The development and assessment of a PEC based platform for the delivery of dietary iron chelators to the large bowel

Iron is a very important micronutrient and unsurprisingly low levels within the body are associated with iron deficiency and anaemia. However, conversely there is also evidence that consuming too much iron is similarly detrimental to health and in particularly the health of your gut. Recent studies have shown that in the majority of adults we consume an excess of iron in our diets and the vast majority of this iron never gets absorbed by our bodies. Instead this pool of iron ends up in the large bowel where it can reside for between hours to days before it is then excreted. In particular recent studies have shown that this pool of iron is detrimental to gut health and this is likely mediated by altering the types of bacteria which normally colonise the large bowel. Thus our application is designed to create a unique formulation which could be used to mop up this pool of toxic iron which resides within the colon and thereby enhance intestinal health. This could be achieved by using experimental drugs with known iron neutralising properties but since these can be toxic we instead propose to identify natural agents which might be able to neutralise iron. One such molecule is alginate which is seaweed derived, used throughout the food industry and which has potent iron neutralising properties. Thus the aim of this study is to screen a large panel of natural food agents like alginate with the hope of identifying a molecule with the strongest iron neutralising properties. Once we identify such a molecule we wish to create a formulation which will ensure that when humans consume it the molecule will only become active in the large bowel where the excess iron resides. This formulation will be tested in an artificial model of the gut and if successful we will conduct a study with healthy volunteers to assess its bioactivity. If successful this could lead to the development of food products which could be used to enhance intestinal health.

Iron is crucial to health and wellbeing as exemplified by too little body iron leading to iron deficiency anaemia. However, there is also evidence that excess 'free' iron is also associated with poor health. In particular there is evidence that in UK adults the average daily intakes of iron were above the recommended nutrient intake for men and post-menopausal women. The excess iron which is not absorbed in the small intestine transits to the colonic lumen where it can adversely affect the gut microbiome, increasing pathogen abundance and intestinal inflammation. Furthermore, a number of other studies have shown that depleting the level of iron in murine intestine through adoption of a diet free of iron enhances intestinal health. Thus our strategy is to identify a dietary agent with strong iron chelating properties and to then formulate it in such a way that it binds only free iron residing in the colonic lumen. We predict that such a strategy will provide a platform for enhancing colonic health. Thus to achieve our goal we will initially screen a large number of dietary agents with predicted iron binding potential and using in vitro and in vivo models identify candidates. These candidates will then be formulated into unique polyelectrolyte complexes to ensure a) maximal bioactivity of the active in the colon and also b) targeting solely to the colon so as not to interfere with small intestinal iron absorption. Formulations will then be tested in artificial gut models to assess dispersal properties and also bioactivity most notably iron binding properties and effects on the microbiota. The leading formulation will then be evaluated in healthy volunteers specifically assessing its effects on iron absorption and the impact on faecal free/complexed iron and on the microbiota.

The beneficiaries of this research include the public, scientists and health care professionals. There is increasing evidence that average daily intakes of iron are above the recommended nutrient intake and with exception of children and pre-menopausal women this high dietary iron intake is likely to have a detrimental effect on intestinal health as exemplified by human and murine studies. The detrimental effect is attributed to the reactive nature of the excess iron which collects in the colon and thus a platform to neutralise this pool of iron may prove beneficial for adult men and post-menopausal women. Similarly, there are a large number of individuals who are on iron supplementation for example to treat iron deficiency anaemia and even in these individuals despite a negative iron balance a large amount of the iron consumed is never absorbed and much of it can be detrimental to the health of the large bowel. This might be particularly problematic in for example patients with ulcerative colitis where their disease may worsen with high supplemental iron (as evidenced by studies in murine models). However the impact of such a platform is likely to be greatest in the developing world for example in Sub-Saharan Africa where iron deficiency is endemic and iron fortification is being considered. Large studies have shown that iron fortification can lead to increased risk of death from malaria and an increased risk of developing gastroenteritis. This has since been attributed to irons detrimental impact on the intestinal bacteria. Thus availability of a safe, "natural" and cheap colonic targeted dietary iron chelator would potentially allow foregut iron supplementation while alleviating the deleterious effects in the hindgut and thus reduce the risk of malaria and gastroenteritis. We also believe that outputs from this project could lead to the development of formulations which could be used to treat individuals with a microbial imbalance (dysbiosis) within the gut. This is particularly interesting as dysbiosis is now being recognised as a possible cause of a whole host of diseases including inflammatory bowel disease. Finally, industry almost certainly will benefit from our work. Our findings will provide a platform for industry to develop agents e.g pre and probiotics for the enhancement of gut health, in addition to the development of formulations which will allow for targeting drugs solely to the colon. Novel and safe iron chelators could have a plethora of applications outside of healthcare as well including a) food preservation by using iron chelating agents to stabilize food colour, aroma and texture ultimately extending shelf life b) Cleaning and laundering industry by using iron chelators to enhance cleaning and germicidal performance c) Pulp and paper processing where the use of an iron chelator could reduce the amount of bleach required to achieve and maintain the desired level of brightness.