Abstract
Iron deficiency anemia (IDA) affects > 500 million people worldwide, and is linked to impaired cognitive development and function in children. Helicobacter pylori, a class 1 carcinogen, infects about half of the world’s population, thus creating a high likelihood of overlapping risk. This study determined the effect of H. pylori infection on iron homeostasis in INS-GAS mice. Two replicates of INS-GAS/FVB male mice (n = 9-12/group) were dosed with H. pylori (Hp) strain SS1 or sham dosed at 6–9 weeks of age, and were necropsied at 27–29 weeks of age. Hematologic and serum iron parameters were evaluated, as was gene expression in gastric and brain tissues. Serum ferritin was lower in Hp SS1-infected mice than uninfected mice (p < 0.0001). Infected mice had a lower red blood cell count (p<0.0001), hematocrit (p < 0.001), and hemoglobin concentration (p <0.0001) than uninfected mice. Relative expression of gastric hepcidin antimicrobial peptide (Hamp) was downregulated in mice infected with Hp SS1 compared to sham-dosed controls (p<0.001). Expression of bone morphogenic protein 4 (Bmp4), a growth factor upstream of hepcidin, was downregulated in gastric tissue of Hp SS1-infected mice (p<0.001). Hp SS1-infected mice had downregulated brain expression of tyrosine hydroxylase (Th) (p = 0.02). Expression of iron-responsive genes involved in myelination (myelin basic protein (Mbp) and proteolipid protein 2 (Plp2)) was downregulated in infected mice (p = 0.001 and p = 0.02). Expression of synaptic plasticity markers (brain derived neurotrophic factor 3 (Bdnf3), Psd95 (a membrane associated guanylate kinase), and insulin-like growth factor 1 (Igf1)) was also downregulated in Hp SS1-infected mice (p = 0.09, p = 0.04, p = 0.02 respectively). Infection of male INS-GAS mice with Hp SS1, without concurrent dietary iron deficiency, depleted serum ferritin, deregulated gastric and hepatic expression of iron regulatory genes, and altered iron-dependent neural processes. The use of Hp SS1-infected INS-GAS mice will be an appropriate animal model for further study of the effects of concurrent H. pylori infection and anemia on iron homeostasis and adult iron-dependent brain gene expression.
Highlights
Despite eradication efforts within defined groups and its decline due to improved socio-economic conditions over the past 20 years, Helicobacter pylori infection remains prevalent worldwide, with infection rates ranging from approximately 20 to 80% in developed and developing countries respectively [1,2,3]
Serum ferritin concentration was significantly lower in mice infected with H. pylori SS1 when compared to sham-dosed control mice (Fig 1) (p
The World Health Organization uses serum ferritin in the screening and diagnosis of Iron deficiency (ID) and iron deficiency anemia (IDA), and describes this assay as “the most specific biochemical test that correlates with relative total body iron stores”[46, 47]
Summary
Despite eradication efforts within defined groups and its decline due to improved socio-economic conditions over the past 20 years, Helicobacter pylori infection remains prevalent worldwide, with infection rates ranging from approximately 20 to 80% in developed and developing countries respectively [1,2,3]. Infection with H. pylori results in gastric inflammation, and may lead to clinical outcomes including peptic ulcers, atrophic gastritis, and gastric cancer [4,5,6]. A multitude of extragastric effects of H. pylori infection have been hypothesized, many of which have not been completely defined [8]. These extragastric disorders may be directly caused by or related to H. pylori infection, and include endocrine disorders, ischemic diseases, and neurological disorders, among others [8]. Eradication of H. pylori improves iron status and anemia in human patients with IDA [10]. Since the populations most likely to be affected by H. pylori and ID overlap throughout much of the developing world, there is a need to better understand the potential clinical sequelae that could result from H. pylori infection and ID co-morbidity
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