Review: Helicobacter pylori and extragastric diseases

In the last year, many studies have demonstrated a potential role of Helicobacter pylori in the pathogenic mechanisms of different extragastric diseases. While the role of H pylori in idiopathic thrombocytopenic purpura, idiopathic iron deficiency anemia, and vitamin B12 deficiency has already been demonstrated, there is growing evidence of other related conditions, especially cardiovascular, metabolic, and neurologic disorders, including neurodegenerative diseases. A summary of the results of the most relevant studies published over the last year on this attractive topic is presented in this review.     

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.     

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.     

Non-Helicobacter pylori helicobacters detected in the stomach of humans comprise several naturally occurring Helicobacter species in animals

Besides the well-known gastric pathogen Helicobacter pylori , other Helicobacter species with a spiral morphology have been detected in a minority of human patients who have undergone gastroscopy. The very fastidious nature of these non- Helicobacter pylori helicobacters (NHPH) makes their in vitro isolation difficult. These organisms have been designated ' Helicobacter heilmannii '. However, sequencing of several genes detected in NHPH-infected tissues has shown that the ' H. heilmannii ' group comprises at least five different Helicobacter species, all of them known to colonize the stomach of animals. Recent investigations have indicated that Helicobacter suis is the most prevalent NHPH species in human. This species has only recently been isolated in vitro from porcine stomach mucosa. Other NHPH that colonize the human stomach are Helicobacter felis, Helicobacter bizzozeronii, Helicobacter salomonis and ' Candidatus Helicobacter heilmannii'. In numerous case reports of human gastric NHPH infections, no substantial information is available about the species status of the infecting strain, making it difficult to link the species with certain pathologies. This review aims to clarify the complex nomenclature of NHPH species associated with human gastric disease and their possible animal origin. It is proposed to use the term 'gastric NHPH' to designate gastric spirals that are morphologically different from H. pylori when no identification is available at the species level. Species designations should be reserved for those situations in which the species is defined.     

Helicobacter spp. Other Than Helicobacter pylori

Non- H. pylori Helicobacter species (NHPHS) are associated with several important human and animal diseases. In the past year research into this group of bacteria has continued to gain attention, and novel species have been described in new niches owing to improvements in detection methods. Polymerase chain reaction and/or sequencing remain the gold standard for the detection of this genus. New insights into the pathogenesis of the NHPHS in hepatobiliary, gastric, and intestinal diseases were gained. In particular, data revealed interaction between hepatic steatosis and infectious hepatitis in the development of hepatocellular carcinoma. Evidence of an association between hepatitis C virus and Helicobacter spp. in hepatocarcinoma development was also provided; and male sex hormone signaling appeared to influence infectious hepatitis induced by Helicobacter hepaticus . More findings support an association between Helicobacter heilmannii and gastric adenocarcinoma; and in mice, mucins MUC4 and MUC5 but not MUC1 influence the colonization and pathogenesis of Helicobacter felis . Data indicated that the roles of the adaptive immune system in H. hepaticus -induced intestinal tumorigenesis are different in the small and large intestines, and environmental factors, such as bile acids may modulate H. hepaticus carcinogenic potential. New reports in the prevention and eradication of NHPHS showed a protective response against Helicobacter suis induced by vaccine administration, and a successful cross-foster rederivation method successfully eradicated Helicobacter spp. from contaminated mice litters. Overall, the studies provided insights into the pathophysiology of Helicobacter species other than Helicobacter pylori.     

幽门螺杆菌动物模型研究进展

幽门螺杆菌动物模型用于HP相关疾病和HP疫苗作用的研究。常规实验动物包括悉生猪、悉生狗、非人类灵长动物、猫、雪貂、小鼠、大鼠、沙鼠等。猫螺杆菌和雪貂螺杆菌感染也被用于模型研究。最近,转基因小鼠和基因敲除小鼠也被用作幽门螺杆菌动物模型研究。     

Comparative chemical and biological characterization of the lipopolysaccharides of gastric and enterohepatic helicobacters

BACKGROUND: The lipopolysaccharide of Helicobacter pylori plays an important role in colonization and pathogenicity. The present study sought to compare structural and biological features of lipopolysaccharides from gastric and enterohepatic Helicobacter spp. not previously characterized. MATERIALS AND METHODS: Purified lipopolysaccharides from four gastric Helicobacter spp. (H. pylori, Helicobacter felis, Helicobacter bizzozeronii and Helicobacter mustelae) and four enterohepatic Helicobacter spp. (Helicobacter hepaticus, Helicobacter bilis, 'Helicobacter sp. flexispira' and Helicobacter pullorum) were structurally characterized using electrophoretic, serological and chemical methods. RESULTS: Structural insights into all three moieties of the lipopolysaccharides, i.e. lipid A, core and O-polysaccharide chains, were gained. All species expressed lipopolysaccharides bearing an O-polysaccharide chain, but H. mustelae and H. hepaticus produced truncated semirough lipopolysaccharides. However, in contrast to lipopolysaccharides of H. pylori and H. mustelae, no blood group mimicry was detected in the other Helicobacter spp. examined. Intra-species, but not interspecies, fatty acid profiles of lipopolysaccharides were identical within the genus. Although shared lipopolysaccharide-core epitopes with H. pylori occurred, differing structural characteristics were noted in this lipopolysaccharide region of some Helicobacter spp. The lipopolysaccharides of the gastric helicobacters, H. bizzozeronii and H. mustelae, had relative Limulus amoebocyte lysate activities which clustered around that of H. pylori lipopolysaccharide, whereas H. bilis, 'Helicobacter sp. flexispira' and H. hepaticus formed a cluster with approximately 1000-10,000-fold lower activities. H. pullorum lipopolysaccharide had the highest relative Limulus amoebocyte lysate activity of all the helicobacter lipopolysaccharides (10-fold higher than that of H. pylori lipopolysaccharide), and all the lipopolysaccharides of enterohepatic Helicobacter spp. were capable of inducing nuclear factor-Kappa B(NF-kappaB) activation. CONCLUSIONS: The collective results demonstrate the structural heterogeneity and pathogenic potential of lipopolysaccharides of the Helicobacter genus as a group and these differences in lipopolysaccharides may be indicative of adaptation of the bacteria to different ecological niches.     

An alternative, sensitive method to detect Helicobacter pylori DNA in feces

Background: Despite the high sensitivity and specificity of PCR, detection of Helicobacter pylori DNA in feces is still challenging. Fecal samples contain inhibitory molecules that can prevent amplification of the target DNA. Even by using specific DNA extraction kits for stools, monitoring of infection by analyzing stool samples remains problematic and endorses the need for improved diagnostic methods. Materials and Methods: The newly proposed method uses selective hybridization of target DNA with biotin‐labeled probes, followed by DNA isolation with streptavidin‐coated magnetic beads. After three washing steps, the purified DNA can be amplified immediately using conventional or quantitative PCR. In order to test this technique on biological samples, Mongolian gerbils were infected with H. pylori ATCC 43504 and fecal samples were analyzed on days 1, 4, and 10 post infection. Results: A detection limit of one bacterial cell per 100 mg stool sample was established, but only after removal of the magnetic beads from the target DNA by heating. This resulted in a 10‐fold increase of sensitivity compared to a commercially available stool DNA extraction kit. Analysis of fecal samples from infected gerbils demonstrated the presence of H. pylori DNA on each time point, while the uninfected animal remained negative. Conclusions: The proposed technique allows detection of very low quantities of H. pylori DNA in biological samples. In laboratory animal models, detailed monitoring of infection and complete clearance of infection can be demonstrated thanks to the low detection limit.     

Impact of reactive oxygen species generation on Helicobacter pylori-related extragastric diseases: a hypothesis

Helicobacter pylori (H. pylori) induces reactive oxygen species (ROS) production that contribute to pathogenesis of a variety of H. pylori-related gastric diseases, as shown in animal and human studies. Helicobacter pylori infection is also associated with variety of systemic extragastric diseases in which H. pylori-related ROS production might also be involved in the pathogenesis of these systemic conditions. We proposed that Hp-related ROS may play a crucial role in the pathophysiology of Hp-related systemic diseases including Alzheimer’s disease, multiple sclerosis, glaucoma and other relative neurodegenerative diseases, thereby suggesting introduction of relative ROS scavengers as therapeutic strategies against these diseases which are among the leading causes of disability and are associated with a large public health global burden. Moreover, we postulated that H. pylori-related ROS might also be involved in the pathogenesis of extragastric common malignancies, thereby suggesting that H. pylori eradication might inhibit the development or delay the progression of aforementioned diseases. However, large-scale future studies are warranted to elucidate the proposed pathophysiological mechanisms, including H. pylori-related ROS, involved in H. pylori-associated systemic and malignant conditions.     

Helicobacter pylori and Non-malignant Diseases

In 2007 Helicobacter pylori research continued to deal with some controversies raised in the last decade. The main problems remain unsolved: peptic ulcer disease negative for H. pylori , synergism of H. pylori infection and aspirin and other nonsteroidal anti-inflammatory drugs or cyclooxygenase 2 specific inhibitors, the role of H. pylori eradication in uninvestigated and nonulcer dyspepsia, and the possible protective effect of H. pylori infection against gastroesophageal reflux disease and its complications such as Barrett's esophagus and adenocarcinoma. The incidence and prevalence of peptic ulcer disease as well as ulcer-related mortality are continuing to decline all over the world. The increasing consumption of anti-inflammatory and antisecretory drugs was not found to change the trend over the last period and therefore H. pylori was considered the key factor in causing ulcer-related mortality. Some progress has been achieved in understanding H. pylori -induced immunological processes, and attack mechanisms, as well as specific pathogenesis in uremic and cirrhotic patients. There is still a lot to learn about the bacterium and host factors related to H. pylori infection and its complications.     

幽门螺杆菌：掀起对胃十二指肠病认识的革命

近些年来有关幽门螺杆菌的科研活动和出版物大量涌现,形成爆炸之势。现已公认,幽门螺杆菌是胃十二指肠疾病的罪魁祸首。大多数消化性溃疡、慢性胃炎和一些胃癌,是由此菌引起的。将近一个世纪以来医学界的古老信条：“无酸则无溃疡”,或将由“无幽门螺杆菌感染则无溃疡”所代替。根治胃十二指肠病的诱人前景,即将成为事实。因此可以说,幽门螺杆菌的发现,是对胃十二指肠疾病认识的一次革命。