NOVEL TOOLS FOR EVALUATING INTESTINAL DYSFUNCTION IN CHILDREN AND ADULTS WITH MALNUTRITION DISORDERS

Mortality in children in Africa with SAM is still far higher than commonly appreciated, usually over 10% even for the 2-3 weeks that a child is in hospital if there is any sort of complication. It continues to occur even after discharge from hospital care. Several clinical trials are under way to try and find interventions to reduce this mortality, but they are hampered by the inadequacy of the tools at our disposable for measuring processes like impaired digestion, impaired absorption, failure of gut immunity, and disturbances of the balance of bacteria in the intestine. Even in highly refined health care systems these processes are difficult to assess, but in Africa this is a very tough obstacle to evaluating novel interventions. The study we propose will use stable (non-radioactive) isotope techniques to measure digestion and absorption, fluorescent tracers to measure leakiness of the lining of the gut, advanced immunology to study responses to molecules derived from bacteria in the gut, genomic sequencing to study the balance of bacteria in the gut, and advanced spectroscopy to analyse the function of those gut bacteria. In the process we will learn a great deal about children with severe acute malnutrition, and will generate new tools for analysing gut function. These tools may then, in turn, be useful for studying rare disorders of gut function in children and adults even in well-resourced countries, conditions which often require complex nutritional support and in which it is still, sadly, very hard to evaluate response to therapy.

Severe acute malnutrition (SAM) is a medical emergency, especially when there are infectious or metabolic complications, and under these circumstances mortality can reach 30% during a 2-3 week hospital admission. Clinical trials of novel interventions suffer from the drawback of inadequate endpoints which do not predict mortality or non-response well, and which reflect pathophysiology only poorly. In addition, those tests which are available are expensive and cumbersome to administer. Here, we propose five work packages, all designed to develop new tools for measuring elements of gut functional capacity which are common disturbances in many nutritional disorders. Stable isotope techniques will be used to analyse digestion and absorption, derangements of which have been neglected for decades. New laser-based sensing will be used to define increased permeability at point of care, using oral fluorescent tracers. Measurements of dendritic cell/monocyte responses to translocated pathogen associated molecular patterns will enable features to be defined for future development. The composition of the microbiome will be quantified using DNA sequencing, and its functionality assessed using metabolomics. Finally, all of these will be brought to bear on children with SAM in Zambia, Zimbabwe and Uganda, who will be followed up during and after their critical illness to determine which tools best map the clinical course. This 5-year study brings together a unique consortium with diverse skill sets to address a singularly important question in global health, but the data generated may be of wider application for people anywhere with intestinal and nutritional problems.