The forms of iron currently available have serious adverse effects that limit their use in addressing prevalent iron deficiency. Iron-supplementation programs have been frustrated by the serious side effects of inorganic forms of iron, which, due to low enteric absorptive efficiency, must be given in relatively high levels (5-20 fold effective levels of heme-iron in foods). Those adverse effects include infectious diarrhea, changes in the gut microbiome and increased serious morbidity among iron-replete children in malaria-endemic areas. The underlying causes of these effects are thought to involve stress on the gut due to excess unabsorbed iron, which can be pro-oxidative and pro-inflammatory. In addition, unabsorbed, soluble iron can be used by the gut microbiome and favor the proliferation of pathogenic enteric bacteria which can contribute to the inflammatory response that leads to down-regulation of iron absorption. Lack of a safe and effective treatment leaves large numbers of children iron deficient, many with associated anemia. Thus, the burden of disease, which includes growth, cognitive and physical performance deficits as well as increased risk of infection, continues to climb in this age group.

The overall goal of this project is to generate evidence to support development of a modality of providing bioavailable iron that does not or produces less adverse effects in iron-replete individuals. The investigators will employ the commonly used iron supplement FeSO4 to compare with two novel forms of iron with features that suggest each may be a useful nutritional source of iron with fewer side effects than FeSO4. The first novel form of iron is a nanoparticulate formulation of iron hydroxide adipate tartrate (IHAT). The second novel form of iron is an organic fungal iron metabolite, Aspiron, which has recently been developed by using a food-grade Aspergillus oryzae cultured in iron-fortified media.

The investigators will evaluate these forms of iron using a randomized clinical trial approach that will robustly test the formal hypotheses and yield useful answers to the primary questions about the relative safety and efficacy of these novel forms of iron in iron-replete subjects. This study is divided to two phases. In Phase I, the investigators will determine of effects of form of low-dose, supplemental iron. Three forms of iron administered at the dose of 60 mg Fe/d will be evaluated against the primary outcomes of ex vivo malarial infectivity, bacterial proliferation potential (also assessed ex vivo) and gut inflammation, and other relevant outcomes in adults. In this protocol the investigators refer to this set of indicators as the "safety profile". The justification for providing 60 mg Fe/d is based on the World Health Organization (WHO) recommendation for daily supplementation for non-anemic, pregnant women with 30-60 mg Fe/d. In addition, the effects on those outcomes of ferrous sulfate administered daily (60 mg Fe/d) vs. weekly (420 mg Fe administered in one weekly dose) will be compared. There is great practical value in addressing this hypothesis of whether a weekly dose can be administered without adverse effects. Nested within this design will be a second comparative study of effects in iron-replete children and adults to validate the applicability of data obtained in adults to children.

For the forms of iron found to produce no adverse effects at the 60 mg Fe/d dose level, Phase II of the study will be conducted in which such forms will be tested at a higher, therapeutic dose of 120 mg Fe/d against the same outcomes.