Environmental enteropathy: critical implications of a poorly understood condition

Abstract

Environmental enteropathy (also called tropical enteropathy) is a subclinical condition caused by constant fecal-oral contamination and resulting in blunting of intestinal villi and intestinal inflammation. Although these histological changes were discovered decades ago, the clinical impact of environmental enteropathy is just starting to be recognized. The failure of nutritional interventions and oral vaccines in the developing world may be attributed to environmental enteropathy, as the intestinal absorptive and immunologic functions are significantly deranged. Here we review the existing literature and examine potential mechanisms of pathogenesis for this poorly understood condition.

Figure 1. Model for the mechanism of Environmental Enteropathy development

(Adapted with permission from [78].

Figure 2. Jejunal biopsies of normal (a) and diseased (b) intestines

(a) Note the finger-like villi and short and narrow crypts of the normal intestine (a) compared with the severely flattened villi and inflammatory infiltration in the lamina propria and epithelium from the diseased tissue (b). This biopsy was taken from a Mexican adult with malnutrition, who may have had concurrent diarrhea. Reproduced with permission from [79].

Figure 2. Jejunal biopsies of normal (a) and diseased (b) intestines

(a) Note the finger-like villi and short and narrow crypts of the normal intestine (a) compared with the severely flattened villi and inflammatory infiltration in the lamina propria and epithelium from the diseased tissue (b). This biopsy was taken from a Mexican adult with malnutrition, who may have had concurrent diarrhea. Reproduced with permission from [79].

Figure 3. Intestinal function in normal and diseased individuals

(a) In normal intestines, goblet cells secrete a layer of mucus that protects epithelial cells from exposure to bacteria. Phagocytosis by macrophages protects against bacteria entering the lamina propria while minimizing tissue injury. Tight junctions are undisrupted. Villi are long and finger-like and crypts are shallow in comparison, with a villus:crypt ratio of 3:1. Adapted with permission from [60]. (b) Constant exposure to fecal-oral contamination and recurrent episodes of gastroenteritis lead to a perpetual state of small bowel injury and hyperstimulation of the mucosal immune system. Luminal bacteria bind to Toll-like receptors (not shown) on dendritic cells and intraepithelial lymphocytes (IELs) on the basolateral surface of epithelial cells. Dendritic cells release chemokines and cytokines and recruit polymorphonuclear neutrophils (PMNs), and act as antigen presenting cells that cause activation and differentiation of CD4+ T-cells. CD4+ cells then release TH1 cytokines stimulating myofibroblasts to release metalloproteases that cause remodeling and blunting of villi. CD4+ T-cells stimulate B-cell production of endotoxin-core antibodies. Release of IL-15 stimulates differentiation of IELs into natural killer cells, resulting in intestinal inflammation and increased permeability. The result is increased intraepithelial lymphocytes and lymphocytic infiltration in the lamina propria, as well as villus atrophy and crypt hyperplasia with a decreased villus:crypt ratio. Adapted with permission [32].