Helicobacter pylori Infection and Iron Stores: A Systematic Review and Meta-analysis

Background and Aims:  We carried out a systematic literature review and meta-analysis to evaluate the existing evidence on the association between Helicobacter pylori infection and iron stores.
Methods:  Twelve case reports and case series, 19 observational epidemiologic studies and six intervention trials were included in the review.
Results:  Although only few studies controlled for multiple potential confounders, most studies reported a positive association, linking between H. pylori and decreased body iron stores in symptomatic and asymptomatic H. pylori -infected subjects. H. pylori infection may be regarded as a risk factor for reduction in body iron stores and also for iron deficiency or iron deficiency anemia, especially in high-risk groups. The results of the meta-analysis of thoroughly designed and analyzed studies revealed an increased risk for iron deficiency anemia; pooled odds ratio (OR) 2.8 (95% confidence interval (CI) 1.9, 4.2) and also for iron deficiency; pooled OR 1.38 (95%CI 1.16–1.65) among H. pylori -infected subjects. The biologic mechanism by which H. pylori induces the alteration in the iron stores is not fully understood, but it seems to involve several pathways, including gastrointestinal blood loss, decrease in the absorption of dietary iron, and enhanced uptake of the iron by the bacterium.
Conclusions:  H. pylori is associated with reduced iron stores. Future research is needed to determine whether this relationship is a causal association and to better understand its biologic mechanism. The impact of anti- H. pylori therapy on improvement of iron stores needs to be further evaluated in large and well-controlled trials.     

Extragastric manifestations of Helicobacter pylori infection--other Helicobacter species

Recent studies have indicated a strong link between Helicobacter pylori and idiopathic thrombocytopenic purpura and iron deficiency anemia. Interesting results have also been obtained for ischemic heart disease, though most putative associations between H. pylori infection and extragastric disease remain speculative. With regard to other Helicobacter species, Helicobacter felis has been shown to play a role in gastric carcinogenesis in mouse models. An increased susceptibility to cholesterol gallstone formation has been described in animals fed a lithogenic diet and infected with Helicobacter bilis, or co-infected with Helicobacter hepaticus and Helicobacter rodentium. Finally, enterohepatic Helicobacter species have also been exploited to better understand inflammatory bowel disease.     

The effect of Helicobacter pylori infection and dietary iron deficiency on host iron homeostasis: a study in mice

BACKGROUND: Helicobacter pylori, which requires iron to survive, may cause host iron deficiency by directly competing with the host for available iron or by impairing iron uptake as a consequence of atrophy-associated gastric hypochlorhydria. The aim of this study was to examine the effect of H. pylori infection and dietary iron deficiency on host iron homeostasis in a mouse model. MATERIALS AND METHODS: H. pylori SS1-infected and uninfected C57BL/6 mice, fed either a normal diet or an iron-deficient diet, were assessed for iron status and infection-associated gastritis over a 30-week period. RESULTS: After 10 weeks, serum ferritin values were higher in H. pylori-infected mice than in uninfected controls, irrespective of dietary iron intake (p = .04). The infection-related increase in body iron stores persisted in the iron-replete mice but diminished over time in mice with restricted dietary iron intake (p < .0001). At 30 weeks serum ferritin levels were lower in these animals (p = .063). No significant difference in bacterial numbers was detected at the 30-week time point (p > .05) and the histological changes observed were consistently associated with infection (p < .01) and not with the iron status of the mice (p = .771). CONCLUSIONS: Infection with H. pylori did not cause iron deficiency in iron-replete mice. However, diminished iron stores in mice as a result of limited dietary iron intake were further lowered by concurrent infection, thus indicating that H. pylori competes successfully with the host for available iron.     

Helicobacter felis infection causes an acute iron deficiency in nonpregnant and pregnant mice

BACKGROUND: The role of Helicobacter pylori infection in iron deficiency during pregnancy is limited. The aim of the present study was to assess the relationship between Helicobacter infection and levels of iron stores in pregnant mice. MATERIALS AND METHODS: Female C57BL/6 mice were either inoculated with 10(8) H. pylori, Helicobacter felis or water. In the nonpregnant study, 15 mice from each group were sacrificed after 4 and 20 weeks of infection. In the pregnancy study, after 6 weeks of infection all female mice were mated and approximately 2 weeks after mating, half of the pregnant mice (n = 9/group) from each group were sacrificed. The remaining mice were allowed to give birth, and approximately 4 weeks after birth, mice were asphyxiated with CO2, followed by heart puncture, and killed by cervical dislocation. Serum ferritin and iron were determined with a micro-particle enzyme immunoassay method and by a timed-endpoint method. RESULTS: Serum iron levels in mice infected with H. felis were significantly (p < .05) lowered compared to control (24%) and H. pylori (27%)-infected mice at 4 weeks of infection. Serum iron in the control, H. pylori and H. felis groups were significantly (p < .05) elevated at 20 weeks by 39, 26 and 77%, respectively, compared to 4 weeks of infection. H. felis-infected mice had a significantly (p < .05) decreased serum ferritin level during pregnancy (61%) compared to H. pylori-infected mice. CONCLUSION: These results suggest that H. felis but not H. pylori infection causes an acute iron deficiency in normal and pregnant mice.     

Children of Helicobacter pylori-infected dyspeptic mothers are predisposed to H. pylori acquisition with subsequent iron deficiency and growth retardation

BACKGROUND: We tested whether Helicobacter pylori-infected dyspeptic mothers had a higher rate of H. pylori infection in their children, and whether such H. pylori-infected children were predisposed to iron deficiency or growth retardation. MATERIALS AND METHODS: A total of 163 children from 106 dyspeptic mothers (58 with and 48 without H. pylori infection) were enrolled to evaluate body weight, height, hemoglobin, serum ferritin, and H. pylori infection using the 13C-urea breath test. A questionnaire was used to evaluate demographic factors of each child. RESULTS: The rate of H. pylori infection in children with H. pylori-infected dyspeptic mothers was higher than that of children with noninfected mothers (20.5% vs. 5.3%; p<.01, OR: 4.6, 95% CI: 1.5-14.2). The rate of H. pylori infection in children elevated as the number of their H. pylori-infected siblings increased (p<.01). For children below 10 years of age, H. pylori infection was closely related to low serum ferritin and body weight growth (p<.05). CONCLUSION: The children of H. pylori-infected dyspeptic mothers had an increased risk for such infection. The risk further increased once their siblings were infected. H. pylori infection in pre-adolescent children may determine iron deficiency and growth retardation.     

The Effect of the Human Gut-Signalling Hormone, Norepinephrine, on the Growth of the Gastric Pathogen Helicobacter pylori

Background and Aims: Helicobacter pylori is an important human pathogen, infecting around half the population of the world. It has developed a number of refinements to allow it to persist in the human stomach. Catecholamine hormones have been shown to enhance growth of other bacterial species and are found in the gastric niche. We aimed to study growth enhancement of H. pylori by the human catecholamine hormones epinephrine and norepinephrine.
Methods: Growth studies were carried out in complex and defined media containing the hormones epinephrine, norepinephrine, and normetanephrine, the main host metabolite of norepinephrine. Bacterial density was measured by viable count or optical density. Intracellular ATP was measured using a bioluminescence assay technique.
Results: Both epinephrine and norepinephrine enhanced H. pylori growth in a dose-dependent strain-independent fashion, with norepinephrine being more effective than epinephrine. We showed a rapid (4 hours) dose-dependent effect on metabolic activity, as measured by intracellular ATP levels. We used a chemically defined medium to study mechanisms: chelation of ferric iron blocked H. pylori growth, which could be overcome by addition of norepinephrine. Disruption of the catechol group of norepinephrine abrogated its H. pylori- growth-promoting activity.
Conclusions: Norepinephrine stimulates growth of H. pylori under otherwise growth-restricted conditions, and this effect is related to the ability of norepinephrine to bind ferric iron. This supports the notion that norepinephrine may aid H. pylori persistence in the stomach.     

Nutrients released by gastric epithelial cells enhance Helicobacter pylori growth

BACKGROUND: Helicobacter pylori survives and proliferates in the human gastric mucosa. In this niche, H. pylori adheres to the gastric epithelial cells near the tight junctions. In vitro, H. pylori proliferated well in tissue-culture medium near gastric epithelial cells. However, in the absence of epithelial cells, growth of H. pylori could only be established in tissue-culture medium when, prior to the experiment, it was preincubated near gastric epithelial cells. Therefore, we aimed to determine whether diffusion of nutrients derived from epithelial cells was required for H. pylori growth in Dulbecco's modified Eagle's minimal essential medium (DMEM) cell culture medium. MATERIALS AND METHODS: Cell culture conditions essential for H. pylori growth in vitro were determined with gastric epithelial HM02 cells. RESULTS: Deprivation of iron in cell-culture-conditioned DMEM resulted in a growth arrest of H. pylori. However, near gastric epithelial cells, growth of H. pylori was resistant to iron deprivation. Evidently, when residing close to epithelial cells, H. pylori was able to fulfil its iron requirements, even when the DMEM was deprived of iron. Nevertheless, supplementation with iron alone did not restore H. pylori growth in DMEM, hence other nutrients were deficient as well in the absence of epithelial cells. Growth of H. pylori in DMEM was restored when hypoxanthine, L-alanine and L-proline were added to the DMEM. CONCLUSIONS: Diffusion of (precursors of) these nutrients from the gastric epithelial cells is essential for H. pylori growth in vitro. We hypothesize that in vivo, H. pylori favors colonization near the tight junctions, to gain maximal access to the nutrient(s) released by gastric epithelial cells.     

Epidemiology of Helicobacter pylori: transmission, translocation and extragastric reservoirs.

Although H. pylori infection is endemic and despite more than 10 years of research, the mode and route of transmission remain elusive. This may, in part, be due to the inherent problems of detecting H. pylori noninvasively. The prevalence of infection varies between countries and is closely related to Growth Domestic Product. An age-cohort effect and data from longitudinal studies suggest that the incidence of infection is much higher in children than adults. In developing countries the prevalence of infection is often more than 80% in young adults, in contrast to less than 10% for similar age groups in developed countries. The observations of mosaicism (in the VacA gene) and a panmycytic population structure imply exchange of genetic material either in or outside of the host, which is supported by the increasing recognition of polyclonal infection and suggests that secondary infection occurs after primary acquisition. In addition, in children persistent primary infection may sometimes occur only after previous (repeated) exposure and/or transient colonisation of the gastric mucosa. H. pylori and other gastric Helicobacter spp are always noninvasive, but other human nongastric Helicobacter spp have sometimes been isolated from the systemic circulation in immunocompromised patients. For nonhuman hosts, intestinal Helicobacter spp are thought to translocate more frequently from the colon to the liver. Within the human host, the oral cavity is the principal extragastric reservoir, although case reports suggest that H. pylori may sometimes be found beyond the 2nd part of the duodenum. The hypothesis that H. pylori is a zoonosis or transmitted as coccoid forms by a vector (pets, houseflies) is not supported by recent research showing that H. pylori is entirely unable to support an aerobic or anaerobic metabolism and that coccoid forms are non-viable. H. pylori is primarily acquired in infancy, most probably via the oroorogastric route, from other family members or close contacts encountered after weaning or socialisation. Further studies to support or refute this hypothesis are required.     

Extragastric Manifestations of Helicobacter pylori Infection

In the last year, different diseases possibly linked to Helicobacter pylori infection but localized outside of the stomach have been investigated. There are, in fact, several studies concerning cardiovascular diseases, hematologic disorders, neurologic diseases, metabolic, hepatobiliary diseases, and other conditions. Some of those studies, such as those on sideropenic anemia and idiopathic thrombocytopenic purpura, are quite large and well conducted, while in other cases there are just small or isolated studies or even case reports. Nonetheless, there is much interest among researchers all over the world for such a topic as demonstrated by the large number of studies published in the last year.     

The Expression of Iron-repressible Outer Membrane Proteins in Helicobacter pylori and Its Association with Iron Deficiency Anemia

Background: Helicobacter pylori infection is known to be a cause of iron deficiency anemia (IDA) that is unresponsive to iron supplements. H. pylori bind iron to a specific receptor by iron-repressible outer membrane proteins (IROMPs) under conditions of restricted iron.
Materials and Methods: We compared the expression of IROMPs from strains of H. pylori under both iron-restricted and iron-supplemented conditions to determine the difference between strains with and without IDA. One standard strain, two clinical strains, and three IDA strains were cultured; and then the IROMPs were extracted under iron-restricted and iron-supplemented conditions. We used SDS-PAGE to compare the expression of the IROMPs from each strain.
Results:  IROMPs were found in IDA strains under iron-restricted conditions and their molecular sizes were estimated to be 56, 48, 41, and 37 kDa. In the iron-repleted media, the IROMPs were no longer present.
Conclusion: In the iron-depleted state, specific H. pylori strains associated with IDA demonstrated an advantage in iron acquisition due to a higher expression of IROMPs. Our results can explain in part why some patients with H. pylori infection are more prone to develop clinical IDA under restricted iron conditions in the host.