Disentangling Microbial Mediators of Malnutrition: Modeling Environmental Enteric Dysfunction

Abstract

Environmental enteric dysfunction (EED) (also referred to as environmental enteropathy) is a subclinical chronic intestinal disorder that is an emerging contributor to early childhood malnutrition. EED is common in resource-limited settings, and is postulated to consist of small intestinal injury, dysfunctional nutrient absorption, and chronic inflammation that results in impaired early child growth attainment. Although there is emerging interest in the hypothetical potential for chemical toxins in the environmental exposome to contribute to EED, the propensity of published data, and hence the focus of this review, implicates a critical role of environmental microbes. Early childhood malnutrition and EED are most prevalent in resource-limited settings where food is limited, and inadequate access to clean water and sanitation results in frequent gastrointestinal pathogen exposures. Even as overt diarrhea rates in these settings decline, silent enteric infections and faltering growth persist. Furthermore, beyond restricted physical growth, EED and/or enteric pathogens also associate with impaired oral vaccine responses, impaired cognitive development, and may even accelerate metabolic syndrome and its cardiovascular consequences. As these potentially costly long-term consequences of early childhood enteric infections increasingly are appreciated, novel therapeutic strategies that reverse damage resulting from nutritional deficiencies and microbial insults in the developing small intestine are needed. Given the inherent limitations in investigating how specific intestinal pathogens directly injure the small intestine in children, animal models provide an affordable and controlled opportunity to elucidate causal sequelae of specific enteric infections, to differentiate consequences of defined nutrient deprivation alone from co-incident enteropathogen insults, and to correlate the resulting gut pathologies with their functional impact during vulnerable early life windows.

Keywords: Enteropathogen; Environmental Enteric Dysfunction; Environmental Enteropathy; Intestinal Barrier; Malnutrition.

Figure 1

Healthy small intestine (green boxes) contrasted with intestinal pathologies observed in murine models of nutritional deficiency alone (yellowboxes) compared with specific pathogen infection during either zinc deficiency (pink boxes) or protein deficiency (blue boxes). *The described features are observed in models of protein deficiency. A diminished CD4:CD8 ratio is seen during both protein and zinc deficiency. Future applications of these models can help to address important knowledge gaps. How do genetic and epigenetic factors shape intestinal adaptations during select nutrient deficiencies? How do microbial communities and intestinal pathogens differentially adapt to select nutrient deficiencies in the small intestine, and what are the consequences of this altered microbial ecology on epithelial cell function, host nutrient availability, inflammation, and metabolism? What are the consequences of nutrient and microbial-dependent acute (episodic) and chronic (persistent) mucosal and systemic inflammation on intestinal function, susceptibility to infection, nutrient demand, metabolism, and host growth?