Abstract
BACKGROUND: Chronic exposure to enteropathogens may result in environmental enteric dysfunction (EED), a subclinical condition associated with poor child growth. Growth faltering is strongly associated with poor neurodevelopment, and occurs during sensitive periods of postnatal brain development. We investigated the role of novel EED biomarkers, systemic inflammation, and micronutrient status on neurodevelopment in Tanzanian children. METHODS: Non-stunted subjects with 6-week and 6-month blood samples and neurodevelopmental measures (n = 107) were included in this study. Samples were tested for biomarkers of gastrointestinal function (citrulline, antibodies to lipopolysaccharide, and flagellin), micronutrient status (iron, retinol binding protein [RBP], and vitamin D), systemic inflammation (C-reactive protein [CRP] and alpha-1-acid glycoprotein), and growth (insulin-like growth factor and insulin-like growth factor binding protein 3). RESULTS: Cognitive scores at 15 months were associated with higher concentrations of 6-month anti-lipopolysaccharide IgG (β = 1.95, P = 0.02), anti-flagellin IgA (β = 2.41, P = 0.04), and IgG (β = 2.99, P = 0.009). Higher receptive language scores were positively associated with anti-flagellin IgG (β = 0.95, P = 0.05), and receptive language and gross motor scores were positively associated with citrulline at 6 months (β = 0.09, P = 0.02; β = 0.10, P = 0.03, respectively). Gross motor scores were positively associated with RBP at 6 months (β = 1.70, P = 0.03). Markers of systemic inflammation were not significantly associated with neurodevelopment. CONCLUSIONS: Plasma citrulline, a marker of gastrointestinal mucosal surface area, and vitamin A status were associated with higher gross motor development scores. Novel markers for EED, but not inflammation, were positively associated with cognitive scores, suggesting a possible mechanistic pathway involving immune response and neuroprotection.