Assessment of environmental enteropathy in the MAL-ED cohort study: theoretical and analytic framework

Abstract

Individuals in the developing world live in conditions of intense exposure to enteric pathogens due to suboptimal water and sanitation. These environmental conditions lead to alterations in intestinal structure, function, and local and systemic immune activation that are collectively referred to as environmental enteropathy (EE). This condition, although poorly defined, is likely to be exacerbated by undernutrition as well as being responsible for permanent growth deficits acquired in early childhood, vaccine failure, and loss of human potential. This article addresses the underlying theoretical and analytical frameworks informing the methodology proposed by the Etiology, Risk Factors and Interactions of Enteric Infections and Malnutrition and the Consequences for Child Health and Development (MAL-ED) cohort study to define and quantify the burden of disease caused by EE within a multisite cohort. Additionally, we will discuss efforts to improve, standardize, and harmonize laboratory practices within the MAL-ED Network. These efforts will address current limitations in the understanding of EE and its burden on children in the developing world.

Keywords: environmental enteropathy; infant growth failure; intestinal infections; lactulose mannitol test; tropical enteropathy.

Figure 1.

General overview of interactions between infection and undernutrition. Although it is recognized that this cycle exists for systemic and other nonenteric infections, enteric infections and undernutrition are clearly linked in a way that is clinically evident. Adapted from Mandell et al [4]. Abbreviation: NAIDS, Nutritionally Acquired Immune Deficiency Syndrome.

Figure 2.

It is hypothesized that alterations in gut structure and physiology have diverse but measureable inputs including symptomatic and asymptomatic enteric infections, micronutrient, and macronutrient availability, as well as genetic and epigenetic factors. Alterations in gut function described as environmental enteropathy, in turn, are able to alter mucosal immune responses and macronutrient/micronutrient absorption and availability to have long-term influences on human potential.

Figure 3.

The relationship between enteric infection and undernutrition has long been noted. However, the relationship is complex and bidirectional, and assessments are rarely made with the temporal definition necessary to determine directionality. Furthermore, they have historically lacked the design completeness that is necessary to determine the relative import of nutritional intake and feeding patterns and intestinal infections in the same individuals or done so in samples large enough to address the recognized complexity of interaction between key variables and outcomes. Measures made on clinical specimens of surveillance monthly stool (s), urine (u), or plasma (p). Adapted from Mata [15] and Guerrant et al [16]. Abbreviations: AGP, α-2-acid glycoprotein; LM, lactulose-mannitol test; MPO, myeloperoxidase.