Environmental enteropathy

Environmental enteropathy (EE or tropical enteropathy or environmental enteric dysfunction) is a disorder of chronic intestinal inflammation. 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), growth stunting, 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.

Causes

The development of 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.

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
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) 
It is postulated that the limited of understanding of EE is partially due to the paucity of reliable biomarkers, making it difficult for researchers to track the epidemiology of the condition and assess the efficacy of interventions.

Classification

In the 1960s, researchers reported a syndrome of non-specific histopathological and functional changes to the small intestine in individuals living in unsanitary conditions. This syndrome was observed predominantly in tropical regions across Latin America, sub-Saharan Africa and Asia. The geographic distribution of the syndrome lead to the original term of "tropical enteropathy" (sometimes also "tropical jejunopathy").

Following initial reports, further investigation revealed that these symptoms were not specific to tropical climates. For example, individuals in more wealthy tropical countries, such as Qatar and Singapore, did not exhibit these symptoms. Similarly, subsequent studies have shown this condition to be common across the developing world, closely associated with impoverished conditions but independent of climate or geography. As a result, the term "environmental enteropathy" was introduced to specify that this condition is not only found in tropical areas and is believed to be caused by environmental factors.

Prevention

Prevention focuses on improving access to water, sanitation and hygiene (WASH).

Another important factor might be contaminated soil in child play spaces, often caused by the presence of livestock such as chicken in the household. Creating a clean play space might therefore be an effective preventive measure for EE in toddlers.

Treatment

Treatment focuses on addressing the central components of intestinal inflammation, bacterial overgrowth and nutritional supplementation.

Epidemiology

Environmental enteropathy (EE) primarily affects children living in low- and middle-income countries (LMICs). Children living in these countries were found to have enteric pathogens related to EE in their systems throughout much of their early childhoods. Gastrointestinal abnormalities associated with EE are not congenital but are acquired during infancy and persist into adulthood. Such abnormalities tend to develop after the first semester of life and are not present in newborns.

Historically, environmental enteropathy has been prevalent in LMICs. The geographic distribution of environmental enteropathy has shown an increase in incidence in such areas of poor sanitation and hygiene. EE was first described in studies from the 1960-70s conducted in Asia, Africa, the Indian subcontinent, and Central America, during which it was discovered that signs of EE were high among otherwise healthy adults and children. A study from 1971 following US Peace Corps volunteers is often cited as being the first study to demonstrate the ability to acquire and recover from EE according to the environment. Participants experienced symptoms of chronic enteric infection during and shortly after returning from their placement in low- and middle-income countries. Symptoms experienced by those abroad were resolved within one to two years after returning home to the US. These results lead to the suggestion of the environment being a cause of EE, and a later study in Zambia was able to draw similar conclusions. By the early 1990s, environmental enteropathy was found to be a widespread problem affecting infants and children. Today, enteric infections and diarrheal diseases like environmental enteropathy account for 760,000 deaths per year worldwide, making EE the second leading cause of death in children under five years old.

The exact causes and consequences of EE have been difficult to establish due, in part, to the lack of a clear disease definition. However, risk factors do exist and they can be both environmental and nutritional. Preexisting conditions such as micronutrient deficiencies, diarrheal diseases, and various chronic infections all serve as risk factors for EE. Environmental conditions such as poor sanitation and unimproved water sources also contribute to the prevalence of EE. Exposure to environmental microbial agents such as these is thought to be the most important factor in the development of EE.

Research initiatives

There are multiple large-field, multi-country research initiatives focusing on strategies to prevent and treat EE.
* Th
MAL-ED
project
* Th
Alive and Thrive
nutrition project
* Th
Sanitation, Hygiene and Infant Nutrition Efficacy (SHINE) Trial
(ClinicalTrials.gov identifier
NCT01824940

* Th
WASH Benefits
Study

References

{{Diseases of Poverty

Human diseases and disorders
Tropical diseases
Intestinal infectious diseases
Sanitation
Environmental health