Dietary iron restriction protects against vaso-occlusion and organ damage in murine sickle cell disease

Sickle cell disease (SCD) is an inherited disorder resulting from a beta-globin gene mutation, and SCD patients experience erythrocyte sickling, vaso-occlusive episodes (VOE), and progressive organ damage. Chronic hemolysis, inflammation, and repeated red blood cell transfusions in SCD can disrupt iron homeostasis. Patients who receive multiple blood transfusions develop iron overload, and another subpopulation of SCD patients manifest iron deficiency. To elucidate connections between dietary iron, the microbiome, and SCD pathogenesis, we treated SCD mice with an iron-restricted diet (IRD). IRD treatment reduced iron availability and hemolysis, decreased acute VOE, and ameliorated chronic organ damage in SCD mice. Our results extend previous studies indicating that the gut microbiota regulate disease in SCD mice. IRD alters microbiota load and improves gut integrity, together preventing crosstalk between the gut microbiome and inflammatory factors such as aged neutrophils, dampening VOE, and organ damage. These findings provide strong evidence for the therapeutic potential of manipulating iron homeostasis and the gut microbiome to ameliorate SCD pathophysiology. Many treatments, which are under development, focus on lowering the systemic iron concentration to relieve disease complications, and our data suggest that iron-induced changes in microbiota load and gut integrity are related-and novel-therapeutic targets.

Automated summary

Sickle cell disease (SCD) is a genetic disorder characterized by erythrocyte sickling, vaso-occlusive episodes (VOE), and organ damage. Red blood cell transfusions cause iron overload in some SCD patients, while others exhibit iron deficiency. In this study, an iron-restricted diet (IRD) was shown to reduce iron availability, hemolysis, and VOE, and improve organ damage in SCD mice. Furthermore, IRD altered the gut microbiota and improved gut integrity, preventing crosstalk between the microbiome and inflammatory factors, and ultimately ameliorating SCD pathophysiology.