Biomarkers of Environmental Enteric Dysfunction: The Good, the Bad, and the Ugly

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Environmental enteric dysfunction (EED) has been described as altered enteric architecture and function resulting in poor absorption, increased permeability, and chronic mucosal inflammation among infants and children who live in low- and middle-income countries (LMICs) (1–3). EED has been hypothesized to underlie high rates of stunting and growth failure among these vulnerable children (4–7), impaired immune response to vaccines (4) and suboptimal cognitive development (8). The etiology of the condition has been thought to be related to chronic gastrointestinal (GI) exposure to enteropathogens via an unhygienic environment, although other contributing factors may include altered mucosal and/or systemic immune function, preceding acute infectious illnesses, micronutrient deficiencies, both pre-and post-natal infant-maternal interactions, heavy metal exposures, and other as yet undiscovered factors.
Despite the wealth of evidence cited above about the important role of EED in child health, development and growth, there is currently no single gold standard diagnostic test for EED. While early studies documented morphometric changes in the small bowel mucosa of residents of South Asia (9,10), findings that are supported by more recent confocal microscopy data (11), routine endoscopic examination among children at risk of EED is thought to be untenable due to its cost, invasiveness, and need for technical expertise. Hence numerous investigators have pursued less invasive measures of EED, including tests of GI permeability, absorption, enterocyte mass and function, inflammation, microbial translocation, and systemic and immune activation (1).
Chief among the proposed biomarkers of EED are urinary measures of GI absorption and permeability and which are feasible via straightforward if laborious field tests, reflect important components of GI barrier and absorptive function. After oral administration of 2 carbohydrates, the ratio of urinary lactulose (a sugar not usually absorbed by intact GI mucosa, whose concentration is therefore taken to correlate with intestinal permeability) and mannitol (a sugar usually passively absorbed, whose concentration is therefore thought related to mucosal surface area) are most commonly used. The noninvasive nature of these markers has facilitated their use as a measure of EED in a variety of settings. Denno et al (12) summarized numerous studies of the urinary L:M ratio in a recent systematic review, noting that despite its many advantages (noninvasiveness, wide availability of substrates, and face validity), variation in data presentation, substrate dosing, subject selection, and fasting status were among several factors that need to be considered in efforts to improve the utility of this test.
In this volume of Journal of Pediatric Gastroenterology and Nutrition, 2 large and detailed studies of numerous markers of EED, including the urinary L:M ratio, are reported. In one study, Kosek et al (13) describe changes in GI absorption and permeability using the urinary L:M test in several large and diverse populations at risk of EED and its associated growth faltering, with the goal of defining a reference standard for this commonly used test of enteropathy. The authors hypothesized that their analyses would provide references across sites, ages, and sex and thus allow the creation of L:M standards for broader use. The study was part of a large parent study “The Etiology, Risk Factors, and Interactions of Enteric Infections and Malnutrition and the Consequences for Child Health and Development” (the MAL-ED study), whose overall goal is to evaluate the association of childhood growth, GI function (14), and infectious disease morbidity with standard tests of neurodevelopmental ability and vaccine response (http://mal-ed.fnih.org). The study used a common protocol to follow and collect samples among infants over time in 8 distinct locations, including both rural and urban sites in several LMICs: Dhaka, Bangladesh; Vellore, India; Bhaktapur, Nepal; Naushero Feroze, Pakistan; Fortaleza, Brazil; Loreto, Peru; Venda, South Africa; and Haydom, Tanzania.
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