Abbeddou, Souheila

Glenn, Kristen V

Loechl, Cornelia

Owino, Victor O

Ghent University Academic Bibliography

106 TECHNICAL MEETING ON EED, THE MICROBIOME AND UNDERNUTRITIONSome 50 experts participated in a technical meeting on envi-ronmental enteric dysfunction organized and hosted by the In-ternational Atomic Energy Agency (IAEA) in Vienna, Austria on October 28–30, 2015. The meeting aimed to discuss current re-search, developments and experiences in diagnosing and evalu-ating EED, and the potential role of stable isotope techniques in EED diagnosis. What is known about EEDStunting develops as a result of sustained inadequate nutrition and recurrent infection.2 Environmental insults affect linear growth through mechanisms that are yet to be fully understood.3 Environmental enteropathy is a combination of infection-under-nutrition induced failure of the mucosal barrier of the gut and has recently been referred to as environmental enteric dysfunc-tion to reflect the numerous gut function deficits associated with it. EED affects approximately 50–95% of children under the age of 5 years in resource-poor settings. There is compelling evidence to support the association of EED with: 1) gut perme-ability/leakiness; 2) nutrient malabsorption; 3) microbial trans-location; 4) alterations in gut microbiota diversity; 5) gut and systemic inflammation; 6) linear growth faltering; 7) reduced effect of vaccines and; 8) severe acute malnutrition (SAM).4Souheila Abbeddou, Victor O Owino,  Kirsten V Glenn, Cornelia Loechl Nutritional and Health-Related Environmental  Studies Section, Division of Human Health,  Department of Nuclear Sciences and Applications, International Atomic Energy Agency (IAEA),  Vienna, AustriaTechnical Meeting on  EED,* the Microbiome and Undernutrition  *Environmental Enteric Dysfunction  Key messages  >  Stunting affects 161 million children under 5 years of age  in low- and middle-income countries.1   >  Evidence-based nutrition interventions, at 90% coverage, amount to only one-third reduction in stunting.   >  Environmental insults acting through damaged gut  function (a phenomenon referred to as environmental  enteric dysfunction [EED]), are hypothesized to be  responsible for a large part of intrauterine growth restriction  and postnatal stunting, but the mechanisms remain  largely unknown.  >  Combating EED and stunting needs an integrated  approach to improve the following: maternal health and  pre-conception nutrition, infant and young child feeding (IYCF) practices, access to health care, and access to  safe water and sanitation.  >  A tool to assess EED is urgently needed to facilitate  evaluation of interventions. >  Application of cutting-edge innovations such as the  omics technologies and stable isotope techniques offer  unprecedented opportunities to diagnose and  characterize EED.   >  Since EED depicts multiple causal pathways,  striking the right mix of evidence-based interventions is a key prerequisite for success. Synergies across disciplines  and sectors are needed.SIGHT AND LIFE | VOL. 30(1) | 2016 107TECHNICAL MEETING ON EED, THE MICROBIOME AND UNDERNUTRITIONmotility5 and is in turn influenced by factors including mode of delivery, breastfeeding practices, dietary diversity, genotype, pathobiology, physiology, age, the environment, immune system and host lifestyle.6  Unfavorable nutritional conditions can influence the micro-bial community composition, most often resulting in sub-optimal microbiota maturity, which is in turn correlated with host weight loss. Although there are no studies to date of the gut microbiome in the specific context of EED, there is evidence that some gut intestinal pathogens have specific mechanisms of action (such as mucin degradation) that make a link with EED biologically plausible.7  2. How does EED limit growth?Insulin growth factor (IGF-I) regulates growth and other func-tions in the body during pregnancy. Inflammation of the small in-testine in EED is associated with high C-reactive protein and may be accompanied by release of cytokines such as interleukin  6 (IL-6) that reduce appetite and food intake and impair produc-tion and action of chondrocyte growth factors. Stress-induced activation of the hypothalamic-pituitary-adrenal axis stimulates a rise in cortisol and insulin-like growth-factor-binding protein-1 (IGFBP-1), which inhibit IGF-1 action and induce chondrocyte apoptosis. A reduction in hepatic growth hormone (GH) receptor expression and inhibition of GH signaling by fibroblast growth 1. Gut microbiome and EEDThe gut microbiota is largely acquired at birth and develops quickly in the first year of life toward an adult-like pattern. It influences host development, immunity, metabolism and gut Participants of the technical meeting come from diverse  professional fields Cornelia Loechl, Head of the Nutritional and Health-Related Environmental Studies Section, welcomes participants,  gives an overview of IAEA’s activities in nutrition, and outlines meeting objectives.108 TECHNICAL MEETING ON EED, THE MICROBIOME AND UNDERNUTRITIONfactor 21 and possibly zinc deficiency, further limit IGF-1 produc-tion and thereby contribute to growth failure.8,9 3. Energy and nutrient requirements in EEDNutrient deprivation is associated with a decrease in epithelial barrier function and elevated detection of indicators for bacte-rial translocation. Vitamin A, zinc and some amino acids such as glutamine, threonine, leucine and cysteine are potentially involved in improving gut barrier function and absorptive ca-pacity. Zinc, probiotics, flavonoids and n-3 polyunsaturated fatty acids (PUFA) have been associated with reduced inflam-mation.4 In contrast, inorganic iron potentially shifts the mi-crobiome towards a more pathogenic profile and increases gut inflammation. Inflammation and reduced absorption, both of which are evident in EED, may result in increased energy and nutrient requirements in children with EED. In children with EED, energy and zinc requirements are increased by up to 15% and 50%, respectively. 4. Use of stable isotopes in evaluating gut dysfunctionStable isotopes have been used to assess gut dysfunction (small intestine bacteria overgrowth [SIBO], celiac disease and chemotherapy-induced small-intestinal damage in rats) with different substrates (starch and other carbohydrates, mixed tri-glycerides, fatty acids, proteins, etc.). An example of a diagnos-tic 13C breath test is the 13C-urea breath test used to diagnose and monitor Helicobacter pylori infection in the stomach. The high specificity and sensitivity associated with the test makes it the ideal non-invasive diagnostic technique.10 The 13C-sucrose breath test is a promising future technique to assess gut function and has been used in Australia to measure the absorptive capac-ity of the small intestine.11 The glucose hydrogen breath test is currently the most accurate non-invasive test to diagnose SIBO. Combined 13C and H2 breath tests could also be used to assess fermentation and SIBO with higher specificity by correcting for gastric emptying rate. 5. Biomarkers of EEDWhile malabsorption, gut barrier dysfunction and gut inflamma-tion are overlapping components of EED, it is difficult to iden-tify specific markers of each that could be used solely for EED diagnosis. An ideal EED biomarker should be highly associated with stunting, age- and population-specific, and classified ac-cording to the underlying causes of EED, namely: 1) intestinal permeability and nutrient absorption (e.g., 13C sucrose breath test, lactulose-mannitol intestinal permeability test), 2) bacte-rial translocation (e.g., lipopolysaccharides), 3) intestinal in-flammation (e.g., myeloperoxidase), 4) systemic inflammation (e.g., C-reactive protein), 5) functional enterocyte mass (e.g., citrulline), 6) intestinal repair (e.g., promoter glucagon-like Panelists from different sectors deliberate how interventions can best be packaged to address EED and stunting.SIGHT AND LIFE | VOL. 30(1) | 2016 109TECHNICAL MEETING ON EED, THE MICROBIOME AND UNDERNUTRITIONReferences01.  Global Nutrition Report 2015; Accessed on 15 February, 2016  at http://globalnutritionreport.org/2015/09/23/infographic-global-nutrition-report-2015/.02.  Prendergast AJ, Humphrey JH. The stunting syndrome in  developing countries. Paediatr Int Child Health 2014;34:250–65.03.  Humphrey JH. Child undernutrition, tropical enteropathy, toilets, and handwashing. Lancet 2009;374:1032–35.04.  Crane RJ, Jones KD, Berkley JA. Environmental enteric dysfunction: an overview. Food Nutr Bull 2015;36 suppl 1:76–87.05.  Bäckhed F. Programming of host metabolism by the gut microbiota. Ann Nutr Metab 2011;58 suppl 2: 44–52.06.  Arrieta M-C, Stiemsma LT, Amenyogbe N et al. The intestinal  microbiome in early life: health and disease. Front Immunol 2014;5:427.07.  Derrien M, Vaughan EE, Plugge CM et al. Akkermansia muciniphila Gen. Nov., Sp. Nov., a human intestinal mucin-degrading bacterium. Int J Syst Evol Microbiol 2004;54:1469–76.08.  De Benedetti F, Alonzi T, Moretta A et al. Interleukin 6 causes  growth impairment in transgenic mice through a decrease in  insulin-like growth factor-I. A model for stunted growth in children with chronic inflammation. J Clin Invest 1997;99:643–50. 09.  Sederquist B, Fernandez-Vojvodich P, Zaman F et al. Recent  research on the growth plate: Impact of inflammatory cytokines on longitudinal bone growth. J Mol Endocrinol 2014;53:T35–44. 10.  Mauro M, Radovic V, Zhou P et al. 13C urea breath test for  helicobacter pylori: determination of the optimal cut-off point  in a Canadian community population. Can J Gastroenterol 2006;20:770–4.11.  Ritchie BK, Brewster DR, Davidson GP et al. 13C-sucrose  breath test: novel use of a noninvasive biomarker of environmental gut health. Pediatrics 2009;124:620–6.12.  Munn DH, Mellor AL. Indoleamine 2,3 dioxygenase and  metabolic control of immune responses. Trends Immunol 2013;34:137–43.peptide-2 [GLP-2]), 7) mucosal immune underachievement (e.g., kynurenine/tryptophan ratio)12 and 8) alterations in mi-crobiota diversity.6. Ongoing interventions to address EEDInterventions to address EED include: a) water, sanitation and hygiene (WASH), b) reduction of exposure to feces and contact with domestic animals; c) provision of probiotics and prebiot-ics; d) improvement of dietary diversity and breastfeeding prac-tices; e) supplementation with nutrients such as zinc, PUFA and amino acids and; f) treatment with anti-inflammatory agents and antibiotics in the context of SAM and infection. Some of these aspects are already being tested individually or combined in large randomized controlled studies in a number of countries. Determining the right mix of evidence-based interventions to maximize effectiveness against EED remains a major gap.7. The way forwardSeveral gaps in knowledge requiring attention include the clas-sification and better understanding of the underlying causes of EED. Developing practical, simple, and affordable tools to diag-nose and characterize EED to allow better targeting of interven-tions in vulnerable populations is overdue. Stable isotopes can be used to assess absorptive capacity/permeability of the gut, bacterial translocation and body composition as a proxy indica-tor of dietary quality and morbidity. Since EED depicts multi-ple causal pathways, striking the right mix of evidence-based interventions is a key prerequisite for success. Synergies across disciplines and sectors are needed.“ There is a need to develop tools  to diagnose and characterize EED  in order to allow better targeting  of interventions in vulnerable  populations”Correspondence: Cornelia Loechl,  Nutrition Specialist, International Atomic Energy Agency (IAEA), Vienna International Centre, PO Box 100, 1400 Vienna, Austria. Email: c.loechl@iaea

Technical meeting on EED, the microbiome and undernutrition

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Technical meeting on EED, the microbiome and undernutrition

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