     

Controlled trial of the effect of cinnamon extract on Helicobacter pylori

Background. Helicobacter pylori has been associated with the pathogenesis of antral gastritis, duodenal ulcer, and gastric lymphoma. Eradication of H. pylori has been shown to reverse or prevent relapse of these diseases. Antimicrobials employed in the eradication of H. pylori are not without adverse effects. Newer treatment modalities, therefore, are required. In vitro studies have shown the effectiveness of cinnamon extract against H. pylori and its urease. In this pilot study, we tested the activity of an alcoholic extract of cinnamon in a group of patients infected with H. pylori.
Materials and Methods. Fifteen patients (11 women, 4 men) aged 16 to 79 years were given 40 mg of an alcoholic cinnamon extract twice daily for 4 weeks; eight patients aged 35 to 79 (7 women, 1 man) received placebo. The amount of H. pylori colonization was measured by the ¹³C urea breath test before and after therapy.
Results. The mean urea breath test counts in the study and control groups before and after therapy were 22.1 and 23.9 versus 24.4 and 25.9, respectively. The cinnamon extract was well tolerated, and side effects were minimal.
Conclusions. We concluded that cinnamon extract, at a concentration of 80 mg /day as a single agent, is ineffective in eradicating H. pylori. Combination of cinnamon with other antimicrobials, or cinnamon extract at a higher concentration, however, may prove useful.     

Evidence for a signaling system in Helicobacter pylori: detection of a luxS-encoded autoinducer

Helicobacter pylori possesses a homolog of the luxS gene, initially identified by its role in autoinducer production for the quorum-sensing system 2 in Vibrio harveyi. The genomes of several other species of bacteria, notably Escherichia coli, Salmonella enterica serovar Typhimurium, and Vibrio cholerae, also include luxS homologs. All of these bacteria have been shown to produce active autoinducers capable of stimulating the expression of the luciferase operon in V. harveyi. In this report, we demonstrate that H. pylori also synthesizes a functional autoinducer (AI-2) that can specifically activate signaling system 2 in V. harveyi. Maximal activity is produced during early log phase, and the activity is diminished when cells enter stationary phase. We show that AI-2 is not involved in modulating any of the known or putative virulence factors in H. pylori and that a luxS null mutant has a two-dimensional protein profile identical to that of its isogenic parent strain. We discuss the implications of having an AI-2-like quorum-sensing system in H. pylori and suggest possible roles that it may play in H. pylori infection.     

The Influence of Helicobacter pylori Status on Circulating Levels of the Coagulation Factors Fibrinogen, von Willebrand Factor, Factor VII, and Factor VIII

Background. Helicobacter pylori (H. pylori) infection has been associated with an increased risk of developing ischemic heart disease (IHD). It has been suggested that a persisting low-grade acute phase response results from the chronic inflammation caused by H. pylori infection, which may give rise to increased circulating levels of certain coagulation factors.
Materials and Methods. One hundred three (53 male) nonconsecutive, randomly selected white subjects with symptoms of dyspepsia were recruited for study from an outpatient endoscopy clinic at Leeds General Infirmary. The presence of H. pylori was determined by histological and microbiological investigation, a rapid urease test, and a ¹³carbon urea breath test (¹³C-UBT). Fibrinogen was measured by the Clauss method, factor VIII:C (FVIII:C) and factor VII:C (FVII:C) were measured by clotting rate assays, and the von Willebrand factor (vWF) was determined by an enzyme-linked immunosorbent assay.
Results. No difference was found in levels of coagulation factors according to H. pylori status. Multiple regression models were used to account for the effect of covariates and H. pylori status on levels of FVII:C, FVIII:C, vWF, and fibrinogen, and again H. pylori status was not a significant determinant of levels of any of these coagulation factors. No difference occurred in full blood count, platelet count, white cell count, or plasma viscosity in individuals who were H. pylori -positive compared with those who were negative.
Conclusions. H. pylori infection is not associated with increased circulating levels of fibrinogen, FVII:C, vWF.Ag, or FVIII:C or hemorrheology in this patient group.     

Protective effects of vitamin E against hypercholesterolemia-induced age-related diseases

Hypercholesterolemia is a major risk factor for age-related diseases such as atherosclerosis and Alzheimer’s disease (AD). Changes in human plasma cholesterol levels results from the interaction between multiple genetic and environmental factors. The accumulation of excess cholesterol in blood vessels leads to atherosclerosis. Many studies on this field show that differential expression of oxidative stress-related proteins, lipid metabolism-related enzymes, and receptors response to atherogenic diet. Additionally, excess brain cholesterol has been associated with increased formation and deposition of amyloid-β peptide from amyloid precursor protein which may contribute to the risk and pathogenesis of AD. To consider genetically, more than 50 genes have been reported to influence the risk of late-onset AD. Some of these genes might be also important in cholesterol metabolism and transport. Epidemiological studies have shown an association between high intake and high serum concentrations of antioxidant vitamins like vitamin E and lower rates of ischemic heart diseases. It has been known that vitamin E also inhibits smooth muscle cell proliferation by non-antioxidant mechanism. On the basis of the previous results, vitamin E has been accepted as an important protective factor against hypercholesterolemia-induced age-related diseases.     

Production of reactive oxygen species in peripheral blood is increased in individuals with Helicobacter pylori infection and decreased after its eradication

BACKGROUND: Helicobacter pylori infection has been reported to cause gastroduodenal ulcer, mucosa-associated lymphoid tissue lymphoma, and gastric cancer. Recent studies have suggested that H. pylori infection may also associate with other diseases, including hematologic and dermatologic disorders, and cardiovascular injury, by unknown mechanisms. METHODS: Production of reactive oxygen species (ROS) was determined in peripheral blood samples from 86 patients (34 H. pylori-negative and 52 H. pylori-positive subjects) using a highly sensitive chemiluminescence probe, L-012 (8-amino-5-chloro-7-phenylpyrido(3,4-d) pyridazine-1 and 4 (2H, 3H) dione). Eleven H. pylori-positive individuals were also analyzed their ROS production in peripheral blood after H. pylori eradication. RESULTS: ROS production was significantly higher in individuals with H. pylori infection than in those without infection. Enhanced production of ROS was decreased significantly after eradication of H. pylori. No correlation was found between the extent of ROS production and sex, age, smoking status, alcohol ingestion, use of medications, or serum level of C-reactive protein. CONCLUSION: These findings suggest that ROS production was enhanced in peripheral blood by H. pylori infection. Chemiluminescence analysis of blood samples using L-012 permits evaluation of systemic oxidative stress in patients with H. pylori infection.     

胃癌与胃微生态的研究进展

胃癌(gastric cancer)是我国常见恶性肿瘤之一,有着较高的发病率和死亡率。胃癌的发生是一个相对缓慢、多步骤、复杂的过程,可能与幽门螺杆菌(Helicobacter pylori,H.pylori)感染、环境、基因、吸烟等因素相关。随着高通量测序技术和宏基因组学等技术的发展和运用,大量研究表明胃肠道微生物与消化道系统疾病息息相关,其中胃微生物中H.pylori已被明确列为I类致癌因子。除了H.pylori,胃内其他共生菌与胃癌的发生也有密切的联系。本文将通过胃癌与H.pylori感染、胃癌与H.pylori根除、H.pylori与胃微生态、胃癌与胃微生态四个方面综述胃癌与胃微生物的关系,为日后胃癌的研究提供参考。     

Extragastric manifestations of Helicobacter pylori infection

In the previous year, some extragastric diseases, possibly linked to Helicobacter pylori infection, have been largely investigated. There are, in fact, several studies concerning cardiovascular diseases, lung diseases, hematologic diseases, eye and skin diseases, hepatobiliary diseases, diabetes mellitus, and neurological disorders. Among them, the relationship between bacterial CagA positivity and coronary heart disease is reportedly emphasized. Concerning normal tension glaucoma, new interesting data are playing in favor of the association with H. pylori infection. For other diseases, there are many interesting results, although more studies are needed to clarify the reality of the proposed association.     

Role of Helicobacter pylori infection in extragastroduodenal disorders: introductory remarks.

Numerous studies initiated by Warren and Marshall in 1982 confirmed the crucial role of H. pylori infection in the pathogenesis of gastritis, peptic ulcer and possibly also gastric cancer leading to reappraisal of fundamental concept of gastric pathophysiology. These topics were covered, in part, by our previous H. pylori-related symposium I (1995), II (1997) and III (1999) organized in Cracow. H. pylori is one of the most frequent causes of gastroduodenal infection worldwide, resulting in the release of various bacterial and host dependent cytotoxic substances including ammonia, platelet activating factor (PAF), cytotoxins and lipopolysaccharides (LPS) as well as cytokines such as interleukins (IL)-1-12, tumor necrosis factor alpha (TNF(alpha), interferon gamma (INFgamma) and reactive oxygen species (ROS). Recently, several extradigestive pathologies have been linked to H. pylori infection including cardiovascular, cutaneous, autoimmune, esophageal and other diseases such as sideropenic anemia, growth retardation, extragastric MALT-lymphoma etc. The potential role of H. pylori infection in the pathogenesis of these extradigestive disorders has been based on facts that 1) local gastric inflammation may exert systemic effects, 2) chronic infection of gastric mucosa induces immune responses that are able to cause the lesions remote to primary site of infection and 3) H. pylori eradication improves the extradigestive disorders. The aim of present III International Symposium is to provide critical reviews based on personal experience and the available literature about extragastric manifestations of H. pylori infection. The ultimate goal of this symposium is to foster interdisciplinary research and exchange of opinion about the possible involvement of H. pylori in extradigestive pathologies.     

Helicobacter pylori from asymptomatic hosts expressing heptoglycan but lacking Lewis O-chains: Lewis blood-group O-chains may play a role in Helicobacter pylori induced pathology.

Helicobacter pylori is a widespread Gram-negative bacterium responsible for the onset of various gastric pathologies and cancers in humans. A familiar trait of H. pylori is the production of cell-surface lipopolysaccharides (LPSs; O-chain --> core --> lipid A) with O-chain structures analogous to some mammalian histo-blood-group antigens, those being the Lewis determinants (Lea, Leb, Lex, sialyl Lex, Ley) and blood groups A and linear B. Some of these LPS antigens have been implicated as autoimmune, adhesion, and colonization components of H. pylori pathogenic mechanisms. This article describes the chemical structures of LPSs from H. pylori isolated from subjects with no overt signs of disease. Experimental data from chemical- and spectroscopic-based studies unanimously showed that these H. pylori manufactured extended heptoglycans composed of 2- and 3-linked D-glycero-alpha-D-manno-heptopyranose units and did not express any blood-group O-antigen chains. The fact that another H. pylori isolate with a similar LPS structure was shown to be capable of colonizing mice indicates that H. pylori histo-blood-group structures are not an absolute prerequisite for colonization in the murine model also. The absence of O-chains with histo-blood groups may cause H. pylori to become inept in exciting an immune response. Additionally, the presence of elongated heptoglycans may impede exposure of disease-causing outer-membrane antigens. These factors may render such H. pylori incapable of creating exogenous contacts essential for pathogenesis of severe gastroduodenal diseases and suggest that histo-blood groups in the LPS may indeed play a role in inducing a more severe H. pylori pathology.     

Extragastric Manifestations of Helicobacter pylori Infection: Other Helicobacters

The finding that Helicobacter pylori is the main cause of gastritis and peptic ulcer disease has opened a new era in the gastrointestinal world. Today there is evidence that H. pylori may also play a role in different nongastric diseases, opening the new "extragastric manifestations of H. pylori infection" field. Concerning this, several studies have been published in the last year. The most convincing data arise from those investigating idiopathic thrombocytopenic purpura and sideropenic anemia, while there is also an increasing evidence for a possible association with atherosclerotic disease. Furthermore, the discovery of a number of other novel Helicobacter species has stimulated the research in different extragastric diseases, in which an infectious hypothesis is plausible. In particular, several species have been studied for a potential role in different liver and intestinal diseases with interesting findings.