Causal pathways from enteropathogens to environmental enteropathy : findings from the MAL-ED birth cohort study

Abstract

Background: Environmentalenteropathy (EE),the adverseimpact offrequent and numerous entericinfections on the gut resulting in a state of persistent immune activation and altered permeability, has been proposed as a key determinant of growth failure in children in low- and middle-income populations. A theory-driven systems model to critically evaluate pathways through which enteropathogens, gut permeability, and intestinal and sys- temic in fl ammation affect child growth was conducted within the framework of the Etiology, Risk Factors and Interactions of Enteric Infections and Malnutrition and the Consequences for Child Health and Development (MAL-ED) birth cohort study that included children from eight countries. Methods: Non-diarrheal stool samples ( N = 22,846) from 1253 children from multiple sites were evaluated for a panel of 40 enteropathogens and fecal concentrations of myeloperoxidase, alpha-1-antitrypsin, and neopterin. Among these same children, urinary lactulose:mannitol (L:M) ( N = 6363) and plasma alpha-1-acid glycoprotein (AGP) ( N = 2797)werealsomeasured.The temporalsampling design was used to create a directedacyclic graph of proposed mechanistic pathways between enteropathogen detection in non-diarrheal stools, biomarkers of in- testinal permeabilityand in fl ammation, systemic in fl ammation and change in length- and weight- for age inchil- dren 0 – 2 years of age. Findings: Children in these populations had frequent enteric infections and high levels of both intestinal and sys- temic in fl ammation. Higher burdens of enteropathogens, especially those categorized as being enteroinvasive or causing mucosal disruption, were associated with elevated biomarker concentrations of gut and systemic in fl am- mation and, via these associations, indirectly associated with both reduced linear and ponderal growth. Evidence for the association with reduced linear growth was stronger for systemic in fl ammation than for gut in fl amma- tion; the opposite was true of reduced ponderal growth. Although Giardia was associated with reduced growth, the association was not mediated by any of the biomarkers evaluated. Interpretation: The large quantity of empirical evidence contributing to this analysis supports the conceptual model of EE. The effects of EE on growth faltering in young children were small, but multiple mechanistic pathways underlying the attribution of growth failure to asymptomatic enteric infections had statistical support in the analysis. The strongest evidence for EE was the association between enteropathogens and linear growth mediated through systemic in fl ammation. Funding: Bill & Melinda Gates Foundation.