Environmental enteropathy (EE or tropical enteropathy or environmental enteric dysfunction or EED) is an acquired small intestinal disorder characterized by gut inflammation, reduced absorptive surface area in small intestine, and disruption of intestinal barrier function. EE is most common amongst children living in low-resource settings. Acute symptoms are typically minimal or absent. EE can lead to malnutrition, anemia (iron-deficiency anemia and anemia of chronic inflammation), stunted growth, impaired brain development, and impaired response to oral vaccinations.
The cause of EE is multifactorial. Overall, exposure to contaminated food and water leads to a generalized state of intestinal inflammation. The inflammatory response results in multiple pathological changes to the gastrointestinal tract: Smaller villi, larger crypts (called crypt hyperplasia), increased permeability, and inflammatory cell build-up within the intestines. These changes result in poor absorption of food, vitamins and minerals.
Standardized, clinically practical diagnostic criteria do not exist. The most accurate diagnostic test is intestinal biopsy. However, this test is invasive and unnecessary for most patients.
Prevention is the strongest and most reliable option for preventing EE and its effects. Therefore, prevention and treatment of EE are often discussed together.
Signs and symptoms Environmental enteropathy is believed to result in chronic malnutrition and subsequent growth stunting (low height-for-age measurement) as well as other child development deficits.
Long-term symptoms Malnutrition EE causes malnutrition by way of both malabsorption and nutritional deficiencies. Growth and physical development The first two years (and the prior 9 months of fetal life) are critical for linear growth. Stunting is an easy to measure symptom of these child development deficits. Neurocognitive (brain development) Effect on oral vaccination Many oral vaccines, both live and non-living, have proven to be less immunogenic or less protective when administered to infants, children or adults living in low socioeconomic conditions in developing countries than they are when used in industrialized countries. Widespread EE is hypothesized to be a contributing cause for this observation.
Nutrient intake and nutritional status in environmental enteropathy The relationship between dietary intake and infection is difficult to study since it is reciprocal in nature.Scrimshaw NS. Historical concepts of interactions, synergism and antagonism between nutrition and infection. J Nutr 2003; 133(1): 316S-21S.Solomons NW. Malnutrition and infection: an update. The British journal of nutrition 2007; 98 Suppl 1: S5-10. Further, the gut tissue consumes the nutrients it requires before passage of excess nutrients to the rest of the body.Thurnham DI, Northrop-Clewes CA, McCullough FS, Das BS, Lunn PG. Innate immunity, gut integrity, and vitamin A in Gambian and Indian infants. J Infect Dis 2000; 182 Suppl 1: S23-8.Van Der Schoor SR, Reeds PJ, Stoll B, et al. The high metabolic cost of a functional gut. Gastroenterology 2002; 123(6): 1931-40. The benefits achieved by improved nutrient intake on environmental enteropathy may thus be independent of nutritional status. Nutrient intake during inflammation is usually decreased.
Reports of "poor appetite" by caregivers in LMICs,Brown KH, Peerson JM, Lopez de Romana G, de Kanashiro HC, Black RE. Validity and epidemiology of reported poor appetite among Peruvian infants from a low-income, periurban community. The American journal of clinical nutrition 1995; 61(1): 26-32. and restriction of complementary foods during illnessPaintal K, Aguayo VM. Feeding practices for infants and young children during and after common illness. Evidence from South Asia. Maternal & child nutrition 2016; 12 Suppl 1: 39-71. is common. Appetite may be reduced both by pro-inflammatory cytokines and leptinSomech R, Reif S, Golander A, Spirer Z. Leptin and C-reactive protein levels correlate during minor infection in children. Isr Med Assoc J 2007; 9(2): 76-8. and low zinc status,Prasad AS. Clinical and biochemical manifestations of zinc deficiency in human subjects. Journal of the American College of Nutrition 1985; 4(1): 65-72. and may be continuous in children with environmental enteropathy.Dewey KG, Mayers DR. Early child growth: how do nutrition and infection interact? Maternal & child nutrition 2011; 7 Suppl 3: 129-42. Nutrient availability for growth in environmental enteropathy is further limited due to reduced intestinal surface area and loss of enzymatic activity causing malabsorption of nutrientsGuerrant RL, Oria RB, Moore SR, Oria MO, Lima AA. Malnutrition as an enteric infectious disease with long-term effects on child development. Nutrition reviews 2008; 66(9): 487-505.Trehan I, Kelly P, Shaikh N, Manary MJ. New insights into environmental enteric dysfunction. Arch Dis Child 2016; 101(8): 741-4. and, following microbial translocation, retention of circulating nutrients (i.e vitamin A, zinc and iron) in body tissues in order to starve pathogens. Associations between nutrient intake and biomarkers for nutrient statusMartin-Prevel Y, Allemand P, Nikiema L, et al. Biological Status and Dietary Intakes of Iron, Zinc and Vitamin A among Women and Preschool Children in Rural Burkina Faso. PloS one 2016; 11(3): e0146810. and nutrient status and growthAhmed T, Auble D, Berkley JA, et al. An evolving perspective about the origins of childhood undernutrition and nutritional interventions that includes the gut microbiome. Ann N Y Acad Sci 2014; 1332: 22-38. are thus likely distorted in children with inflammation.
The systemic inflammation resulting from microbial translocation will increase basal metabolic rate and nutrient needs by the immune system.Syed S, Ali A, Duggan C. Environmental Enteric Dysfunction in Children. J Pediatr Gastroenterol Nutr 2016; 63(1): 6-14. At the same time, nutrient losses increase due to intestinal secretion.Krebs NF, Miller LV, Hambidge KM. Zinc deficiency in infants and children: a review of its complex and synergistic interactions. Paediatrics and international child health 2014; 34(4): 279-88. The associations are thus complex, and further complicated by intestinal host-pathogen-microbiome interactionsPrendergast A, Kelly P. Enteropathies in the developing world: neglected effects on global health. Am J Trop Med Hyg 2012; 86(5): 756-63. and the effects of these interactions on intestinal nutrient availability,Yatsunenko T, Rey FE, Manary MJ, et al. Human gut microbiome viewed across age and geography. Nature 2012; 486(7402): 222-7.Biesalski HK. Nutrition meets the microbiome: micronutrients and the microbiota. Ann N Y Acad Sci 2016; 1372(1): 53-64. where additional research is needed. Finally, evidence of whether nutrition interventions may be successful in children with repeated episodes of infection or persistent subclinical infection is scant. Meanwhile, there seems to be agreement that successful interventions to improve complementary feeding practicesStewart CP, Iannotti L, Dewey KG, Michaelsen KF, Onyango AW. Contextualising complementary feeding in a broader framework for stunting prevention. Maternal & child nutrition 2013; 9 Suppl 2: 27-45. and reduce stuntingOwino V, Ahmed T, Freemark M, et al. Environmental Enteric Dysfunction and Growth Failure/Stunting in Global Child Health. Pediatrics 2016; 138(6).McKay S, Gaudier E, Campbell DI, Prentice AM, Albers R. Environmental enteropathy: new targets for nutritional interventions. Int Health 2010; 2(3): 172-80. must encompass both immediate and underlying causes.
Causes The development of environmental enteropathy (EE) is multifactorial, but predominantly associated with chronic exposure to contaminated food and water. This is especially true in environments where widespread open defecation and lack of sanitation are common.
The main cause of environmental enteropathy is likely repeated exposure to enteric pathogens through fecal contamination.MAL-ED Network Investigators. Childhood stunting in relation to the pre- and postnatal environment during the first 2 years of life: The MAL-ED longitudinal birth cohort study. PLOS Medicine 2017.George CM, Burrowes V, Perin J, et al. Enteric Infections in Young Children are Associated with Environmental Enteropathy and Impaired Growth. Trop Med Int Health 2018; 23(1): 26-33. Rotavirus, norovirus, cryptosporidium, shigella, campylobacter and E-coli are among the most prevalent causative agents.Prendergast AJ, Kelly P. Interactions between intestinal pathogens, enteropathy and malnutrition in developing countries. Curr Opin Infect Dis 2016; 29(3): 229-36.Platts-Mills JA, Babji S, Bodhidatta L, et al. Pathogen-specific burdens of community diarrhoea in developing countries: a multisite birth cohort study (MAL-ED). Lancet Glob Health 2015; 3(9): e564-75.
Mechanism Long-term exposure to environmental pathogens leads to a generalized state of intestinal inflammation. Chronic inflammation leads to both functional and structural changes which alter gut permeability and ability of the intestine to absorb nutrients.
Specifically, structural changes within the intestine include smaller villi, larger crypts (called crypt hyperplasia), increased permeability, and inflammatory cell build-up within the intestines. These changes result in poor absorption of food, vitamins and minerals – or "modest malabsorption".
Diagnosis The current gold standard diagnostic test for EE is intestinal biopsy and histological analysis. Histological changes observed include: Villous blunting Crypt hypertrophy Villous fusion Mucosal inflammation The key histological features are villous flattening, crypt hyperplasia and inflammation in the epithelium and lamina propria.Crane RJ, Jones KD, Berkley JA. Environmental enteric dysfunction: an overview. Food Nutr Bull 2015; 36(1 Suppl): S76-87.
However, this procedure is considered too invasive, complex and expensive to be implemented as standard of care. As a result, there are various research efforts underway to identify biomarkers associated with EE, which could serve as less invasive, yet representative, tools to screen for and identify EE from stool samples. In an effort to identify simple, accurate diagnostic tests for EE, the Bill and Melinda Gates Foundation (BMGF) has established an EE biomarkers consortium as part of their Global Grand Challenges initiative (specifically, the Discover Biomarkers of Gut Function challenge).
So far, various biomarkers have been selected and studied based on the current understanding of EE pathophysiology: Gut permeability/barrier function Dual sugar permeability (lactose-to-mannitol ratio) Intestinal inflammation Alpha-1 anti-trypsin Neopterin Myeloperoxidase Exocrine (hormonal) markers Bacterial translocation markers Endotoxin core antibody Markers of systemic inflammation Alpha-1 glycoprotein C-reactive protein (CRP)