Novel therapeutic approaches to malnutrition enteropathy

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Severe acute malnutrition (SAM) is often complicated by infection and metabolic derangements, and in this situation it becomes a medical emergency with appreciable mortality (up to 35%, depending on the nature of the complications, over one month). Although early, protocol-based management in the community can bring the mortality down to 4%, this is still unacceptable for a benign disorder affecting many hundreds of thousands of the world's children. One of the most difficult management problems is SAM complicated by persistent diarrhoea, indicative of an intestinal derangement we refer to as malnutrition enteropathy. We know, from previous and current work, that malnutrition enteropathy is a failure of the barrier function of the intestine - its ability to absorb nutrients while simultaneously excluding the bacteria which inhabit the gut from the moment of birth. Under the microscope this barrier failure appears as gaps in the epithelium - the lining cell layer of the intestine - and it allows microbial components into the bloodstream where they generate an inflammatory response. This process is called microbial translocation and we have evidence that it is one of the critical disturbances leading to deterioration and death in children with SAM. If we can identify treatments to heal this barrier failure we may be able to interrupt the fundamental derangements of malnutrition enteropathy and save many thousand of lives, particularly in Africa and South Asia.We propose to test out five novel treatments in an attempt to heal malnutrition enteropathy. If these are successful in reversing the laboratory abnormalities we have identified in children with SAM, we will go on and carry out a large-scale multi-centre clinical trial to measure any reduction in mortality in several countries. We will also have demonstrated the usefulness of novel strategies for repairing the barrier failure which characterises other disorders common in Europe and North America, such as inflammatory bowel disease and a sort of infectious disorder common in patients in critical care units.We will test the first four interventions - bovine colostrum, N-acetyl glucosamine, teduglutide and budesonide - against standard care by randomising suitable children with SAM and persistent diarrhoea in Zambia and Zimbabwe. The most promising of these will then be evaluated against a treatment which we already know has some impact in this condition - elemental feeding - in a more intensive study designed to provide very detailed confirmation of safety and healing ability in the intestine. Once the two parts of this study are complete, we hope to have a candidate treatment for further testing, as well as detailed information on its activity which will enable us to test it across the world in the most rigorous medical scientific trial format. We will also generate large amounts of scientific data to help us to understand better the pathways of damage, which is essential in case the interventions work less well than we hope.The team we have assembled draws on years of experience of malnutrition enteropathy and the interventions we propose to evaluate, and will establish a scientific consortium in the UK and southern Africa dedicated to reducing the impact of this neglected but important disorder. Capacity development in Africa is an integral part of our strategy, and we have deep experience of this in both countries. We are also fully conversant of the ethical and regulatory requirements of such work, as we are currently engaged in non-therapeutic studies in the same groups of children. Ethical issues have been considered fully in the preparation of this proposal and are set out in detail.