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Title: Amino acid and/or multiple micronutrient supplementation in environmental enteropathy : effects on small intestinal barrier structure and function
Author: Louis-Auguste, John Richard
ISNI:       0000 0004 8504 014X
Awarding Body: Queen Mary University of London
Current Institution: Queen Mary, University of London
Date of Award: 2019
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Environmental enteropathy (EE) is thought to underlie stunting, a widely prevalent phenomenon in the developing world with lifelong detrimental consequences. EE is characterised by increased intestinal permeability and reduced absorptive capacity in a chronically inflamed gut, and occurs in nutritionally vulnerable populations. Deficits of amino acids and micronutrients may cause intestinal immune and barrier dysfunction, mediated through cellular nutrient sensing pathways. Mechanistic target of rapamycin complex 1 (MTORC1) is the most important of these, and is of particular interest in EE due to its roles in both epithelial and immune cell function. It was hypothesised that supplementation with the amino acids (AA) L-Glutamine, L-Tryptophan and L-Leucine +/- high dose multiple micronutrients (MM) could modify the abnormal small intestinal histology and permeability seen in EE, and would modify lamina propria lymphocyte (LPL) MTORC1 signalling. A randomised controlled trial was therefore undertaken. Assessments of many of the pathophysiological domains of EE (absorptive area; mucosal inflammation; microbial translocation; permeability; systemic immune activation; host-microbiota interactions; enterohumoral signalling), as well as LPL MTORC1 signalling, were performed in 84 healthy adult Zambians with EE before and after 16 weeks' supplementation. AA supplementation improved villus height, whereas AA with MM supplementation improved in vivo barrier permeability. Supplementation did not affect LPL MTORC1 signalling; however, MTORC1 activity correlated with villus height and the size of the LP TH1 population. Metabonomics identified several potentially relevant metabolites which were upregulated by the interventions. Of note, other observed abnormalities (e.g. elevated translocation/activation markers; depressed levels of GLP2) did not change with supplementation and were mainly not correlated with the improvements in histology and permeability, suggesting that one or more pathophysiological domains (e.g. absorptive area; permeability) may be independently modifiable. These results and others explored in this thesis provide new insights into the complex relationship between nutrition, intestinal health, and EE.
Supervisor: Not available Sponsor: CORE ; Nutritional Research Foundation ; Bill & Melinda Gates Foundation
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available
Keywords: Environmental enteropathy ; Amino acids ; Nutrition ; Multiple micronutrients