Abstract/Summary

Childhood malnutrition and iron deficiency anemia (IDA) remain significant global health challenges, particularly in low-resource settings, and can lead to life-long health implications. Malnutrition appears to contribute to the development of environmental enteric dysfunction (EED) resulting in nearly 25% of the world's children aged <5 years having stunted growth. EED is commonly defined as an acquired subclinical disorder of the small intestine, although etiology is unknown. Iron deficiency (ID) is the most prevalent cause of global micronutrient malnutrition affecting 273 million children globally. These conditions both appear to hinder immune function and gut health, but the lack of reliable animal models, especially during the neonatal period, means there is little understanding of the mechanisms involved. Piglets are valuable models for human infants since they share many physiological characteristics. In addition, their precocial nature permits early separation from maternal interference so their environment and nutrition can be tightly controlled. Furthermore, if left untreated with iron, piglets will reliably develop IDA in the first weeks of life, and characteristics of EED are observed in early and abruptly weaned piglets, although the gut recovers within 2 weeks. Oral iron supplementation is the most common strategy used worldwide to prevent and treat IDA. However, oral iron is associated with detrimental side effects including diarrhoea and increased risk of infectious diseases, although there is limited mechanistic understanding in this area. The aims of this PhD were firstly to explore the effects of global malnutrition following early, abrupt weaning, and secondly to explore IDA and different forms of iron supplementation on growth and immune system development during both the neonatal and post-weaning phase of growth, all using piglet models for human infants. To generate a model for EED (Chapter 2), twelve 21d old piglets were early and abruptly weaned before being litter-matched into 2 treatment groups (n=6): control (adequate diet) and EED (subsistence diet), To explore the effects of IDA and different forms of iron supplementation during the neonatal phase (Chapter 3), twenty-four 1d old piglets were litter-matched into 4 treatment groups (n=6):IDA (no iron); control (intramuscular iron, 200 mgs Fe); oral iron (150 mg/kg feed); oral and IM iron (excess iron). To determine the effects of low and high oral iron supplementation post-weaning (Chapter 4), twelve 25-day old piglets, which all received an IM injection of iron at 1 day old, were litter-matched into 2 treatment groups (n=6): high iron (69.4 mg/kg feed +150 mg/kg feed); low iron (69.4 mg/kg feed). Piglet growth and indicators of iron status were monitored throughout and fluorescence immunohistology was used to quantify the expression of proteins associated with intestinal barrier function and mucosal immune development. The results showed that following abrupt and early weaning, a subsistence-type diet-maintained characteristics of EED, including reduced barrier function and increased infiltration of immune-associated cells all along the intestinal tract, consistent with the generation of a piglet model for EED in infants. Neonatal IDA was associated with severely impeded immune development along with increased potential to absorb luminal iron. While oral iron supplementation prevented the development of neonatal IDA, it was associated with increased potential for antigen presentation and immune-associated protein expression at several intestinal locations. Finally, we showed that there were no benefits of high levels of oral iron supplementation at weaning on piglet growth or iron status, but this treatment did reduce intestinal barrier function. Our findings provide novel insight into the molecular effects of EED, IDA and oral iron supplementation during early-life in an animal model which closely reflects human infants, thus increasing translational potential. The results suggest that caution should be taken when designing iron supplementation strategies to prevent the development of IDA since over-supplementation is not only unbeneficial but appears to have detrimental effects on gut health.