Intestinal hepcidin overexpression promotes iron deficiency anemia and counteracts iron overload via DMT1 downregulation
Abstract
Abstract Hepcidin is the key hyposideremic hormone produced primarily by the liver. However, recent reports reveal extrahepatic functional sources of hepcidin, including the intestine, the site of dietary iron absorption. To determine whether intestinal hepcidin may play a role in plasma iron lowering, we generated transgenic mice overexpressing the peptide specifically in this tissue. At 1 month of age, transgenic mice exhibited severe iron deficiency along with decreased hematologic indices and a drastic suppression of liver hepcidin in response to hyposideremia. Mechanistically, we showed that intestinal hepcidin was produced in the intestine lumen, inducing a striking downregulation of divalent metal transporter 1 (DMT1) protein at the enterocyte. To confirm the capacity of hepcidin to decrease DMT1, we developed food-grade recombinant lactic acid bacteria (recLAB) genetically modified to deliver hepcidin directly into the intestinal lumen. These recLAB induced a rapid decrease of duodenal DMT1 and, most importantly, when daily orally administrated, protected against iron overload in a mouse model of hemochromatosis. Taken together, our data reveal a previously unrecognized role of intestinal hepcidin as a regulator of systemic iron homeostasis, acting on DMT1 on the apical side of enterocytes, with potential therapeutic relevance for hematologic or iron disorders.
Article Details
Authors (15)
Marion Falabrègue
1Université Paris Cité, Centre National de la Recherche Scientifique, INSERM, Institut Cochin, Paris, France
Candice Aurrand
1Université Paris Cité, Centre National de la Recherche Scientifique, INSERM, Institut Cochin, Paris, France
Léa Cazaulon
1Université Paris Cité, Centre National de la Recherche Scientifique, INSERM, Institut Cochin, Paris, France
Nadia Boussetta
1Université Paris Cité, Centre National de la Recherche Scientifique, INSERM, Institut Cochin, Paris, France
Sara Zumerle
1Université Paris Cité, Centre National de la Recherche Scientifique, INSERM, Institut Cochin, Paris, France
Nouzha Djebrani-Oussedik
3Laboratoire de Toxicologie Biologique, Hôpital Lariboisière, Paris, France
Joel Poupon
3Laboratoire de Toxicologie Biologique, Hôpital Lariboisière, Paris, France
Sandra Guilmeau
1Université Paris Cité, Centre National de la Recherche Scientifique, INSERM, Institut Cochin, Paris, France
Zoubida Karim
5Université de Toulouse, INSERM, Centre National de la Recherche Scientifique, Institut Toulousain des Maladies Infectieuses et Inflammatoires (Infinity), Université Paul Sabatier, Toulouse, France
Emeric Dupe
6Université Paris-Saclay, Institut National de Recherche pour l'Agriculture, l'Alimentation et l'Environnement, AgroParisTech, Micalis Insitute, Domaine de Vilvert, Jouy-en-Josas, France
Anne Aucouturier
6Université Paris-Saclay, Institut National de Recherche pour l'Agriculture, l'Alimentation et l'Environnement, AgroParisTech, Micalis Insitute, Domaine de Vilvert, Jouy-en-Josas, France
Philippe Langella
Luis G. Bermudez-Humarán
6Université Paris-Saclay, Institut National de Recherche pour l'Agriculture, l'Alimentation et l'Environnement, AgroParisTech, Micalis Insitute, Domaine de Vilvert, Jouy-en-Josas, France
Sophie Vaulont
1Université Paris Cité, Centre National de la Recherche Scientifique, INSERM, Institut Cochin, Paris, France
Carole Peyssonnaux
1Université Paris Cité, Centre National de la Recherche Scientifique, INSERM, Institut Cochin, Paris, France