Infection, inflammation and hepcidin-mediated iron deficiency anaemia in African children

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Iron deficiency (ID), and the more serious iron deficiency anaemia (IDA), causes multiple health problems especially in reproductive women and young children in low-income settings. Iron is crucial for neural development and early deficiencies during foetal and infant growth cause irreparable damage to brain development and cognition. Figures from the latest Global Burden of Disease analysis estimate that 1.225 billion people suffer from IDA worldwide and it is the fourth largest contributor to years lived with disability (YLD). This burden is concentrated in sub-Saharan Africa and South Asia. It has been thought that IDA is largely caused by diets low in iron and by the effects of infections such as malaria and intestinal helminths. However carefully controlled trials of iron supplements have very poor efficacy in Africa. The recent discovery of the hormone hepcidin - which acts as the master regulator of iron - throws a new light on the causes of IDA and may guide future therapeutic pathways. We have recently discovered that even low-grade inflammation is a major contributor to IDA in rural African children because it up-regulates hepcidin levels with a consequent blockade of intestinal absorption of iron. This project will try to identify the sources of this low-grade inflammation in well and sick Gambian children. It will additionally try to understand the complex interacting mechanisms linking iron absorption, distribution and erythropoiesis to the effects of inflammation mediated through hepcidin, erythropoietin (EPO) and the newly discovered hormone erythroferrone (ERFE) which signals to the liver that the bone marrow requires iron. Finally we will conduct a randomised controlled trial to test whether it is possible to circumvent the inflammation-induced blockade of iron absorption by administering iron in the form of haem. Another arm of this trial will be a proof-of-principle trial to assess the impact of reducing systemic and gut inflammation by co-administering azithromycin and galacto-oligosaccharides with iron.These studies, if successful, would suggest the need for a radical revision of current policies to combat IDA. It is likely that children will require major improvements in their environment achieved through intensive efforts to improve water, sanitation and hygiene (WASH++). If, as we speculate, the origins of IDA are more strongly determined by inflammation than by low dietary iron this would have important implications for future nutritional, agricultural and livestock policies.