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.

Baseline Gut Microbiota Composition Is Associated With Schistosoma mansoni Infection Burden in Rodent Models

“…Similarly, HMA mice have been reported to display altered immune responses and susceptibility to intestinal bacterial infections ( 38 , 40 , 41 ). In humans, gut microbial dysbiosis has been associated with a number of pathological conditions ( 42 ); importantly, in resource-limited settings, such as those where schistosomiasis is endemic ( 13 ), young children are often affected by environmental enteric dysfunction, a multifactorial disorder associated with early childhood malnutrition, growth retardation and impaired immune function ( 43 , 44 ). Intestinal dysbiosis is key to the pathogenesis of environmental enteric dysfunction ( 43 , 44 ); therefore, causal relationships may occur between gut microbial imbalances in children from these areas and susceptibility to schistosomiasis that deserve to be thoroughly investigated.…”

Immunoglobulin recognition of fecal bacteria in stunted and non-stunted children: findings from the Afribiota study

“…Undernutrition is associated with dysbiosis and immaturity of the gut microbiota [7][8][9][10] and increased susceptibility to diarrheal disease [11]. Recently, we showed that stunted children have a dysbiotic fecal microbiota characterized by an overabundance of pathobionts and of bacteria typically associated with the oral cavity, including Haemophilus, Campylobacter, and Escherichia-Shigella [12].…”

“…In low-income regions with poor sanitation, undernutrition is frequently associated with chronic intestinal inflammation and permeability, a condition referred to as environmental enteropathy or environmental enteric dysfunction (EED) [9,10,13]. EED is hypothesized to interfere with nutrient absorption and thus exacerbate undernutrition, but it is a heterogeneous condition that is difficult to define or diagnose, and its etiology is unclear [5].…”

The impact of maternal and early life malnutrition on health: a diet-microbe perspective

“…EE, also known as environmental enteric dysfunction, is a major contributor to early childhood stunting [14]. EE is a subclinical disorder associated with altered dietmicrobe-host interactions and characterized by intestinal injury, nutrient malabsorption, and inflammation [15,16]. EE can induce stunting and wasting through poor digestion and autoimmune dysfunction rather than food shortage [14].…”