Environmental enteric dysfunction: a review of potential mechanisms, consequences and management strategies

Abstract

Background: Environmental enteric dysfunction (EED) is an acquired enteropathy of the small intestine, characterized by enteric inflammation, villus blunting and decreased crypt-to-villus ratio. EED has been associated with poor outcomes, including chronic malnutrition (stunting), wasting and reduced vaccine efficacy among children living in low-resource settings. As a result, EED may be a valuable interventional target for programs aiming to reduce childhood morbidity in low and middle-income countries.

Main text: Several highly plausible mechanisms link the proposed pathophysiology underlying EED to adverse outcomes, but causal attribution of these pathways has proved challenging. We provide an overview of recent studies evaluating the causes and consequences of EED. These include studies of the role of subclinical enteric infection as a primary cause of EED, and efforts to understand how EED-associated systemic inflammation and malabsorption may result in long-term morbidity. Finally, we outline recently completed and upcoming clinical trials that test novel interventions to prevent or treat this highly prevalent condition.

Conclusions: Significant strides have been made in linking environmental exposure to enteric pathogens and toxins with EED, and in understanding the multifactorial mechanisms underlying this complex condition. Further insights may come from several ongoing and upcoming interventional studies trialing a variety of novel management strategies.

Keywords: Acute malnutrition; Childhood malnutrition; Enteric dysfunction; Environmental enteric dysfunction; Stunting.

Fig. 1

Biomarkers of environmental enteric dysfunction (EED), microbiome dysfunction, systemic inflammation and growth hormone resistance. Adapted from McGrath (2017) [17]. Abbreviations: AAT, α-1-antitrypsin; AGP, α-1 acid glycoprotein; CAL, calprotectin; CRP, C-reactive protein; EndoCAb, anti-endotoxin core antibody; FGF-21, fibroblast growth factor 21; Flic, flagellin; GH, Growth hormone; I-FABP, intestinal fatty acid binding protein; IgA, immunoglobulin A; IgG, immunoglobulin G; IGF-1, insulin-like growth factor 1; Kyn, kynurenine; K:T, kynurenine:tryptophan ratio; LPS, lipopolysaccharides; L:M, lactulose:mannitol; L:R, lactulose:rhamnose; MAZ, microbiota-for-age Z score; MPO, myeloperoxidase; NEO, neopterin; Reg1β, regenerating protein 1β; SIBO, small intestinal bacterial overgrowth; SIRT1, Sirtuin 1; Trp, tryptophan