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Title: Inflammation and immunity in severe acute malnutrition
Author: Jones, Kelsey David
ISNI:       0000 0004 7656 9287
Awarding Body: Imperial College London
Current Institution: Imperial College London
Date of Award: 2016
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Background: Malnutrition is responsible for 45% of child deaths because it is associated with an increased vulnerability to major infectious disease. The mechanisms behind this association are undefined. It occurs despite the fact that malnourished children have increased levels of enteric and systemic inflammatory activation. Methods: Case-control study of inflammatory activation and response to ex vivo pathogen challenge determined relationships between existing and potential inflammatory function and nutrition. Randomised controlled trial of a gut-specific immunomodulatory agent assessed for functional redundancy in enteric inflammation. Randomised controlled trial of nutritional rehabilitation strategies with enhanced n-3 polyunsaturated fatty acid provision assessed for potentially beneficial effects on inflammation. Results: SAM was not associated with abnormalities in systemic cytokine response to innate immune challenge in an ex vivo model compared to control children, but more severe intestinal inflammation, and kwashiorkor may be. Children with SAM and stunting have clear evidence of enteric inflammation, and have evidence of cytokine-mediated inhibition of the GH-IGF-1 axis, which may play a role in linear growth failure. Treatment of children with SAM and stunting with mesalazine appeared to be safe, and there was limited evidence of an impact on enteric inflammation. Stunting is associated with LC-PUFA deficiency, but acute malnutrition is not. Production and administration of a ready-to-use therapeutic food with elevated n-3 PUFA was technically feasible, but was not associated with positive outcomes in growth, recovery or immune function compared to standard treatment. Provision of pre-formed DHA in RUTF may be essential to preserve optimal tissue levels during nutritional rehabilitation. Conclusions: Further strategies targeting inflammatory activation as part of the management of SAM should be trialled. The relationship between systemic and enteric inflammation and nutrition deserves further study.
Supervisor: Warner, John ; Mitchell, Jane Sponsor: Wellcome Trust ; Bill and Melinda Gates Foundation ; National Institute for Health Research
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral