Multiple Micronutrient Supplementation Transiently Ameliorates Environmental Enteropathy in Malawian Children Aged 12-35 Months in a Randomized Controlled Clinical Trial

Background: Environmental enteropathy (EE) is subclinical, diffuse villous atrophy characterized by T cell infiltration of the small intestinal mucosa associated with nutrient malabsorption and stunting. EE is assessed by the lactulose:mannitol (L:M) test, whereby nonmetabolized sugars are ingested and quantified in the urine. Multiple micronutrient (MN) deficiency morphologically mimics EE, and omega-3 (n-3) polyunsaturated fatty acids reduce mucosal inflammation in Crohn disease. Objective: We tested the hypothesis that supplementary MNs, with or without fish oil (FO), would improve L:M in rural Malawian children aged 1-3 y compared with a control (C) group receiving a placebo. Methods: The MNs and FO provided the Recommended Dietary Intake for 26 vitamins, minerals, eicosapentaenoic acid, and docosahexaenoic acid. This was a 3-arm, randomized, double-blind, placebo-controlled clinical trial, with the primary outcomes being the change in L:M (Delta L:M) after 12 and 24 wk of supplementation. Comparisons were made for Delta L:M after 12 and 24 wk within each group by using a Wilcoxon matched pairs signed rank test, because the data are not normally distributed. Results: A total of 230 children had specimens adequate for analysis; all had an abnormal baseline L:M, defined as >0.10. After 12 wk, children who received MNs + FO had a Delta L:M [mean (95% CI)] of -0.10 (-0.04, 0.15; P = 0.001), and children receiving only MNs had Delta L:M of -0.12 (-0.03, -0.21; P = 0.002). After 24 wk, children who received MNs + FO had a Delta L:M of -0.09 (-0.03, -0.15; P = 0.001); children receiving only MNs had a Delta L:M of -0.11 (-0.02, 0.20; P = 0.001), and the C group had Delta L:M of -0.07 (0.02, -0.16); P = 0.002). Linear growth was similar in all groups, similar to 4.3 cm over 24 wk. Conclusion: Although the effect was modest, these data suggest MNs can transiently ameliorate EE in rural African children. The trial was registered at clinicaltrials.gov as NCT01593033.