Assessment of Environmental Enteric Dysfunction in the SHINE Trial: Methods and Challenges.

Andrew J Prendergast,Lawrence H Moulton,Jean H Humphrey,Rebecca J Stoltzfus,Kuda Mutasa,Margaret Govha,Sandra Rukobo,Mduduzi N N Mbuya,Florence D Majo

doi:10.1093/cid/civ848

Abstract

Environmental enteric dysfunction (EED) is a virtually ubiquitous, but poorly defined, disorder of the small intestine among people living in conditions of poverty, which begins early in infancy and persists. EED is characterized by altered gut structure and function, leading to reduced absorptive surface area and impaired intestinal barrier function. It is hypothesized that recurrent exposure to fecal pathogens and changes in the composition of the intestinal microbiota initiate this process, which leads to a self-perpetuating cycle of pathology. We view EED as a primary gut disorder that drives chronic systemic inflammation, leading to growth hormone resistance and impaired linear growth. There is currently no accepted case definition or gold-standard biomarker of EED, making field studies challenging. The Sanitation Hygiene Infant Nutrition Efficacy (SHINE) trial in Zimbabwe is evaluating the independent and combined effects of a package of infant feeding and/or water, sanitation, and hygiene interventions on stunting and anemia. SHINE therefore provides an opportunity to longitudinally evaluate EED in a well-characterized cohort of infants, using a panel of biomarkers along the hypothesized causal pathway. Our aims are to describe the evolution of EED during infancy, ascertain its contribution to stunting, and investigate the impact of the randomized interventions on the EED pathway. In this article, we describe current concepts of EED, challenges in defining the condition, and our approach to evaluating EED in the SHINE trial.

Highlights

A key hypothesis of the Sanitation Hygiene Infant Nutrition Efficacy (SHINE) trial is that environmental enteric dysfunction (EED), a subclinical disorder of the small intestine, is a major cause of child stunting [1]
Within SHINE, the cluster-randomized design will enable us to investigate the impact of water, sanitation, and aMembers of the SHINE Trial Team are shown in SHINE Trial Team, “The Sanitation Hygiene Infant Nutrition Efficacy (SHINE) trial: rationale, design, and methods,” Clin Infect Dis 2015; 61(suppl 7):S685–702
We recently showed that Zimbabwean infants have extremely high plasma concentrations of intestinal fatty acid binding protein (I-FABP), indicating extensive damage to small-intestinal villi, with levels exceeding those reported among healthy children in Europe or among unhealthy children with celiac disease [11]

Summary

Introduction

A key hypothesis of the Sanitation Hygiene Infant Nutrition Efficacy (SHINE) trial is that environmental enteric dysfunction (EED), a subclinical disorder of the small intestine, is a major cause of child stunting [1]. We lack understanding of the geographical variation in EED because of challenges in defining the condition consistently, recent findings from the Malnutrition and Enteric Disease (MAL-ED) study, which used standardized methods to assess gut biomarkers in 8 birth cohorts across 3 continents, confirm that this condition is almost ubiquitous among young children in impoverished communities [10]. Infants across these diverse settings had elevated markers of intestinal inflammation that far exceeded levels typically seen among infants in developed countries [10]. We found that infants with poor linear growth had elevated acute phase proteins and reduced concentrations of insulin-like growth factor 1 (IGF-1), suggesting a central role for chronic inflammation and growth hormone resistance in stunting [11]

Objectives

Methods

Findings

Conclusion