Iron is essential for cellular function and for transporting oxygen in the blood. However, excess iron can be harmful, as it promotes the production of free radicals that cause tissue damage. Since the body has no active mechanism for eliminating iron, its regulation depends mainly on the hormone hepcidin, produced by the liver. Hepcidin controls iron absorption in the intestine and its recycling by macrophages by degrading ferroportin, the body’s only iron exporter.
A deficiency in hepcidin is responsible for hereditary hemochromatosis, a condition marked by systemic iron overload, while an excess of hepcidin leads to iron-deficiency anemia. Until recently, hepcidin was regarded as an almost exclusively liver-derived hormone. Yet several studies have shown that it can also be produced ectopically in other tissues, including the intestine, under pathological conditions. This is the question Carole Peyssonnaux’s team set out to explore: could intestinal hepcidin also play a role in regulating iron in the body?
The researchers created a transgenic mouse model that overexpresses hepcidin in intestinal cells. These animals quickly developed iron-deficiency anemia, with reduced circulating iron, ferritin, and hemoglobin levels. Analysis revealed that hepcidin secreted into the intestinal lumen inhibits iron uptake by degrading DMT1, the apical iron transporter of enterocytes.
This discovery provides the first in vivo evidence that intestinal hepcidin, when produced in excess, acts locally to reduce iron absorption. To explore its therapeutic potential, the team developed a recombinant probiotic strain (LAB-Hepc) capable of producing hepcidin directly in the intestine. When administered to mice with hemochromatosis (lacking hepatic hepcidin), this strategy significantly reduced iron accumulation in the body, particularly in the liver.
These findings demonstrate that local intestinal production of hepcidin can be harnessed as an innovative and non-invasive therapeutic strategy.
This work opens the door to the development of oral treatments based on recombinant probiotics to limit iron overload. Such an approach could benefit patients with hemochromatosis, as well as those with hemoglobin-related disorders such as thalassemia, sickle cell disease, or myelodysplastic syndromes. The researchers now aim to further investigate the role of intestinal hepcidin in different inflammatory and infectious contexts, and to better understand the molecular mechanisms linking this hormone to the DMT1 transporter.
Overexpression of intestinal hepcidin
A. In a transgenic mouse model overexpressing the hormone in enterocytes, the authors show that the hormone is secreted into the intestinal lumen and that, by inhibiting the iron importer, DMT1, it is able to directly reduce iron absorption, leading to a phenotype of iron deficiency and anemia. B. To directly deliver hepcidin into the intestinal lumen, the authors generated recombinant LAB-Hepc probiotics and showed that the use of these probiotics in gavage mode reduced iron overload in a model of hemochromatosis (Hepc knockout mice).
Reference
Intestinal hepcidin overexpression promotes iron deficiency anemia and counteracts iron overload via DMT1 downregulation. Marion Falabrègue, Candice Aurrand, Léa Cazaulon, Nadia Boussetta, Sara Zumerle, Nouzha Djebrani Oussedik, Joel Poupon, Sandra Guilmeau, Zoubida Karim, Emeric Dupe, Anne Aucouturier, Philippe Langella, Luis G. Bermudez-Humarán, Sophie Vaulont, Carole Peyssonnaux. Blood, Sep 9:blood.2025028370. doi: 10.1182/blood.2025028370
