Biomarkers of environmental enteric dysfunction are not consistently associated with linear growth velocity in rural Zimbabwean infants

Abstract

Background: Child stunting remains a poorly understood, prevalent public health problem. Environmental enteric dysfunction (EED) is hypothesized to be an important underlying cause.

Objectives: Within a subgroup of 1169 children enrolled in the SHINE (Sanitation Hygiene Infant Nutrition Efficacy) trial in rural Zimbabwe, followed longitudinally from birth to 18 mo of age, we evaluated associations between the concentration of 11 EED biomarkers and linear growth velocity.

Methods: At infant ages 1, 3, 6, 12, and 18 mo, nurses measured child length and collected stool and blood; the lactulose-mannitol urine test was also conducted at all visits except at 1 mo. Stool neopterin, α-1 antitrypsin, myeloperoxidase, and regenerating gene 1β protein; urinary lactulose and mannitol; and plasma kynurenine, tryptophan, C-reactive protein, insulin-like growth factor-1 (IGF-1), soluble CD14, intestinal fatty acid binding protein, and citrulline were measured. We analyzed the change in relative [∆ length-for-age z score (LAZ)/mo] and absolute (∆ length/mo) growth velocity during 4 age intervals (1-3 mo; 3-6 mo; 6-12 mo; and 12-18 mo) per SD increase in biomarker concentration at the start of each age interval.

Results: In fully adjusted models, we observed only 3 small, statistically significant associations: kynurenine:tryptophan ratio at 12 mo was associated with decreased mean LAZ velocity during the 12-18 mo interval (-0.015 LAZ/mo; 95% CI: -0.029, -0.001 LAZ/mo); mannitol excretion at 6 mo was associated with increased LAZ velocity during the 6-12 mo interval (0.013 LAZ/mo; 95% CI: 0.001, 0.025 LAZ/mo), and plasma IGF-1 at 1 mo was associated with increased LAZ velocity during the 1-3 mo interval (0.118 LAZ/mo; 95% CI: 0.024, 0.211 LAZ/mo). Results for absolute growth velocity were similar, except IGF-1 was also associated with growth during the 12-18 mo interval. We found no other associations between any EED biomarker and linear growth velocity.

Conclusions: None of 11 biomarkers of EED were consistently associated with linear growth among Zimbabwean children.This trial was registered at clinicaltrials.gov as NCT01824940.

Keywords: Zimbabwe; biomarkers; child growth; environmental enteric dysfunction; stunting.

FIGURE 1

Flow of participants through the trial. A1AT, fecal α-1 antitrypsin; CIT, plasma citrulline; CRP, plasma C-reactive protein; EED, environmental enteric dysfunction; I-FABP, plasma intestinal fatty acid binding protein; IGF-1, insulin-like growth factor 1; KTR, kynurenine-to-tryptophan ratio; LM, lactulose–mannitol; LMR, lactulose-to-mannitol ratio (urinary); MPO, fecal myeloperoxidase; NEO, fecal neopterin; REG-1β, fecal regenerating gene 1β; sCD14, plasma soluble CD14.

FIGURE 2

Adjusted mean change in LAZ (SD/mo) per 1-SD increase in biomarker concentration at the start of each follow-up interval. The mean (95% CI) LAZs at 1, 3, 6, 12, and 18 mo of age were −0.84 (−0.93, −0.75); −0.85 (−0.92, −0.77); −0.84 (−0.91, −0.76); −1.13 (−1.20, −1.07); and −1.42 (−1.48, −1.36), respectively. A1AT, fecal α-1 antitrypsin; CRP, plasma C-reactive protein; EE score, environmental enteropathy score; I-FABP, plasma intestinal fatty acid binding protein; IGF-1, insulin-like growth factor 1; KTR, kynurenine-to-tryptophan ratio; LAZ, length-for-age z score; LMR, lactulose-to-mannitol ratio (urinary); MPO, fecal myeloperoxidase; NEO, fecal neopterin; REG-1β, fecal regenerating gene 1β; sCD14, plasma soluble CD14.