Environmental enteric dysfunction (EED) is commonly defined as an acquired subclinical disorder of the small intestine, characterized by villous atrophy and crypt hyperplasia. EED has been proposed to underlie stunted growth among children in developing countries. A collection of biomarkers, organized into distinct domains, has been used to measure different aspects of EED. Here, we examine whether these hypothesized relationships, among EED domains and between each domain and stunting, are supported by data from recent studies. A systematic literature search was conducted using PubMed, MEDLINE, EMBASE, Web of Science, and CINAHL between January 1,2010 and April 20,2017. Information on study objective, design, population, location, biomarkers, and results were recorded, as well as qualitative and quantitative definitions of EED. Biomarkers were organized into five EED domains, and the number of studies that support or do not support relationships among domains and between each domain with stunting were summarized. There was little evidence to support the pathway from intestinal permeability to microbial translocation and from microbial translocation to stunting, but stronger support existed for the link between intestinal inflammation and systemic inflammation and for intestinal inflammation and stunting. There was conflicting evidence for the pathways from intestinal damage to intestinal permeability and intestinal damage to stunting. These results suggest that certain EED biomarkers may require reconsideration, particularly those most difficult to measure, such as microbial translocation and intestinal permeability. We discuss several issues with currently used biomarkers and recommend further analysis of pathogen-induced changes to the intestinal microbiota as a pathway leading to stunting.
One-quarter of children under the age of 5 years are stunted, defined as a height-for-age > 2 standard deviations below the median as defined by the World Health Organization growth standards. Children whose linear growth is impaired during the first 1000 days after conception have an increased risk of poor cognitive development and educational performance, lost productivity and lower adult earnings, chronic diseases, and mortality over their lifetime [1–3]. There is a well-recognized network of interacting determinants that underlie stunting [4–13]. For many years, studies have focused predominantly on nutrition-specific interventions for stunting; however, previous systematic reviews highlight that neither food quantity nor quality fully explains impaired linear growth in children [14,15]. Diarrhea has been proposed as a major contributor to growth failure in young children, though results are inconsistent [16–19]. While diarrheal episodes in the first few months after birth lead to increased prevalence of stunting at 24 months [20], catch-up growth between diarrheal episodes can be sufficient for linear growth recovery in some children [21]. Environmental enteric dysfunction (EED) is commonly defined as an acquired subclinical disorder of the small intestine, characterized by villous atrophy and crypt hyperplasia. Previous reviews have described the history and epidemiology of environmental enteric dysfunction in detail [1,22–26] and have refocused attention on EED as a potential cause of stunting in developing countries. Exposure to bacteria through fecal contamination is postulated to induce morphological changes, leading to intestinal epithelial damage, increased permeability, and microbial translocation into the lamina propria. This invasion prompts an influx of inflammatory cells to the intestine and leads to local and systematic inflammation, resulting in the reallocation of resources normally directed toward child growth and development, and disruption of hormonal pathways that regulate growth plate activity in long bones. Chronic inflammation and reduced intestinal nutrient absorption are also hypothesized to affect brain development, inducing lasting negative effects on cognition, educational achievement, and linear growth [27]. There are currently no clear diagnostic criteria for EED, which presents a major problem in investigating the role of EED in stunting, and in evaluating treatment and prevention strategies. Intestinal biopsy is used to diagnose diseases with similar pathological changes, such as celiac disease [28]; however, collection of small bowel biopsy samples is technically and ethically infeasible in young children. Over recent years, studies have evaluated a range of potential biomarkers of EED, with a general agreement that these should be organized into distinct domains to measure different aspects of the pathogenic pathway that characterizes EED. Studies have included noninvasive biomarkers of intestinal damage and repair, epithelial permeability and absorption, digestion, epithelial morphology, intestinal inflammation, microbial drivers, systemic immune activation, and non-small intestine organ function. Multiple research groups have used this domain-based approach, focusing on longstanding physiologic relationships to study the complex mechanisms that may underlie EED. Here, we examine whether these relationships are supported by recent and rich new data from studies conducted between 2010–2017, building on the review conducted by Denno et al for the time period 2000–2010 [29]. We define five contributing domains of EED to provide supporting evidence for our two aims: (i) to evaluate the relationships between individual EED domains; and (ii) to evaluate the relationships between each EED domain and stunting. We focus on stunting as the primary outcome in this review, as it is the most common outcome of the included studies and is objectively measured. Although our ultimate interest is in cognition and child development, these have not been as commonly measured, and the mechanistic pathways between stunting and neurodevelopment remain unclear [30].
Our search strategy followed PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines for the reporting of systematic reviews [31]. A search for articles in any language between January 1,2010, and April 20,2017, was conducted using PubMed, MEDLINE, EMBASE, Web of Science, and CINAHL. Abstracts were independently screened by two reviewers (K. H. and M. M.) and full-text articles that were related in any way to “environmental enteric dysfunction”, “environmental enteropathy”, or “tropical enteropathy” were selected for review. The reference lists of all review articles and original publications were also screened for any relevant studies. Published study abstracts were also included in this review. Disagreements regarding study inclusion were resolved by consensus. Our population of interest included individuals of all ages for whom two or more EED domains, or at least one domain and stunting, were measured. Only human studies were included. While most studies focused on children under 5 years, no age restriction was imposed in the search criteria as some adult studies provide valuable histopathological data that is less frequently collected in young children. Studies in both developed and developing countries were included in the search, though only one study in the final selection included individuals from a developed country [32]. Studies selected for inclusion can be categorized into three groups: (i) observational studies in which EED was defined as either an exposure or as an outcome; (ii) studies investigating potential EED biomarkers and/or identification/diagnosis of EED; and (iii) intervention studies designed to treat or prevent EED. A standardized data abstraction form was used to extract information from each study. Abstracted data included: study objective, study design, location, subject eligibility and description of study population, inclusion or exclusion of subjects with diarrhea or human immunodeficiency virus (HIV), results and final conclusions. Biomarkers and diagnostic tests were recorded, as well as any qualitative and quantitative definitions of EED provided by the authors (S1 Table). To review the evidence supporting the complex mechanisms that may contribute to child stunting we have elected to organize results according to these five EED domains: (1) intestinal damage and repair, (2) permeability and absorption, (3) microbial translocation, (4) intestinal inflammation, and (5) systemic inflammation. These domains were determined by consensus from reviewing previous conceptual frameworks and descriptions [2,3, 23,24,29,33–41]. Each domain and its respective non-invasive biomarkers are described below. Studies were included if they reported results for two or more EED domains, or at least one domain and stunting. In the situation where multiple studies included the same EED measurements on the same study subjects, only the most complete report was included in the review. For each of the 5 EED domains, we first present the number of studies that support (or not) the relationships of each domain to stunting. Second, we present the number of studies that report data in support of the relationship between each EED domain and the other domains, where data are available. These associations are summarized in Tables 1 and 2.
Of the 40 reports included in this analysis, 10 (25%) of the studies were conducted in Central or South America, 16 (40%) were conducted in Asia, and 29 (73%) were conducted in Africa. Half of the studies were conducted in rural locations, and 1 study was conducted in both urban and rural populations, while 9 (23%) studies did not specify the setting. Thirty-six (90%) reports included participants under the age of 5 years, and 19 (48%) studies were restricted to children less than 2 years. Three studies were conducted exclusively in adults. Diarrhea was used as an exclusion criterion in 16 (40%) studies; 16 (40%) studies included participants regardless of diarrheal status and 8 (20%) studies did not mention diarrhea in their analyses. Twenty-nine (73%) reports did not specify the HIV status of participants. Seven (17%) studies used HIV as an exclusion criterion and 4 (10%) studies included individuals regardless of HIV status.
In this review, we evaluated individual pathways between domains within EED and between each domain and stunting using studies published between 2010–2017. We found evidence to support the link between intestinal and systemic inflammation and stunting, but little support for the link between microbial translocation and stunting within the limits of current tests. There was conflicting evidence for the associations between intestinal damage and intestinal permeability, as well as intestinal damage and stunting. These results suggest that current biomarkers and proposed mechanisms of EED pathogenesis may need reconsideration, and future studies of pathogen-induced changes to the intestinal microbiota should investigate alternative pathways of the effect of intestinal and systemic inflammation on growth in children.
Globally, one-quarter of children under the age of five are affected by poor linear growth, known as stunting. Interventions, including giving children supplemental foods or improving hygiene to prevent diarrhea, have only been partially successful at restoring normal growth. Environmental enteric dysfunction (EED) is a disease characterized by damage to the lining of the small intestine and is thought to contribute to stunting, though the exact mechanism is still unclear. EED was first diagnosed by removing samples of the intestinal lining and analyzing them under a microscope; however, these procedures are costly and invasive, and recent research has focused on discovering easier ways to identify EED. These tests focus on the many interconnected aspects of EED, including damage and function of the intestinal wall, inflammation, and presence of pathogenic bacteria outside the gut. We conducted a systematic review to evaluate the evidence of relationships between each aspect of EED and stunting. We found the most evidence for the relationship between inflammation and stunting, but less evidence for the relationship between stunting and the presence of pathogenic bacteria outside the gut. Our results suggest that EED may be more complex than previously conceived and that some frequently used EED tests may need reconsideration.
children
medicine and health sciences
microbiome
pathology and laboratory medicine
immunology
permeability
microbiology
biomarkers
diarrhea
age groups
signs and symptoms
materials science
gastroenterology and hepatology
bacteria
families
digestive system
microbial genomics
inflammation
genomics
medical microbiology
immune response
gastrointestinal tract
people and places
biochemistry
diagnostic medicine
anatomy
genetics
biology and life sciences
population groupings
physical sciences
material properties
organisms
Environmental enteric dysfunction pathways and child stunting: A systematic review