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Original article
Dietary haem stimulates epithelial cell turnover by downregulating feedback inhibitors of proliferation in murine colon
  1. Noortje IJssennagger1,2,
  2. Anneke Rijnierse1,2,
  3. Nicole de Wit1,3,
  4. Denise Jonker-Termont1,4,
  5. Jan Dekker1,
  6. Michael Müller1,2,3,
  7. Roelof van der Meer1,2
  1. 1Top Institute Food and Nutrition, Wageningen, The Netherlands
  2. 2Nutrition, Metabolism and Genomics Group, Division of Human Nutrition, Wageningen University, Wageningen, The Netherlands
  3. 3Netherlands Nutrigenomics Centre, Wageningen, The Netherlands
  4. 4NIZO Food Research, Health Department, Ede, The Netherlands
  1. Correspondence to Noortje IJssennagger, Nutrition, Metabolism and Genomics Group, Division of Human Nutrition, Wageningen University, Bomenweg 2, NL-6703 HD Wageningen, The Netherlands; noortje.ijssennagger{at}


Objective Colon cancer is a leading cause of cancer deaths in Western countries and is associated with diets high in red meat. Haem, the iron-porphyrin pigment of red meat, induces cytotoxicity of gut contents and damages the colon surface epithelium. Compensatory hyperproliferation leads to epithelial hyperplasia which increases the risk of colon cancer. The aim of this study was to identify molecules signalling from the surface epithelium to the crypt to initiate hyperproliferation upon stress induced by haem.

Methods C57Bl6/J mice (n=9/group) received a ‘westernised’ control diet (40 en% fat) with or without 0.5 μmol/g haem for 14 days. Colon mucosa was used to quantify cell proliferation and for microarray transcriptome analysis. Gene expression profiles of surface and crypt cells were compared using laser capture microdissection. Protein levels of potential signalling molecules were quantified.

Results Haem-fed mice showed epithelial hyperproliferation and decreased apoptosis, resulting in hyperplasia. Microarray analysis of the colon mucosa showed 3710 differentially expressed genes (false discovery rate (q) <0.01), with many involved in the cell cycle. Expression levels of haem- and stress-related genes showed that haem affected surface cells but did not directly affect crypt cells. Injured surface cells should therefore signal to crypt cells to induce compensatory hyperproliferation. Haem downregulated the inhibitors of proliferation, Wnt inhibitory factor 1, Indian Hedgehog and bone morphogenetic protein 2. Interleukin-15 was also downregulated. Haem upregulated amphiregulin, epiregulin and cyclo-oxygenase-2 mRNA in surface cells. Their protein/metabolite levels were, however, not increased as haem induced surface-specific inhibition of translation by increasing 4E-BP1.

Conclusions Haem induces colonic hyperproliferation and hyperplasia by inhibiting the surface to crypt signalling of feedback inhibitors of proliferation.

  • Colon cancer
  • cytotoxic stress
  • translation inhibition
  • Wnt inhibitory factor 1
  • dietary—colon cancer
  • cell signalling
  • nutrition
  • epithelial proliferation
  • intestinal stem cell

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  • Funding This study was funded by the program council of TIFN (grant A-1001). The council had no vote in study design, data collection and analysis, preparation of the manuscript or decision to publish.

  • Competing interests None.

  • Ethics approval The experiments were approved by the Ethical Committee on Animal Testing of Wageningen University and were in accordance with national law.

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

  • Data sharing statement Array data have been submitted to the Gene Expression Omnibus, accession number GSE27849.

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