The developing gut microbiota and immune system: Iron and zinc - friend or foe?

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Under normal conditions, the pre-weaned gut is largely iron-free since breastmilk contains only limited iron. However, the sudden introduction of oral iron at weaning generates an iron-rich gut environment. This promotes the growth of pathogenic microbial populations in the gut with high-iron requirements whilst disadvantaging beneficial bacteria that have low-iron requirements. This is likely to skew the pattern of microbial colonisation of the gut during a critical phase of development. Since gut microbes are the primary drivers of immune development, changes to these populations during early life is likely to change how the immune system develops and combats infectious disease. We do not have clear understanding of how luminal iron availability affects microbiota development, or subsequent immunity.To reduce pathogen-induced infant diarrhoea in low-income countries, diets are often supplemented with high levels of zinc oxide (ZnO). This is because it has antimicrobial properties leading to reductions in pathogen growth and colonisation of the gut. However, since genes encoding antibiotic resistance and genes encoding zinc resistance often occur on the same plasmids, ZnO could actively promote the generation of antibiotic resistant microbes by selecting for these plasmids. The mechanisms of ZnO actions are unknown making it difficult to develop alternatives which do not promote antibiotic resistance.We hypothesis that ZnO reduces enteric infection during infancy by inhibiting microbial iron uptake and reducing pathogenic expansion and virulence in the gut. Low-iron diets could reduce enteropathogen growth and thus negate the need for ZnO. Piglets are valuable models for nutrition studies since they share many characteristics of gut physiology, immunity, microbiota and diet with humans. Specific to this study, piglets are born with very low iron reserves and quickly develop iron deficiency anaemia. This means iron levels can be tightly controlled making piglets valuable models to study the negative effects of oral iron supplementation.The aim of this study is to determine whether limiting luminal iron during infancy reduces enteropathogenic growth and therefore provides a simple, yet effective, alternative to ZnO, thus reducing levels of antibiotic resistant microbes in the gut. It will also explore whether patterns of both microbiota and immune development return to normal in the absence of iron and zinc using a piglet model for human infants. It then explores alternative methods of iron supplementation which do not flood the gut with iron during a critical phase of development for both the gut microbiota and immune system.