Environmental Enteric Dysfunction: Pathogenesis, Diagnosis, and Clinical Consequences

Abstract

Stunting is common in young children in developing countries, and is associated with increased morbidity, developmental delays, and mortality. Its complex pathogenesis likely involves poor intrauterine and postnatal nutrition, exposure to microbes, and the metabolic consequences of repeated infections. Acquired enteropathy affecting both gut structure and function likely plays a significant role in this outcome, especially in the first few months of life, and serve as a precursor to later interactions of infection and malnutrition. However, the lack of validated clinical diagnostic criteria has limited the ability to study its role, identify causative factors, and determine cost-effective interventions. This review addresses these issues through a historical approach, and provides recommendations to define and validate a working clinical diagnosis and to guide critical research in this area to effectively proceed. Prevention of early gut functional changes and inflammation may preclude or mitigate the later adverse vicious cycle of malnutrition and infection.

Causes of Impaired Oral Vaccine Efficacy in Developing Countries

“…Owing to its pervasive nature in developing countries and the changes in intestinal immune function with which it is likely associated, EED has been hypothesized to play a key role in shaping geographic trends in oral vaccine performance [162,166,167]. Specific inhibitory effects might include the induction of a hostile pro-inflammatory state in the small intestine, the increased production of short-chain fatty acids or other immunomodulatory molecules that are inhibitory to oral vaccines, and the dampening of immune responses due to alterations in regulatory T-cell or dendritic-cell function [168].…”

“…These manifestations may begin to appear soon after birth: during a study in India, the majority of infants displayed some degree of villous blunting within the first 30 days of life [164]. The precise etiology of EED is unclear; however, it appears to be associated with poor environmental conditions, and in a murine model, inadequate diet and repeated microbial exposure were sufficient to promote the features of EED [165].Owing to its pervasive nature in developing countries and the changes in intestinal immune function with which it is likely associated, EED has been hypothesized to play a key role in shaping geographic trends in oral vaccine performance [162,166,167]. Specific inhibitory effects might include the induction of a hostile pro-inflammatory state in the small intestine, the increased production of short-chain fatty acids or other immunomodulatory molecules that are inhibitory to oral vaccines, and the dampening of immune responses due to alterations in regulatory T-cell or dendritic-cell function [168].…”

Contribution of Maternal Immunity to Decreased Rotavirus Vaccine Performance in Low- and Middle-Income Countries

“…A number of hypotheses have been put forward to explain the differences in efficacy and vaccineelicited immunity between HIC and LMIC. The hypotheses include (i) maternal factors (such as interference from transplacental antibodies and antibody and nonantibody breast milk components [13,[19][20][21][22][23]), (ii) coadministration with the oral polio vaccine (24-27), (iii) concurrent infection with other enteric pathogens (28), (iv) micronutrient or protein-energy malnutrition (29-31), (v) effects of environmental enteropathy or dysbiosis of the gut microbiome (32)(33)(34)(35)(36)(37), and (vi) host genetic factors (histo-blood group antigens [38,39]). A better understanding of these factors which decrease the efficacy of RV in LMIC may help to inform interventions to improve efficacy and to further reduce the number of child deaths due to rotavirus disease.…”

The potential role of optical biopsy in the study and diagnosis of environmental enteric dysfunction

“…Newly developed techniques, such as the Crosby capsule, then began to reveal differences between the intestinal villous morphology of residents of developed and developing countries, particularly individuals in India and sub-Saharan Africa. These changes were to some extent reversible if an individ ual moved between regions 7 . This 'tropical enteropathy' was later understood to be more closely linked to economic conditions than geographical location, and was re-termed 'environmental entero pathy' or EED, with the latter term emphasizing that it is characterized by a global disturbance of gut function 7 .…”

“…These changes were to some extent reversible if an individ ual moved between regions 7 . This 'tropical enteropathy' was later understood to be more closely linked to economic conditions than geographical location, and was re-termed 'environmental entero pathy' or EED, with the latter term emphasizing that it is characterized by a global disturbance of gut function 7 .…”