Background Environmental enteropathy (EE), the adverse impact of frequent and numerous enteric infections 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 systemic inflammation 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) were also measured. The temporal sampling design was used to create a directed acyclic graph of proposed mechanistic pathways between enteropathogen detection in non-diarrheal stools, biomarkers of intestinal permeability and inflammation, systemic inflammation and change in length- and weight- for age in children 0–2 years of age. Findings Children in these populations had frequent enteric infections and high levels of both intestinal and systemic inflammation. Higher burdens of enteropathogens, especially those categorized as being enteroinvasive or causing mucosal disruption, were associated with elevated biomarker concentrations of gut and systemic inflammation 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 inflammation than for gut inflammation; 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 inflammation. Funding Bill & Melinda Gates Foundation.
Bibliographical noteFunding Information:
The Etiology, Risk Factors and Interactions of Enteric Infections and Malnutrition and the Consequences for Child Health and Development Project (MAL-ED) is carried out as a collaborative project supported by the Bill & Melinda Gates Foundation ( 47075 ), the Foundation for the National Institutes of Health , and the National Institutes of Health , Fogarty International Center . We particularly want to thank the children and caregivers who participated in the study for their invaluable contributions. Tom Brewer and Gretchen Meller are also thanked for their early support of the project. We are truly indebted to the following individuals for their advisory role in the MAL-ED study: Henry Binder, Maureen Black, Kathleen Braden, Robert Breiman, Susan Bull, Katherine Dewey, Christopher Duggan, Christine Grady, Gerry Keusch, Nancy Krebs, Claudio Lanata, James Nataro, Jerome Singh, Peter Smith, Phillip Tarr, Katherine Tucker and Theodore Wachs. Fraser Lewis is recognized and appreciated for his critical review of and guidance on the analytical methods and statistical approaches applied in the MAL-ED study. We thank Leslie Pray and Alicia Livinski for their editorial assistance. Special thanks go to Roger Glass and George Griffin for their continued support and guidance.
© 2017 The Authors
- Child growth
- Child health