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Depletion of luminal iron alters the gut microbiota and prevents Crohn's disease-like ileitis
  1. Tanja Werner1,
  2. Stefan J Wagner1,
  3. Inés Martínez2,
  4. Jens Walter2,
  5. Jung-Su Chang1,
  6. Thomas Clavel1,
  7. Sigrid Kisling1,
  8. Klaus Schuemann3,
  9. Dirk Haller1
  1. 1Chair for Biofunctionality, ZIEL – Research Center for Nutrition and Food Science, CDD – Center for Diet and Disease, Technische Universität München, Freising-Weihenstephan, Germany
  2. 2Department of Food Science and Technology, University of Nebraska, 333 Food Industry Complex, Lincoln, Nebraska, USA
  3. 3Molecular Nutrition Unit, ZIEL – Research Center for Nutrition and Food Science, Technische Universität München, Freising-Weihenstephan, Germany
  1. Correspondence to Professor Dirk Haller, Biofunctionality, Technische Universität München, Gregor-Mendel-Str. 2, 85350 Freising-Weihenstephan, Germany; haller{at}


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 TNFΔARE/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 TNFΔARE/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.

Conclusion 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.

  • Iron
  • Crohn's disease
  • microbiota
  • endoplasmic reticulum stress
  • inflammatory bowel disease
  • intestinal epithelium
  • iron nutrition
  • stress

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  • See Commentary, p 287

  • Linked articles 229047.

  • Funding German Research Foundation (DFG) GRK 1482.

  • Competing interests None.

  • Ethics approval The animal-use protocols were approved by the Bavarian Animal Care and Use Committee (AZ 55.2-1-54-2531-74-06).

  • Provenance and peer review Not commissioned; externally peer reviewed.

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