Biomarkers of environmental enteric dysfunction and neurodevelopmental outcomes among children in rural Bangladesh and Kenya: a prospective cohort study

Background: Environmental enteric dysfunction (EED) may worsen undernutrition, with potential adverse effects on the developmental trajectories of millions of children in low-resource settings. Objectives: This study aimed to assess associations between EED biomarkers and subsequent child development. Methods: In a prospective cohort of 2646 children nested within 2 randomized trials in rural Bangladesh (n = 1374) and Kenya (n = 1272), EED was measured by markers of intestinal permeability (fecal alpha-1 antitrypsin; urinary lactulose and mannitol assessed through the dual sugar absorption test), inflammation (fecal myeloperoxidase and neopterin), and repair (fecal regenerating gene 1β). In Bangladesh, EED biomarkers were measured at ages 3 and 14 mo, whereas in Kenya, they were measured at 6 and 17 mo. Child development was measured by Communicative Development Inventories and World Health Organization (WHO) motor milestones at 1 y of age and by the Extended Ages and Stages Questionnaire at 2 y of age. We used generalized additive models to estimate associations between EED biomarkers and child development, adjusting for potential confounders and controlling for the false discovery rate (FDR). Results: In Bangladesh, higher concentrations of lactulose, mannitol, and alpha-1 antitrypsin were associated with worse subsequent child motor development outcomes. Elevated mannitol at 3 mo was associated with a lower WHO motor milestones sum score {–0.22 adjusted mean difference between the 25th and 75th percentile of mannitol distribution [(95% confidence interval (CI): −0.36, −0.08); FDR-corrected P value = 0.03]} and lower attainment of hands-and-knees crawling at year 1 [hazard ratio 0.74 (95% CI: 0.64, 0.86); FDR-corrected P value < 0.001]. In Kenya, we observed weak positive associations that were neither consistent nor significant after FDR correction. Conclusions: Higher concentrations of biomarkers of intestinal permeability were associated with poor child motor development in Bangladesh. These relationships were not replicated in the Kenyan cohort. The associations between EED and child neurodevelopment vary across geographic contexts, highlighting the need for further research to determine the generalizability of these findings.