Environmental Enteric Dysfunction and Growth Failure/Stunting in Global Child Health Victor Owino, PhD,a Tahmeed Ahmed, PhD,b Michael Freemark, MD, c Paul Kelly, MD, d, e Alexander Loy, PhD,f Mark Manary, MD, g Cornelia Loechl, PhDa Approximately 25% of the world’s children aged <5 years have stunted abstract growth, which is associated with increased mortality, cognitive dysfunction, and loss of productivity. Reducing by 40% the number of stunted children is a global target for 2030. The pathogenesis of stunting is poorly understood. Prenatal and postnatal nutritional deficits and enteric and systemic a International Atomic Energy Agency, Vienna, Austria; infections clearly contribute, but recent findings implicate a central role bInternational Centre for Diarrhoeal Research, Bangladesh, for environmental enteric dysfunction (EED), a generalized disturbance Dhaka, Bangladesh; cDivision of Pediatric Endocrinology, Duke University Medical Center, Durham, North Carolina; of small intestinal structure and function found at a high prevalence in dUniversity of Zambia, Lusaka, Zambia; eBlizard Institute, children living under unsanitary conditions. Mechanisms contributing Queen Mary University of London, London, United Kingdom; fDepartment of Microbiology and Ecosystem Science, to growth failure in EED include intestinal leakiness and heightened Research Network “Chemistry meets Microbiology, ” permeability, gut inflammation, dysbiosis and bacterial translocation, University of Vienna, Vienna, Austria; and gWashington systemic inflammation, and nutrient malabsorption. Because EED has University, St Louis, Missouri multiple causal pathways, approaches to manage it need to be multifaceted. Dr Owino drafted the initial manuscript, wrote the Potential interventions to tackle EED include: (1) reduction of exposure to conclusion, formatted the manuscript to conform to Pediatrics style, and reviewed and revised feces and contact with animals through programs such as improved water, the manuscript; Dr Ahmed wrote the section on sanitation, and hygiene; (2) breastfeeding and enhanced dietary diversity; emerging approaches for prevention and treatment (3) probiotics and prebiotics; (4) nutrient supplements, including zinc, of environmental enteric dysfunction (EED), and reviewed and revised the manuscript; Dr Freemark polyunsaturated fatty acids, and amino acids; (5) antiinflammatory agents wrote the section on growth failure and stunting such as 5-aminosalicyclic acid; and (6) antibiotics in the context of acute in malnutrition and EED and edited the manuscript; malnutrition and infection. Better understanding of the underlying causes Dr Kelly wrote the section on pathobiology of of EED and development of noninvasive, practical, simple, and affordable EED and contributed to Future Directions, and reviewed and revised the manuscript; Dr Loy point-of-care diagnostic tools remain key gaps. “Omics” technologies wrote the section on the diagnostic potential of (genomics, epigenomics, transcriptomics, proteomics, and metabolomics) stable isotope assays, and reviewed and revised and stable isotope techniques (eg, 13C breath tests) targeted at children and the manuscript; Dr Manary wrote the section on application of –“-omic” technology in EED diagnosis, their intestinal microbiota will enhance our ability to successfully identify, contributed to Future Directions, and reviewed and manage, and prevent this disorder. revised the manuscript; Dr Loechl conceptualized and facilitated discussions for the perspective, and reviewed and revised the manuscript; and all z authors approved the fi nal manuscript as submitted Malnutrition in young children scores less than –2. The pathogenesis and agree to be accountable to all aspects of the increases the risks of death from of stunting, which is more prevalent work. diarrhea, pneumonia, and other than wasting, is poorly understood. DOI: 10.1542/peds.2016-0641 infectious diseases and is associated Prenatal and postnatal nutritional Accepted for publication May 10, 2016 with growth failure, cognitive deficits and enteric and systemic Address correspondence to Victor Owino, PhD, delay, and loss of productivity. 1 – 4 infections clearly contribute, but Nutritional and Health-Related Environmental Malnutrition manifests as “wasting, ” recent findings implicate a central role with loss of tissue mass and marked for environmental enteric dysfunction reductions (>2 SDs below the mean) (EED), a generalized disturbance of To cite: Owino V, Ahmed T, Freemark M, et al. in weight-for-height z scores, and small intestinal structure and function Environmental Enteric Dysfunction and Growth “stunting, ” a chronic condition with blunting or atrophy of intestinal Failure/Stunting in Global Child Health. Pediatrics. 2016;138(6):e20160641 associated with height-for-age villi, inflammatory cell infiltrates, Downloaded from www.aappublications.org/news by guest on September 29, 2021 PEDIATRICS Volume 138 , number 6 , December 2016 :e 20160641 STATE-OF-THE-ART REVIEW ARTICLE TABLE 1 Determinants and Complications of EED Determinants Mechanisms, Consequences, and Treatment Socioeconomic Gross domestic product Environmental Water, sanitation, and hygiene Exposure to animal feces Crowding Seasonality Helminthic and parasitic infections Early life exposures Maternal microbiome and EED Mode of birth (vaginal versus cesarean) Infant and young child feeding practices Gut microbiota Microbiome diversity Functions of specifi c members of the microbiota Microbial translocation Prebiotics and probiotics Dietary diversity Nutrients Nutrient defi ciencies (eg, zinc defi ciency) Increased nutrient requirements Proinfl ammatory nutrients (eg, iron) Nutrient malabsorption Immunity Vaccine responses Growth failure/undernutrition Stunting Severe acute malnutrition Infl ammation Gut infl ammation Systemic infl ammation Antiinfl ammatory agents and hyperplasia of small intestinal and water. It is unlikely that any 1 FIGURE 1 crypts (Fig 1). EED is found at a high pathogen explains the pathology Histologic sections from distal duodenal biopsy prevalence in stunted children living of EED and more likely that it specimens from Zambian patients with EED. (A) Relatively normal mucosa has long, slender under unsanitary conditions and is represents frequent, low-inoculum villi and short crypts, with only a slight increase pandemic in developing countries exposure to a range of pathogens, 5, 6 in lamina propria lymphocytes; the villus height: with limited resources ( Table 1). which could be regarded as a form of crypt depth ratio approximates 3:1. (B) A biopsy Major gaps in our understanding dysbiosis. specimen from a child with severe EED and moderate malnutrition showing villus shortening of the pathogenesis of EED and its The identification that there is a and reduction in villus height: crypt depth ratio relationship to stunting limit our change in small intestinal structure to slightly more than 1:1. (C) Confocal laser ability to diagnose and effectively endomicroscopy shows leakage of fl uorescein and function in the tropics originated prevent and treat this condition. (arrows) around a villus after an intravenous in the 1960s, 1 but it is only in the injection into the intestinal lumen. The present state-of-the-art last ∼2 decades that we have come consensus statement summarizes to understand that it may have microbial translocation (entry of a 3-day meeting organized by implications for nutrition and long- gastrointestinal organisms into the the International Atomic Energy term health of children living in systemic compartment) but not much 2–4 Agency, which focused on EED and low-resource settings. In early malabsorption, whereas another the prospects for its reduction or reports, the focus was on structural child may have more significant amelioration in children living in the derangements (shortened, blunted malabsorption but only mild developing world. villi and increased crypt depth) and translocation. The meeting organized disturbances of permeability and by the International Atomic Energy absorption. More recently, additional Agency identified several domains PATHOBIOLOGY OF EED derangements have been identified, that may need to be individually EED may be defined as a global including intestinal inflammation, 7 disturbance of intestinal structure systemic inflammation, 8 and measured to provide a full picture and function that has its origin in changes in the microbiome. 9 The of gut dysfunction and to assess the environmental factors. The condition complexity of the EED syndrome impact of different interventions. occurs with high frequency in is such that these derangements These domains describe axes developing areas with poor sanitation cannot be assumed to operate of measurement and aspects of and limited public health resources, to the same degree in different pathophysiology: (1) gut leakiness/ in association with microbial and children. For example, 1 child may permeability 10; (2) microbial parasitic contamination of food have a very “leaky” gut with severe translocation 10, 11; (3) gut Downloaded from www.aappublications.org/news by guest on September 29, 2021 2 OWINO et al inflammation 7; (4) systemic weight-for-age z scores of –3 SDs or gestational age infants who fail to inflammation 8; (5) dysbiosis9 ; and less, it has high (10%–20%) mortality achieve adequate catch-up growth. 11–13 (6) nutrient malabsorption. when complicated by diarrhea, Indeed, in 20% to 25% of infants pneumonia, sepsis, hypoglycemia, As opposed to focal defects