Adaptation of the small intestine to microbial enteropathogens in Zambian children with stunting

Abstract

Environmental enteropathy is a major contributor to growth faltering in millions of children in Africa and South Asia. We carried out a longitudinal, observational and interventional study in Lusaka, Zambia, of 297 children with stunting (aged 2–17 months at recruitment) and 46 control children who had good growth (aged 1–5 months at recruitment). Control children contributed data only at baseline. Children were provided with nutritional supplementation of daily cornmeal-soy blend, an egg and a micronutrient sprinkle, and were followed up to 24 months of age. Children whose growth did not improve over 4–6 months of nutritional supplementation were classified as having non-responsive stunting. We monitored microbial translocation from the gut lumen to the bloodstream in the cohort with non-responsive stunting (n = 108) by measuring circulating lipopolysaccharide (LPS), LPS-binding protein and soluble CD14 at baseline and when non-response was declared. We found that microbial translocation decreased with increasing age, such that LPS declined in 81 (75%) of 108 children with non-responsive stunting, despite sustained pathogen pressure and ongoing intestinal epithelial damage. We used confocal laser endomicroscopy and found that mucosal leakiness also declined with age. However, expression of brush border enzyme, nutrient transporter and mucosal barrier genes in intestinal biopsies did not change with age or correlate with biomarkers of microbial translocation. We propose that environmental enteropathy arises through adaptation to pathogen-mediated epithelial damage. Although environmental enteropathy reduces microbial translocation, it does so at the cost of impaired growth. The reduced epithelial surface area imposed by villus blunting may explain these findings.

Gut integrity and duodenal enteropathogen burden in undernourished children with environmental enteric dysfunction

“…In the context of histopathological features, enteropathogens significantly correlated with chronic inflammation, intra-epithelial lymphocytosis and enterocyte injury. Although we did not find association with villous blunting, a recently published study proposed that in EED, reduced villous surface was a compensatory mechanism to minimize microbial translocation yet, at the cost of impaired growth [ 20 ]. Our group has previously reported greater magnitude of lamina propria T-cell infiltrates and intraepithelial lymphocytes in EED cases as compared to celiac disease in the presence of microbial overgrowth in duodenal aspirate [ 5 ].…”

Gene expression profiles compared in environmental and malnutrition enteropathy in Zambian children and adults

“…We directly compared environmental enteropathy in three groups: hospitalised children with SAM and persistent diarrhoea, asymptomatic children with stunting unresponsive to nutritional therapy, and apparently healthy adults from a community in which EE is known to be almost ubiquitous. The last two groups were recruited exclusively from the same disadvantaged community (Misisi, Lusaka), and the groups have been described in previous publications [ 16 , 21 , 22 ]. The adults and children from Misisi were in apparently good health; potential participants with clinical illness did not donate samples for this study.…”

“…The adults and children from Misisi were in apparently good health; potential participants with clinical illness did not donate samples for this study. The adults were volunteers [21] , and the children had been requested to undergo endoscopy and biopsy in order to search for infections or other explanations for severe acute, or chronic non-responsive, malnutrition [16] . The presence of EE in each group was confirmed using formal morphometry of mucosal biopsies.…”

“…Environmental enteropathy (EE, now also often referred to as environmental enteric dysfunction, EED) is an asymptomatic disorder, originally termed ‘tropical enteropathy’ [ 10 , 11 ]. It seems likely that adverse environmental conditions, including frequent exposure to enteropathogens or pathobionts [12] , [13] , [14] , [15] , [16] , cause intestinal damage, manifest as mucosal inflammation, increased intestinal permeability, microbial translocation and systemic inflammation [15] . Children hospitalised with SAM have high in-hospital and post discharge mortality [ 4 , 17 ], and a severe enteropathy [18] which may include defective glycosylation in the epithelium in the oedematous form of SAM (kwashiorkor) [19] .…”

Single-cell profiling of environmental enteropathy reveals signatures of epithelial remodeling and immune activation in severe disease

“…That study demonstrated that immunohistochemical staining of DUOX2 protein in the villus epithelium distinguished EE biopsies from controls. Given that reduced villus height in EE has been shown to associate with decreased microbial translocation over time (11), it is remarkable that surface mucosal cells scored highly for signatures of both reduced villus height and decreased microbial translocation (as measured by decreased plasma LPS concentrations). This suggests that this cell subset may be associated with adaptive shortening of the villus in response to enteropathogen exposure.…”