Abstract
ABSTRACTBackgroundEnvironmental enteropathy (EE) refers to villus blunting, reduced absorption, and microbial translocation in children and adults in tropical or deprived residential areas. In previous work we observed an effect of micronutrients on villus height (VH).ObjectiveWe aimed to determine, in a randomized controlled trial, if amino acid (AA) or multiple micronutrient (MM) supplementation can improve intestinal structure or barrier dysfunction in Zambian adults with EE.MethodsAA (tryptophan, leucine, and glutamine) and/or MM supplements were given for 16 wk in a 2 × 2 factorial comparison against placebo. Primary outcomes were changes in VH, in vivo small intestinal barrier dysfunction assessed by confocal laser endomicroscopy (CLE), and mechanistic (or mammalian) target of rapamycin complex 1 (MTORC1) nutrient responsiveness in lamina propria CD4+ lymphocytes.ResultsOver 16 wk AA, but not MM, supplementation increased VH by 16% (34.5 μm) compared with placebo (P = 0.04). Fluorescein leak, measured by CLE, improved only in those allocated to both AA and MM supplementation. No effect was seen on MTORC1 activation, but posttreatment MTORC1 and VH were correlated (ρ = 0.51; P = 0.001), and change in MTORC1 was correlated with change in VH in the placebo group (ρ = 0.63; P = 0.03). In secondary analyses no effect was observed on biomarkers of microbial translocation. Metabolomic analyses suggest alterations in a number of microbial- and host-derived metabolites including the leucine metabolite β-hydroxy-β-methylbutyrate, which was increased by AA supplementation and correlated with VH.ConclusionsIn this phase 2 trial, AA supplementation protected against a decline in VH over the supplementation period, and improved barrier function when combined with micronutrients. Leucine and MTORC1 metabolism may be involved in the mechanism of effect. This trial was registered at www.pactr.org as PACTR201505001104412.
Highlights
Environmental enteropathy (EE) was first recognized as “tropical enteropathy,” a phenomenon of uncertain significance [1,2,3]
EE is a subclinical alteration in small intestinal mucosal architecture and function, widely prevalent in the tropics and in disadvantaged communities
Previous trials have identified few interventions which consistently and successfully target any of the domains of pathophysiology, but nutritional or other interventions are needed. In this double-blinded randomized controlled trial, on a background of a seasonal reduction in villus height (VH) and villus surface area, supplementation with amino acid (AA) but not multiple micronutrient (MM) increased VH and surface area compared with placebo
Summary
Environmental enteropathy (EE) was first recognized as “tropical enteropathy,” a phenomenon of uncertain significance [1,2,3]. The micronutrient supplement and matching placebo were generously manufactured and donated by Vitabiotics Ltd, UK. In previous work we observed an effect of micronutrients on villus height (VH). Objective: We aimed to determine, in a randomized controlled trial, if amino acid (AA) or multiple micronutrient (MM) supplementation can improve intestinal structure or barrier dysfunction in Zambian adults with EE. In secondary analyses no effect was observed on biomarkers of microbial translocation. Metabolomic analyses suggest alterations in a number of microbial- and host-derived metabolites including the leucine metabolite β-hydroxy-β-methylbutyrate, which was increased by AA supplementation and correlated with VH. Leucine and MTORC1 metabolism may be involved in the mechanism of effect. This trial was registered at www.pactr.org as PACTR201505001104412.
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