Mediating effects of hepcidin on iron requirements with undernutrition

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Anemia is commonly observed with undernutrition and is associated with more severe complications and poorer outcomes, including death. Undernourished children with anemia are also less likely to recover than those without anemia. In the presence of infection, this represents the anemia of inflammation and manifests from increases in the iron regulatory hormone hepcidin in response to inflammatory signals. However, most cases of undernutrition are uncomplicated where there is no sign of infection or other underlying condition, yet they still present a similar clinical manifestation that includes low serum iron levels but intact or elevated iron stores. In addition, undernourished children paradoxically absorb less iron compared to apparently healthy children, which may explain why the anemia is extremely resistant to iron supplementation. The overall objective of this proposal is to determine the mechanism underlying the anemia that develops with uncomplicated undernutrition and its contribution to the lack of effectiveness of current treatment regimens. Our preliminary data demonstrate that gluconeogenic signals from food restriction increase hepcidin and lead to functional anemia (i.e., hypoferremia, but increased tissue iron concentrations). We will use wildtype and hepcidin knockout mice to determine whether increases in hepcidin in response to food restriction contribute to the anemia observed with undernutrition. Restricted iron supply may not only contribute to the anemia observed with undernutrition, but may also limit the re-establishment of a normal red blood cell mass during recovery with refeeding. We will determine the effects of refeeding on recovery from the anemia observed with undernutrition. Understanding the mechanism by which anemia develops with uncomplicated undernutrition may inform the development of more effective prevention and treatment strategies for anemia in undernourished children, potentially leading to improved outcomes and reduced mortality rates. Additionally, findings may guide recommendations for optimizing the iron content of lipidbased nutrient supplements used to prevent or treat undernutrition.