Pathophysiology of environmental enteric dysfunction and its impact on oral vaccine efficacy

Abstract

Environmental enteric dysfunction (EED) refers to a subclinical disorder of intestinal function common in tropical countries and in settings of poverty and economic disadvantage. The enteropathy that underlies this syndrome is characterized by mucosal inflammation and villus blunting mediated by T cell activation. Epithelial cell disruption and microbial translocation drive systemic inflammation. EED in young children is associated geographically with growth failure, malnutrition, and greatly impaired responses to oral vaccines, notably rotavirus and poliovirus vaccines. In this review, we describe the pathophysiology of EED and examine the evidence linking EED and oral vaccine failure. This evidence is far from conclusive. Although our understanding of EED is still sketchy, there is limited evidence of disturbed innate immunity, B cell disturbances including aggregation into lymphoid follicles, and autoantibody generation. Pathways of T cell activation and the possibility of dendritic cell anergy, which could help explain oral vaccine failure, require further work.

A novel histological index for evaluation of environmental enteric dysfunction identifies geographic-specific features of enteropathy among children with suboptimal growth

“…The working hypothesis is that an environmental driver, including recurrent or persistent enteric infection, infections from specific pathogen(s), an abundance of nonpathogenic fecal microbes, or distortion of intestinal microbiota composition, could precipitate and/or perpetuate the small bowel response. This process is analogous to the small bowel response to gluten in gluten-sensitive enteropathy (GSE), also known as celiac disease [9,11,23]. After a flurry of biopsy studies four decades ago [24][25][26][27][28], there has been a paucity of histologic studies of the small bowel until recently.…”

Current Understanding of Innate Immune Cell Dysfunction in Childhood Undernutrition

“…Longitudinal studies provide an opportunity to compare immune cell function between children at admission, when infections are present, and during recovery when children are still wasted but infections have been treated with broad-spectrum antibiotics. However, characterizing immunological recovery is challenging since “healthy” immune function is poorly defined and sub-clinical pathogen carriage (47–49) and enteropathy (50) are common even among adequately-nourished children in LMIC. Some studies have enrolled adequately-nourished children from high-income countries (HIC) as controls, but their utility in determining immunological thresholds for children in LMIC is limited by their vastly different developmental and environmental exposure histories.…”

“…Mechanical damage to the epithelial barrier ranges from localized abrasions and loss of tight junction proteins between epithelial cells to widespread reductions in epithelial surface area due to villous atrophy (69). There is an associated increase in leukocyte infiltration into the lamina propria (50, 69), which may be driven by a number of signals, including damage-associated molecular patterns (DAMPs) and chemoattractants released by activated epithelial cells and tissue-resident immune cells. One consequence of these epithelial changes is increased gut permeability (12, 69, 70), which can be measured indirectly by increased urinary excretion of compounds that are usually not absorbed (e.g., lactulose) and/or increased blood levels of bacterial antigens that would usually be retained on the apical side of the epithelium in the gut lumen (microbial translocation) (12).…”

Malnutrition in HIV/AIDS: Aetiopathogenesis

“…Due to MT, some important biomarkers of MT are now being used to detect EED. These include bacterial cell wall lipopolysaccharide (LPS), soluble lipopolysaccharide co-receptor (sCD14) and antibodies to the LPS core antigen (EndoCAb) [71]. The clinical impact of EE, apart from stunting, is decreased immunological response to oral vaccines.…”