Intestinal hepcidin overexpression promotes iron deficiency anemia and counteracts iron overload via DMT1 downregulation
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.
Authors
- Sandra Guilmeau (ORCID: https://orcid.org/0000-0002-8260-1218)
- Philippe Langella (ORCID: https://orcid.org/0009-0002-7882-3464)
- Sara Zumerle (ORCID: https://orcid.org/0000-0001-6980-0629)
- Luis G. Bermúdez‐Humarán (ORCID: https://orcid.org/0000-0001-7525-3131)
- Joël Poupon (ORCID: https://orcid.org/0000-0003-4314-4998)
- Anne Aucouturier (ORCID: https://orcid.org/0000-0002-8587-1969)
- Carole Peyssonnaux (ORCID: https://orcid.org/0000-0002-1392-8225)
- Marion Falabrègue (ORCID: https://orcid.org/0000-0001-7747-7294)
- Nouzha Djebrani‐Oussedik (ORCID: https://orcid.org/0009-0009-1344-3955)
- Zoubida Karim (ORCID: https://orcid.org/0000-0002-3724-5592)
- Sophie Vaulont
- Nadia Boussetta
- Emeric Dupe (ORCID: https://orcid.org/0009-0004-6288-0872)
- Candice Aurrand
- Léa Cazaulon (ORCID: https://orcid.org/0009-0004-9176-4109)
Institutions
- Centre National de la Recherche Scientifique (FR)
- Université Toulouse III - Paul Sabatier (FR)
- Inserm (FR)
- Université Fédérale de Toulouse Midi-Pyrénées (FR)
- Université Paris Cité (FR)
- Université Paris-Saclay (FR)
- Microbiologie de l’alimentation au service de la santé (FR)
- Institut National de Recherche pour l'Agriculture, l'Alimentation et l'Environnement (FR)
- Université Sorbonne Paris Nord (FR)
- Assistance Publique – Hôpitaux de Paris (FR)
- Istituto Oncologico Veneto (IT)
- Hôpital Lariboisière (FR)
- Institut Cochin (FR)
- Biologie intégrée du globule rouge et de l'Erythropoïèse (FR)
- Istituti di Ricovero e Cura a Carattere Scientifico (IT)
- Institut Toulousain des Maladies Infectieuses et Inflammatoires (FR)
Publication Details
- Journal
- Blood
- Published
- 2025-09-09
- DOI
- https://doi.org/10.1182/blood.2025028370
- Citations
- 2
- Primary Topic
- Iron Metabolism and Disorders
- Type
- article
- Field-Weighted Citation Impact
- 3.54