Gut-derived erythroferrone contributes to intestinal homeostasis

The hormone erythroferrone (ERFE) is secreted by erythroid progenitors in the marrow during stimulated erythropoiesis. ERFE represses hepcidin to ensure the supply of iron to the erythron by inhibiting the BMP/SMAD signaling. However, ERFE is also expressed in the gastrointestinal tract (Kautz, Nat Genet 2014), in which its function is unknown.

We explored the role of ERFE in intestinal homeostasis using wild-type (WT) and Erfe-deficient (Erfe-/-) mice. The mice were subjected to an experimental colitis induced by dextran sodium sulfate (DSS), a model of inflammatory bowel disease.

We first determined by in situ hybridization that Erfe mRNA was expressed in the colon in intestinal epithelial cells at the bottom of the crypts and in secretory cells. Interestingly, Erfe-/- mice exhibited shorter crypts and increased paracellular permeability in the ileum and the colon compared to WT mice. When challenged with DSS, Erfe-/- mice developed a more severe inflammatory phenotype than WT mice.  Indeed, Erfe-/- mice presented with increased body weight loss, macroscopic (colitis, bleeding, colon length) and microscopic inflammatory scores (edema, mucus depletion, immune cells infiltration…) and premature death compared to WT mice. Consistent with the alteration of barrier function, Erfe-/- mice exhibited a blunted immune response with increased expression of inflammatory cytokines and antimicrobial peptides in the large intestine. Finally, using hematopoietic chimeras, we demonstrated that the protective effect was not conferred by hematopoietic ERFE.

ERFE plays a role in maintaining intestinal homeostasis. We are currently investigating the mechanisms triggered by ERFE in the colon using mice and organoid models.