Environmental Enteric Dysfunction and Growth Failure/Stunting in Global 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 style, and reviewed and revised feces and contact with animals through programs such as improved water, the manuscript; Dr Ahmed wrote the section on , and hygiene; (2) 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 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. , pneumonia, and other than , 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 delay, and loss of productivity. 1 – 4 infections clearly contribute, but Address correspondence to Victor Owino, PhD, 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) 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 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 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 and children considered “stunted,” and/or dehydration. 17, 18 EED may (as seen in Crohn’s disease), the growth failure begins in utero: also include components of HIV- EED predominantly affects the prematurity and intrauterine related enteropathy5 and aflatoxin- proximal small intestine in a global growth restriction, particularly in mediated enteropathy, 19 distribution. The condition is combination, increase the risk of conditions that we currently know seasonal, 5 reversible, 14 and generally postnatal stunting 22 – 25 by twofold to very little about. 1 asymptomatic, as distinct from sevenfold. This explains, in part, the can cause enteropathy, but diarrheal disease. The anatomic high rates of stunting in developing extensive experience with zinc and pathophysiologic basis of EED countries, where mean length-for- supplementation suggests that it can is reflected in the aforementioned age z scores at birth approximate ameliorate the effects of diarrhea and domains. As with other –0.5, and low (LBW) is reduce gastrointestinal permeability enteropathies, EED is characterized 6 times more common than in the but does not improve nutrient by villus blunting, inflammation in developed world.23, 25 absorption. 20 Helminth infection, the epithelium and lamina propria, established for hookworm but not The health, maturity, and economic and leakiness due to perturbation clearly shown for other helminths, and social status of the of tight junction integrity and may also contribute to EED. central roles in the pathogenesis microerosions ( Fig 1). Evidence is of LBW and the growth of the child 15 also found of disturbances of mucus It is self-evident from these after birth. Factors predisposing to 16 and antimicrobial peptides, observations that interventions for LBW and childhood stunting include: which, together with tight junction the various elements of EED are a history of moderate or severe failure and microerosions, could distinct and should be evaluated maternal malnutrition, stunting, or permit entry of microorganisms separately. A recent review proposed early age at pregnancy; suboptimal and their component parts into the the inclusion of exposure to chemical pregnancy weight gain; maternal systemic compartment from which, toxicants such as pesticides and smoking; and inadequate infant in health, they would be excluded. drugs as potential causes of EED. 21 feeding practices. 22 – 25 The advent This translocation drives gut Put simply, EED does not have a of EED in infancy or early childhood inflammation, further exacerbating single cause, and it is unlikely to be likely amplifies growth deficits gut dysfunction, and systemic resolved by a single intervention. sustained during the intrauterine inflammation, 8 which can further and perinatal periods, resulting in perturb immune function and lead stunting. Length-for-age z scores of to . This positive feedback stunted children typically decline GROWTH FAILURE AND STUNTING IN underlies the vicious cycle of from birth to a nadir between 18 MALNUTRITION AND EED malnutrition, infection, and immune and 24 months of age, presumably failure described >5 decades ago The term “stunted” is applied to because rapidly growing infants and in classic studies of malnutrition in infants and children whose lengths toddlers are particularly vulnerable Central America. 4 (or heights) are >2 SDs below the to nutritional, infectious, and toxic Within the spectrum of EED, several median for age as determined by environmental insults. In concert disorders are recognized that look using World Health Organization with nutritional deficits incurred phenotypically similar and may growth standards. Stunting in the during fetal, perinatal, and early have similar effects on childhood developing world results most postnatal life, the imposition of growth. Although these disorders commonly from chronic nutrient EED may limit nutrient delivery have a common origin in unsanitary deficiencies, recurrent infection(s), and utilization and thereby impair environments, 4, 6 they likely have and/or chronic inflammation the maturation and proliferation of distinct etiopathogeneses and (including EED). Nevertheless, large small intestinal epithelial cells, renal β therefore present different or cohorts of “stunted” subjects may nephrons, pancreatic cells, and overlapping targets for intervention. also include infants and children skeletal myocytes and growth plate 26,27 For example, the enteropathy with hormonal or metabolic chondrocytes. of severe acute malnutrition disorders causing postnatal growth The specific mechanisms by which comprises elements of acute and failure; children with genetic or EED causes growth failure and chronic infection, inflammation, and familial forms of ; postnatal stunting are poorly malabsorption. Seen in children with and premature and/or small for understood, although inadequate or

Downloaded from www.aappublications.org/news by guest on September 29, 2021 PEDIATRICS Volume 138 , number 6 , December 2016 3 inconsistent energy intake, recurrent production and action 41 and thereby of nutrient deprivation, infection, infection, and local and systemic attenuate linear growth. and cytokine excess associated with inflammation likely play important small bowel inflammation. The Growth failure in EED may be roles. Factors contributing to growth SHINE (Sanitation Hygiene Infant exacerbated by the development of failure may include immaturity of the Nutrition Efficacy) trial is currently acute malnutrition, most commonly a gut microbiome 28 and deficiencies of investigating the hypothesis that EED consequence of gastrointestinal and certain gut microbes and/or breast has adverse consequences in addition pulmonary infections and sepsis. 42 milk constituents such as sialylated to postnatal growth failure, including Endocrinologic studies 36, 37 provide reduced oral vaccine efficacy, oligosaccharides that promote gut insight into the pathogenesis of anemia, impaired neurocognitive barrier integrity, nutrient utilization, growth failure in malnourished 29–31 development, and fetal growth and tissue anabolism. Even in the children. Nutrient deprivation restriction and prematurity resulting absence of diarrhea, the permeability provokes a striking increase in from maternal EED.51 EED has of the small bowel toward growth hormone and fall in insulin, α recently been linked to reduced carbohydrates and 1-antitrypsin which in concert promote lipolysis 7, 32 efficacy of oral polio and rotavirus is increased, suggesting a role and deplete white adipose fat vaccines in Bangladeshi infants. 52 for macronutrient malabsorption. stores and thereby reduce levels Many children with EED also have of the adipocyte hormone leptin. deficiencies in micronutrients Hypoleptinemia downregulates absorbed by the small bowel such EED BIOMARKERS AND DIAGNOSTIC the hypothalamic-pituitary-thyroid TESTS as iron and zinc, which, if depleted, axis and inhibits conversion of can reduce appetite, villous surface T4 to its more active form, T3. 43 Difficulties in identifying the area, and gastrointestinal absorptive The fall in T3 impairs chondrocyte multiple etiologies of EED and in capacity. 33, 34 maturation and growth. The distinguishing EED from other types stress of acute malnutrition and of intestinal dysfunctions impose Inflammation of the small intestine concurrent infection activates the considerable challenges for diagnosis in EED is associated with high hypothalamic-pituitary-adrenal axis and hamper development of specific C-reactive protein levels and may and stimulates a rise in cortisol36, 37 diagnostic tests. Endoscopic and be accompanied by release of and IGF binding protein 1, which in histopathologic evaluation of small cytokines that reduce appetite combination inhibit IGF-1 action and intestinal biopsy specimens, with and food intake 35 and impede induce chondrocyte apoptosis. 44, 45 continuous measures of mucosal production and action of chondrocyte A reduction in hepatic growth architecture (villus height in growth factors. Recent studies 36, 37 hormone receptor expression46 micrometers rather than ordinal found that stunted, malnourished and inhibition of growth hormone scales of blunting), 5 allow for direct Ugandan infants and children (age signaling47 by fibroblast growth observation of aberrant epithelial 6 months–5 years) had high levels factor 21 limit IGF-1 production and structures and inflammation of interleukin 6 (IL-6), which blocks thereby contribute to growth failure status. However, noninvasive or growth hormone induction of in patients with EED. less-invasive diagnostic assays are preferred for logistic reasons insulin-like growth factor 1 (IGF-1) Therapeutic measures in EED, (ie, use in nonclinical settings and production and inhibits IGF action including nutritional supplements 38, 39 because they are better accepted by at the growth plate. Likewise, and antibiotics, may fail to restore patients). Depending on the aspect IL-6 levels were elevated soon after growth in children stunted before of gut function or dysfunction of delivery in a subset of Zimbabwean the age of 2 years. 24 In some cases, interest, biomarkers of EED may fall infants with LBW. 8 Interestingly, this outcome may simply reflect under 1 of 5 categories, 53 namely: (1) IL-6 levels are high in children and a genetic or familial tendency to intestinal absorption and mucosal adults with inflammatory bowel short stature. Alternatively, failure permeability; (2) enterocyte mass disease and correlate inversely with of catch-up growth in children with and function; (3) inflammation; (4) childhood growth rates and IGF-1 prenatal or early postnatal growth microbial translocation and immune levels. 40 Thus, the rise in IL-6 (and failure might be explained by: (1) activation; and (5) intestinal injury other cytokines) in association with inadequate reserve, or epigenetic and repair. small bowel inflammation may limit changes, 48, 49 in cells critical for food intake, IGF-1 production, and growth, including myocytes and The most commonly applied linear growth in children with EED. chondrocytes; (2) long-term defects noninvasive assay to assess EED Inadequate intake and malabsorption in small intestinal maturation and is a dual sugar test, the lactulose: of zinc in EED may also reduce IGF-1 growth 50; and/or (3) recurrent bouts mannitol test, which is based

Downloaded from www.aappublications.org/news by guest on September 29, 2021 4 OWINO et al on oral dosing and subsequent about the mechanisms through which stable isotope techniques are urinary measurement of lactulose it exerts its deleterious effects. emerging as promising noninvasive/ and mannitol to evaluate both less invasive, safe tools for measuring A large transcriptomic study of epithelial absorptive capacity and gastrointestinal function and rural African children using a novel permeability in the small intestine determining EED. The foundation of method to assess host transcripts (aforementioned domains 1 and these methods is oral administration in feces found diverse activation of 7).54, 55 In addition, recent research of an isotopically labeled compound many of the immunologic responses has identified various serum and and subsequent monitoring of the seen in the gut epithelium. 59 Twelve fecal biomarkers of intestinal appearance of the compound or transcripts were associated with inflammation in the context of its catabolic products in breath, the severity of EED, including EED. 3, 56 Serum biomarkers include feces, urine, and/or blood. 61 chemokines that stimulate T-cell lipopolysaccharide, soluble CD Depending on the type of labeled proliferation, Fc fragments of 14, IGF-1, ferritin, IL-6, IL-1β, compound, stable isotope assays multiple immunoglobulin families, C-reactive protein, zonulin, and can assess epithelial function in interferon-induced proteins, endogenous endotoxin-core several domains (ie, absorption, activators of neutrophils and B antibody (EndoCab, Hycult Biotech, permeability, metabolism) and cells, and mediators that dampen Uden, the Netherlands). Fecal can be used to characterize a cellular responses to hormones. EED- biomarkers include regenerating particular microorganism or group associated transcripts were mapped islet-derived 1 beta, calprotectin, of microorganisms that catabolize to pathways related to cell adhesion myeloperoxidase, neopterin, the ingested compound. This and responses to a broad spectrum α -antitrypsin, and lactoferrin. latter feature is especially useful 1 of viruses, bacteria, and parasites. Although these biomarkers permit for probing microbial activities in Several mucins, regulatory factors, assessment of intestinal/systemic the upper gastrointestinal tract in and protein kinases associated with inflammation and/or intestinal EED; analysis of fecal microbiota 9 maintenance of the mucous layer epithelial barrier dysfunction, the provides an inadequate proxy for were expressed at lower levels in main limitation to their use is that the composition and function of children with EED than in normal they are not specific for EED because microbiota in the stomach, the children. The pattern of expression they correlate with prevalence, duodenum, or the small bowel. was compatible with an assault activity, and/or severity of various by multiple microorganisms from Characterizing microbial other gastrointestinal diseases. One diverse phyla. In addition, antiviral activity, particularly in the upper of the downstream consequences transcripts were detected. This rich gastrointestinal tract, is important of EED is vaccine failure, 28, 57 but it data set offers clues for those seeking for 2 reasons. First, EED is associated has not been generally accepted as a pharmacologic intervention against with infections by pathogens (eg, diagnostic measure of EED. Cutting EED as well as novel fecal biomarkers Helicobacter pylori) and microbial edge innovations such as -omics and for the condition. overgrowth and general dysbiosis nuclear technologies (stable isotope in the small intestine in humans. techniques) may provide a much- Epigenomics and proteomics have Second, exposure to a defined needed capability to diagnose and not been applied to EED as far as we know. Metabolomic analysis has mixture of commensal bacterial better understand EED. Escherichia coli been undertaken, but major findings isolates, including Bacteroidales have not been released. 60 Although and members of the , triggered a phenotype in moderately APPLICATION OF -OMICS TECHNOLOGY the complex effects of prenatal and postnatal environmental factors malnourished mice that resembled human EED. 62 This finding provides Much has been learned about the clearly complicate the analysis of strong evidence for the role played by biology of health and disease states children with EED, we anticipate microorganisms in the pathogenesis through application of -omics future research using genomic and of EED. technologies: genomics, epigenomics, metabolomic approaches to dissect transcriptomics, proteomics, and the pathobiology of EED. Available noninvasive, stable isotope metabolomics. 58 The essence of breath tests for potential use in -omics is an agnostic survey across EED include, but are not limited the total spectrum of a given type DIAGNOSTIC POTENTIAL OF STABLE to, a highly sensitive and specific ISOTOPE ASSAYS of molecule or analyte class. As 13C-urease assay for H pylori 63 and a pathologic condition, EED is an Beyond the use of the lactulose: application of various 13C-sugars (eg, excellent candidate for -omics mannitol test and various serum and sucrose, xylose, glucose, lactose) 64, 65 surveys because so little is known fecal biomarkers, 11, 56 nonradioactive, or 13C-labeled glycosyl ureides 66, 67 to

Downloaded from www.aappublications.org/news by guest on September 29, 2021 PEDIATRICS Volume 138 , number 6 , December 2016 5 measure epithelial barrier function, compared with children living in preventive and therapeutic absorptive capacity, and intestinal default conditions. 71 Moreover, measures include increasing access transit time, and to identify small stunting prevalence was reduced of children to appropriate and intestinal bacterial overgrowth and by 22%. More recently, a public adequate diets containing animal- dysbiosis. In addition, intestinal sanitation program in Mali showed source foods, supplementation with absorption and bioavailability of that enhanced access to did zinc, and adequate treatment of specific micronutrients, in particular not reduce the prevalence of diarrhea recurrent illnesses such as diarrhea iron and zinc, from diets can be but increased childhood growth, and pneumonia. Population- measured after oral ingestion of particularly in those <2 years of wide prevention of EED will isotopically labeled iron (54Fe, 57Fe, age. 72 A possible explanation could require adequate nutrition and and 58Fe)68 and zinc (67Zn, 68Zn, be reduced chronic exposure to health maintenance of all girls of and 70Zn)12, 69 compounds. Although pathogenic bacteria, resulting in reproductive age and women prior the use of different stable isotope reduced severity or prevalence of to, during, and after pregnancy. compounds in a single composite EED. Under conditions of extreme food assay for simultaneous assessment Ensuring hygiene at critical times is insecurity, supplementation with of multiple intestine-associated critical to preventing EED. A study nutritious ready-to-use food for clinical end points has not yet been conducted in slums and villages in children with severe or moderate fully exploited, the available and Bangladesh revealed that 40% of acute malnutrition has been shown to established stable isotope assays complementary foods prepared by enhance clinical recovery. 76, 77 have great potential for application in were contaminated with Agents that can offset or reduce EED diagnostics and research. E coli; this contamination resulted chronic inflammation at the in higher rates of diarrhea and gut mucosal level are currently malnutrition. 73 It is now believed being evaluated. These include EMERGING APPROACHES FOR THE that zinc deficiency, rampant in PREVENTION AND TREATMENT OF EED 5-aminosalicyclic acid, which in a developing countries, co-exists with recent study was not efficacious 78; The treatment of EED is fraught with EED and increases the severity of the the nasal steroid budesonide; and an difficulties. First, in the absence of condition. 20, 33, 34 Given the inadequate immunomodulatory small molecule robust point-of-care biomarkers, the dietary intake of zinc in children called oglufanide disodium. 3 identification of EED in the individual living in developing countries, the Only well-designed, randomized child is problematic. Moreover, there importance of its supplementation, 74 controlled trials that assess efficacy is no robust evidence from clinical either long term or at least as part of and adverse effects in settings of trials that specific interventions can treatment of diarrhea, cannot be over high prevalence of stunting/EED can cure or ameliorate the signs and estimated. The claim that exclusive lead the way to effective and safe symptoms of EED. breastfeeding can reduce gut treatments. inflammation was recently validated Because EED has its roots in the in South African children. 75 environment, the mainstay of SUMMARY AND FUTURE DIRECTIONS preventing the condition is to In summary, emerging evidence “clean” the environment. This suggests that the following factors, Reducing by 40% the number of approach is challenging because in combination, can reduce the children aged <5 years who are water scarcity still afflicts 40% of incidence, prevalence, and severity of stunted is a global target for 2030. the world’s population, and 13% EED: (1) access to safe drinking water Systematic reviews have revealed of the population still defecates and improved hygiene practices in that optimal nutrition intervention in the open. 70 Furthermore, one- low-income countries; (2) provision packages for high-risk children may sixth of the world’s people lack of sanitary facilities and only partially reduce the prevalence access to safe drinking water. The changes in public behavior regarding and severity of stunting. 79, 80 We do provision of basic sanitation facilities, their use; (3) exclusive breastfeeding not know if nutritional therapies potable water, and improved for the first 6 months and continued fail because stunted children have hygiene practices cut the chain of breastfeeding thereafter; and (4) zinc altered intestinal microbiota, transmission of pathogenic bacteria supplementation. insufficient nutrient intake, nutrient that can colonize the small intestine Because stunting is a hallmark malabsorption, or disordered and cause EED. Indeed, a study in of EED, a major goal should be to partition of nutrients. It is also Bangladesh found that ensuring prevent the condition as well as treat unclear if nutrient utilization/ a clean environment increased its complications. In the context wastage is too high to permit population height-for-age 0.54 SD of poor socioeconomic conditions, adequate lean tissue accretion.

Downloaded from www.aappublications.org/news by guest on September 29, 2021 6 OWINO et al Finally, we don't know if insults sanitation and hygiene, including CONCLUSIONS inflicted before or soon after birth are reduction of exposure to feces EED does not have a single cause or fully reversible even with adequate and contact with animals; (2) even a single causal pathway, and it postnatal nutrient repletion. promotion of dietary diversity is unlikely to be resolved by a single The complexity of the EED syndrome and breastfeeding; (3) adequate intervention. The identification is such that gastrointestinal supplementation with micro- and of EED is fraught with difficulties derangements cannot be assumed macronutrients including zinc and due to the absence of robust to operate to the same degree in amino acids; (4) antiinflammatory point-of-care biomarkers. Better different children. There may be agents; and (5) antibiotics for understanding of the underlying considerable individual variation children with severe acute causes and pathogenesis of EED, in gut "leakiness", bacterial malnutrition and infection. Some development of noninvasive, translocation, malabsorption, and of these interventions (especially practical, simple, and affordable nutrient requirements. Given the water, sanitation, and hygiene, point-of-care diagnostic tools, burden of concurrent infection infant feeding practices, and and longitudinal studies designed and inflammation, EED-afflicted nutrient repletion) are being tested to treat or ameliorate signs and children may require considerably individually or combined in large symptoms of EED remain key higher nutrient intakes than healthy randomized controlled studies in a gaps. Cutting-edge innovations children in order to maintain normal number of countries. Information using the field of -omics and stable weight gain. gained from these investigations isotope techniques may provide a may guide the development of novel much-needed capability to better Our understanding of EED is severely therapies in the future. limited by its complex spectrum, understand, prevent, and treat EED. absence of robust biomarkers, and The application of omics technologies noninvasive, simple point-of-care (eg, genomics, epigenomics, ACKNOWLEDGMENTS diagnostic tools. Several domains transcriptomics, proteomics, We sincerely thank all participants may need to be evaluated in each metabolomics) and use of stable who generated the information on child to provide a full picture of isotopes should allow us to better which this article is based during gut dysfunction and to assess the define the nature and extent of the technical meeting of EED held impact of different interventions. gastrointestinal damage and at the International Atomic Energy These domains include: (1) gut dysfunction in EED and can be used Agency headquarters, Vienna, leakiness/permeability; (2) to characterize microbial activities Austria, October 28–30, 2015. We microbial translocation; (3) in the upper gastrointestinal tract are also grateful to Kirsten Glenn for gut inflammation; (4) systemic in affected children. Stable isotopes proofreading the manuscript. inflammation; (5) dysbiosis; and can also be employed to assess body (6) nutrient malabsorption. Further composition as a proxy for dietary investigation will be needed to quality and nutritional status and as characterize fully the effects of a determinant of childhood morbidity ABBREVIATIONS gut dysfunction on hormonal and and mortality. While validation of EED: environmental enteric metabolic status, childhood growth, the various diagnostic techniques is dysfunction and neurocognitive function. obligatory, these new approaches IGF: insulin-like growth factor Potential interventions to tackle should ultimately enhance our ability IL-6: interleukin 6 EED should include: (1) increased to prevent and treat environmental LBW: low birth weight access to clean water, and improved enteropathy.

Studies Section, Division of Human Health, International Atomic Energy Agency, Vienna International Centre, PO Box 100, 1400 Vienna, Austria. E-mail: v.owino@ iaea.org PEDIATRICS (ISSN Numbers: Print, 0031-4005; Online, 1098-4275). Copyright © 2016 by the American Academy of Pediatrics FINANCIAL DISCLOSURE: Drs Owino and Loechl are employees of the International Atomic Energy Agency. Drs Freemark, Kelly, Loy, and Manary received travel reimbursement from the International Atomic Energy Agency to attend the technical meeting. FUNDING: All aspects of the technical meeting on Environmental Enteric Dysfunction, Undernutrition and the Microbiome were funded by the International Atomic Energy Agency. Dr Loy is supported by the Vienna Science and Technology Fund (WWTF, project LS12-001) and the Austrian Science Fund (FWF, project I 2320-B22). Dr Freemark received support from the Duke Global Health Institute. POTENTIAL CONFLICT OF INTEREST: The authors have indicated they have no potential confl icts of interest to disclose.

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Downloaded from www.aappublications.org/news by guest on September 29, 2021 Environmental Enteric Dysfunction and Growth Failure/Stunting in Global Child Health Victor Owino, Tahmeed Ahmed, Michael Freemark, Paul Kelly, Alexander Loy, Mark Manary and Cornelia Loechl Pediatrics originally published online November 4, 2016;

The online version of this article, along with updated information and services, is located on the World Wide Web at: http://pediatrics.aappublications.org/content/early/2016/11/02/peds.2016-0641

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