title: Low dietary iron intake restrains the intestinal inflammatory response and pathology of enteric infection by food-borne bacterial pathogens.
abstract: Orally administrated iron is suspected to increase susceptibility to enteric infections among children in infection endemic regions. Here we investigated the effect of dietary iron on the pathology and local immune responses in intestinal infection models. Mice were held on iron-deficient, normal iron, or high iron diets and after 2 weeks they were orally challenged with the pathogen Citrobacter rodentium. Microbiome analysis by pyrosequencing revealed profound iron- and infection-induced shifts in microbiota composition. Fecal levels of the innate defensive molecules and markers of inflammation lipocalin-2 and calprotectin were not influenced by dietary iron intervention alone, but were markedly lower in mice on the iron-deficient diet after infection. Next, mice on the iron-deficient diet tended to gain more weight and to have a lower grade of colon pathology. Furthermore, survival of the nematode Caenorhabditis elegans infected with Salmonella enterica serovar Typhimurium was prolonged after iron deprivation. Together, these data show that iron limitation restricts disease pathology upon bacterial infection. However, our data also showed decreased intestinal inflammatory responses of mice fed on high iron diets. Thus additionally, our study indicates that the effects of iron on processes at the intestinal host-pathogen interface may highly depend on host iron status, immune status, and gut microbiota composition.
authors.affiliation: Department of Laboratory Medicine-Translational Metabolic Laboratory, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, The Netherlands.
authors.forename: Guus A M
authors.initials: GA
authors.lastname: Kortman
authors.affiliation: Department of Laboratory Medicine-Translational Metabolic Laboratory, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, The Netherlands.|Mucosal Immunology and Biology Research Center, Massachusetts General Hospital, Boston, MA, USA.
authors.forename: Michelle L M
authors.initials: ML
authors.lastname: Mulder
authors.affiliation: Department of Laboratory Medicine-Translational Metabolic Laboratory, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, The Netherlands.|Mucosal Immunology and Biology Research Center, Massachusetts General Hospital, Boston, MA, USA.
authors.forename: Thijs J W
authors.initials: TJ
authors.lastname: Richters
authors.affiliation: Mucosal Immunology and Biology Research Center, Massachusetts General Hospital, Boston, MA, USA.
authors.forename: Nanda K N
authors.initials: NK
authors.lastname: Shanmugam
authors.affiliation: Mucosal Immunology and Biology Research Center, Massachusetts General Hospital, Boston, MA, USA.
authors.forename: Estela
authors.initials: E
authors.lastname: Trebicka
authors.affiliation: NIZO Food Research B.V, Ede, The Netherlands.
authors.forename: Jos
authors.initials: J
authors.lastname: Boekhorst
authors.affiliation: NIZO Food Research B.V, Ede, The Netherlands.
authors.forename: Harro M
authors.initials: HM
authors.lastname: Timmerman
authors.affiliation: Department of Laboratory Medicine-Translational Metabolic Laboratory, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, The Netherlands.
authors.forename: Rian
authors.initials: R
authors.lastname: Roelofs
authors.affiliation: Department of Laboratory Medicine-Translational Metabolic Laboratory, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, The Netherlands.
authors.forename: Erwin T
authors.initials: ET
authors.lastname: Wiegerinck
authors.affiliation: Department of Laboratory Medicine-Translational Metabolic Laboratory, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, The Netherlands.
authors.forename: Coby M
authors.initials: CM
authors.lastname: Laarakkers
authors.affiliation: Department of Laboratory Medicine-Translational Metabolic Laboratory, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, The Netherlands.
authors.forename: Dorine W
authors.initials: DW
authors.lastname: Swinkels
authors.affiliation: Department of Pharmacy and Pharmacology, University of Bath, Bath, United Kingdom.
authors.forename: Albert
authors.initials: A
authors.lastname: Bolhuis
authors.affiliation: Mucosal Immunology and Biology Research Center, Massachusetts General Hospital, Boston, MA, USA.
authors.forename: Bobby J
authors.initials: BJ
authors.lastname: Cherayil
authors.affiliation: Department of Laboratory Medicine-Translational Metabolic Laboratory, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, The Netherlands.
authors.forename: Harold
authors.initials: H
authors.lastname: Tjalsma
mesh_terms: D000209:Acute-Phase Proteins / Q000096:biosynthesis / Q000276:immunology; D000818:Animals; D001835:Body Weight / Q000276:immunology; D017173:Caenorhabditis elegans / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism / Q000382:microbiology; D044082:Citrobacter rodentium / Q000276:immunology; D004032:Diet / Q000379:methods; D004756:Enterobacteriaceae Infections / Q000276:immunology / Q000378:metabolism / Q000382:microbiology / Q000473:pathology*; D005243:Feces / Q000382:microbiology; D005260:Female; D007113:Immunity, Innate; D007413:Intestinal Mucosa / Q000276:immunology / Q000378:metabolism / Q000382:microbiology / Q000473:pathology*; D007422:Intestines / Q000276:immunology / Q000382:microbiology / Q000473:pathology*; D019266:Iron, Dietary / Q000008:administration & dosage* / Q000009:adverse effects; D039841:Leukocyte L1 Antigen Complex / Q000096:biosynthesis / Q000276:immunology; D000071068:Lipocalin-2; D054834:Lipocalins / Q000096:biosynthesis / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D015513:Oncogene Proteins / Q000096:biosynthesis / Q000276:immunology; D012481:Salmonella Infections, Animal / Q000276:immunology / Q000378:metabolism* / Q000382:microbiology / Q000401:mortality; D012486:Salmonella typhimurium / Q000276:immunology; D016019:Survival Analysis
chemical_list: D000209:Acute-Phase Proteins; D019266:Iron, Dietary; D039841:Leukocyte L1 Antigen Complex; D000071068:Lipocalin-2; D054834:Lipocalins; D015513:Oncogene Proteins; C071332:Lcn2 protein, mouse
keywords: Caenorhabditis elegans; gut microbiome; intestinal pathogens; iron supplementation; lipocalin-2