title: Depletion of luminal iron alters the gut microbiota and prevents Crohn's disease-like ileitis.
abstract: BACKGROUND
  Iron replacement therapy is a common treatment in patients with anaemia and Crohn's disease, but oral iron supplements are less tolerated. The pathogenesis of Crohn's disease is attributed to intestinal bacteria and environmental factors that trigger disease in a genetically predisposed host. The aim of this study was to characterise the interrelationship between luminal iron sulfate, systemic iron, the gut microbiota and the development of chronic ileitis in a murine model of Crohn's disease.
  
  
  METHODS
  Wild type (WT) and heterozygous TNF(ΔARE/WT) mice were fed with an iron sulfate containing or iron sulfate free diet in combination with intraperitoneal control injections or iron injections for 11 weeks.
  
  
  RESULTS
  TNF(ΔARE/WT) mice develop severe inflammation of the distal ileum but remained completely healthy when transferred to an iron sulfate free diet, even if iron was systemically repleted. Absence of luminal iron sulfate reduced cellular markers of endoplasmic reticulum (ER) stress responses and pro-apoptotic mechanisms in the ileal epithelium. Phenotype or reactivity of major effector intraepithelial CD8αβ(+) T cells were not altered in the absence of luminal iron. Interestingly, ER stress mechanisms sensitised the small intestinal epithelial cell (IEC) line Mode-K to cytotoxic function of effector T cells from TNF(ARE/WT) mice. Pyrosequencing of 16S rRNA tags of the caecal microbiota revealed that depletion of luminal iron sulfate induced significant compositional alterations, while total microbial diversity (Shannon's diversity index) and number of total operational taxonomic units were not affected.
  
  
  CONCLUSIONS
  This study showed that an iron sulfate free diet in combination with systemic iron repletion prevents the development of chronic ileitis in a murine model of Crohn's disease. Luminal iron may directly affect IEC function or generate a pathological milieu in the intestine that triggers epithelial cell stress-associated apoptosis through changes in microbial homeostasis. These results suggest that oral replacement therapy with iron sulfate may trigger inflammatory processes associated with progression of Crohn's disease-like ileitis.
authors.affiliation: Biofunctionality, Technische Universität München, Freising-Weihenstephan, Germany.
authors.forename: Tanja
authors.initials: T
authors.lastname: Werner
authors.forename: Stefan J
authors.initials: SJ
authors.lastname: Wagner
authors.forename: Inés
authors.initials: I
authors.lastname: Martínez
authors.forename: Jens
authors.initials: J
authors.lastname: Walter
authors.forename: Jung-Su
authors.initials: JS
authors.lastname: Chang
authors.forename: Thomas
authors.initials: T
authors.lastname: Clavel
authors.forename: Sigrid
authors.initials: S
authors.lastname: Kisling
authors.forename: Klaus
authors.initials: K
authors.lastname: Schuemann
authors.forename: Dirk
authors.initials: D
authors.lastname: Haller
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology; D002432:Cecum / Q000382:microbiology*; D002460:Cell Line; D002908:Chronic Disease; D018920:Coculture Techniques; D003424:Crohn Disease / Q000378:metabolism / Q000382:microbiology / Q000517:prevention & control*; D004195:Disease Models, Animal; D004721:Endoplasmic Reticulum / Q000502:physiology; D007079:Ileitis / Q000378:metabolism / Q000382:microbiology / Q000517:prevention & control*; D007082:Ileum / Q000473:pathology; D007413:Intestinal Mucosa / Q000473:pathology; D007501:Iron / Q000494:pharmacology / Q000502:physiology; D000090463:Iron Deficiencies; D019266:Iron, Dietary / Q000008:administration & dosage; D051379:Mice; D008810:Mice, Inbred C57BL; D013312:Stress, Physiological / Q000187:drug effects / Q000502:physiology; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology
chemical_list: D019266:Iron, Dietary; D007501:Iron