Impact of Daily Preventive Zinc or Therapeutic Zinc Supplementation for Diarrhea on Plasma Biomarkers of Environmental Enteric Dysfunction among Rural Laotian Children: A Randomized Controlled Trial

Abstract

Environmental enteric dysfunction (EED) may be ameliorated by zinc supplementation. The objective of this study was to investigate the impact of different forms of zinc supplementation on biomarkers of EED (i.e., plasma citrulline, kynurenine, and tryptophan concentrations and the kynurenine:tryptophan [KT] ratio) among young Laotian children. In a double-blind randomized controlled trial, 3,407 children aged 6-23 months were randomized into one of four groups: daily preventive zinc dispersible tablets (PZ; 7 mg zinc), daily multiple micronutrient powders (MNP; 10 mg zinc, 6 mg iron, and 13 other micronutrients), therapeutic zinc supplements for diarrhea treatment (TZ; 20 mg/day for 10 days), or daily placebo powder, and followed up for ∼36 weeks. Plasma samples at baseline and endline for 359 children were analyzed for citrulline, kynurenine, and tryptophan concentrations. At baseline, the prevalence of stunting and zinc deficiency was 37% and 76.5%, respectively. The mean plasma citrulline, kynurenine, and tryptophan concentrations were 24.6 ± 5.4 μmol/L, 3.27 ± 0.83 μmol/L, and 72.3 ± 12.9 μmol/L, respectively; the mean KT ratio (×1,000) was 45.9 ± 12.0. At endline, neither plasma citrulline, kynurenine, or tryptophan concentrations, nor the KT ratio differed among intervention groups (P > 0.05). In this population, PZ, MNP, and TZ had no overall effect on plasma concentrations of citrulline, kynurenine, and tryptophan, or the KT ratio. The need remains to better understand the etiology of EED, and the development of biomarkers to diagnose EED and evaluate the impact of interventions.

Impact of Different Strategies for Delivering Supplemental Zinc on Selected Fecal Markers of Environmental Enteric Dysfunction among Young Laotian Children: A Randomized Controlled Trial

“…Similarly, we did not find an impact of PZ and TZ supplementation or MNP on plasma concentrations of citrulline and the kynurenine: tryptophan (KT) ratio. 57 Direct comparison of our findings with previous zinc or MNP intervention trials is made difficult by the use of different biomarkers of EED and different doses and combinations of supplementary micronutrients across the different studies. Two trials assessed the impact of MNPs with and without iron on fecal CAL among children in Kenya 40 , 41 ; the first one found that fecal CAL was significantly higher in infants receiving iron-containing MNP (12.5 mg of iron as ferrous fumarate) than infants receiving MNP without iron, but no difference was reported with a MNP containing 2.5 mg of iron as NaFeEDTA compared with infants receiving the same MNP without iron.…”

“…However, this beneficial impact on diarrhea outcomes did not result in lower concentrations of MPO, NEO, and CAL in the TZ group nor did age modify the effect of the intervention on intestinal inflammation. In addition, there was no overall impact on other biomarkers of EED, namely, plasma citrulline and the KT ratio, 57 suggesting that the intervention may have not affected intestinal damage and repair and systemic inflammation. Moreover, the modifying effects of EED on growth outcomes identified in the present study were no longer significant after multiple hypothesis testing, suggesting that these biomarkers of EED may not play a role in the pathway to linear growth failure in the present study population.…”

“…This study is weakened by the fact that we were only able to assess intestinal inflammation. Unfortunately, because of logistical challenges, plasma citrulline, kynurenine, tryptophan, and the KT ratio were assessed in a different subsample of children, 57 and we can thus not contribute to the comparison of different EED markers.…”

Citrulline and kynurenine to tryptophan ratio: potential EED (environmental enteric dysfunction) biomarkers in acute watery diarrhea among children in Bangladesh

“…This is why the negative correlation between citrulline and kynurenine levels and lymphocyte and basophil count observed in the current study was not entirely unexpected. A study conducted among rural Laotian children found, that the KT ratio was not associated with blood leukocyte concentrations (lymphocytes, monocytes, neutrophils, eosinophils, and basophils) but tryptophan level is positively associated with Lymphocyte count 51 . Confirmation of this hypothesis would require further work with more specific characterization of systemic inflammation.…”

The Role of Micronutrients and Toxic Metals in the Management of Epidemics in Cambodia

“…It is possible that for Cambodia and Thailand the most important deviation from expected results for zinc augmentation was from neighboring Laos. A trial was done with 3407 Laotian children where the prevalence of stunting and zinc deficiency was 37% and 76.5%, respectively [139]. Despite improving zinc status, preventive zinc and micronutrient powder had no impact on growth of Laotian children.…”