title: Helicobacter pylori Infection Induces Anemia, Depletes Serum Iron Storage, and Alters Local Iron-Related and Adult Brain Gene Expression in Male INS-GAS Mice.
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.
authors.affiliation: Division of Comparative Medicine, Massachusetts Institute of Technology, Cambridge, Massachusetts, United States of America.
authors.forename: Monika
authors.initials: M
authors.lastname: Burns
authors.affiliation: Division of Comparative Medicine, Massachusetts Institute of Technology, Cambridge, Massachusetts, United States of America.
authors.forename: Sureshkumar
authors.initials: S
authors.lastname: Muthupalani
authors.affiliation: Division of Comparative Medicine, Massachusetts Institute of Technology, Cambridge, Massachusetts, United States of America.
authors.forename: Zhongming
authors.initials: Z
authors.lastname: Ge
authors.affiliation: Department of Medicine, Columbia University, New York, New York, United States of America.
authors.forename: Timothy C
authors.initials: TC
authors.lastname: Wang
authors.affiliation: Division of Comparative Medicine, Massachusetts Institute of Technology, Cambridge, Massachusetts, United States of America.
authors.forename: Vasudevan
authors.initials: V
authors.lastname: Bakthavatchalu
authors.affiliation: Division of Comparative Medicine, Massachusetts Institute of Technology, Cambridge, Massachusetts, United States of America.|School of Medicine and Dentistry, University of Aberdeen, Aberdeen, Scotland, United Kingdom.
authors.forename: Catriona
authors.initials: C
authors.lastname: Cunningham
authors.affiliation: Division of Neonatology, Department of Pediatrics, University of Minnesota Medical School, Minneapolis, Minnesota, United States of America.
authors.forename: Kathleen
authors.initials: K
authors.lastname: Ennis
authors.affiliation: Division of Neonatology, Department of Pediatrics, University of Minnesota Medical School, Minneapolis, Minnesota, United States of America.
authors.forename: Michael
authors.initials: M
authors.lastname: Georgieff
authors.affiliation: Division of Comparative Medicine, Massachusetts Institute of Technology, Cambridge, Massachusetts, United States of America.|Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, Massachusetts, United States of America.
authors.forename: James G
authors.initials: JG
authors.lastname: Fox
mesh_terms: D000740:Anemia / Q000097:blood / Q000382:microbiology*; D000818:Animals; D001921:Brain / Q000378:metabolism*; D019208:Brain-Derived Neurotrophic Factor / Q000378:metabolism; D048429:Cell Size; D016207:Cytokines / Q000235:genetics / Q000378:metabolism; D004912:Erythrocytes / Q000502:physiology; D041905:Erythroid Cells / Q000378:metabolism; D004921:Erythropoietin / Q000097:blood; D005293:Ferritins / Q000097:blood; D005753:Gastric Mucosa / Q000378:metabolism; D005756:Gastritis / Q000097:blood / Q000382:microbiology; D015870:Gene Expression; D016481:Helicobacter Infections / Q000097:blood / Q000150:complications*; D016480:Helicobacter pylori / Q000502:physiology*; D054884:Host-Pathogen Interactions; D019266:Iron, Dietary / Q000097:blood*; D008297:Male; D051379:Mice; D004676:Myelin Basic Protein / Q000097:blood; D009928:Organ Specificity; D013270:Stomach / Q000382:microbiology; D015854:Up-Regulation
chemical_list: D019208:Brain-Derived Neurotrophic Factor; D016207:Cytokines; D019266:Iron, Dietary; D004676:Myelin Basic Protein; D004921:Erythropoietin; D005293:Ferritins