Impaired Barrier Function and Autoantibody Generation in Malnutrition Enteropathy in Zambia

Abstract

Intestinal damage in malnutrition constitutes a threat to the survival of many thousands of children globally. We studied children in Lusaka, Zambia, with severe acute malnutrition (SAM) and persistent diarrhea using endoscopy, biopsy and analysis of markers and protective proteins in blood and intestinal secretions. We carried out parallel investigations in apparently healthy adults, and analyzed biomarkers only in apparently healthy children. Villus height and crypt depth did not differ in children with SAM and adult controls, but epithelial surface was reduced in children with SAM (median 445, interquartile range (IQR) 388, 562 μm per 100 μm muscularis mucosae) compared to adults (578, IQR 465,709; P = 0.004). Histological lesions and disruptions of claudin-4 and E-cadherin were most pronounced in children with SAM. Circulating lipopolysaccharide, a marker of bacterial translocation, was higher in malnourished children (251, IQR 110,460 EU/ml) than in healthy children (51, IQR 0,111; P = 0.0001). Other translocation markers showed similar patterns. Anti-Deamidated Gliadin Peptide IgG concentrations, although within the normal range, were higher in children with SAM (median 2.7 U/ml, IQR 1.5–8.6) than in adults (1.6, 1.4–2.1; P = 0.005), and were inversely correlated with villus height (ρ = − 0.79, n = 13, P = 0.001). Malnutrition enteropathy is associated with intestinal barrier failure and immune dysregulation.

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

“…A recent study found that children with severe acute malnutrition had increased concentrations of two celiac auto-antibodies: tissue transglutaminase and deamidated gliadin peptides. 38 Though within normal ranges, auto-antibody concentrations were inversely correlated with villus height and positively correlated with the systemic inflammatory marker LPS-binding protein. Thus it appears that autoreactivity may exacerbate (or possibly just reflect) mucosal pathology in EED as well as in CD.…”

“…Evidence from Malawi implicates dysbiosis (a flora altered in composition and usually reduced in complexity) in EED, 34,35 though whether dysbiosis initiates EE or merely perpetuates it is an unresolved question. Composition and function of the gut microbiota of 2-3-year-old children could be linked with the child and mother's genetically determined secretor status, presumably mediated by associated alterations in host glycans and breast milk-associated human milk oligosaccharides .36 PATHOLOGY AND PATHOPHYSIOLOGY OF EED In populations affected by EED, measurements of villus height or intestinal permeability vary continuously over a wide range, but the distributions of villus height 25,37,38 and permeability 39 measurements are reduced compared to populations in industrialized countries. There are disturbances in multiple domains of pathophysiology such as morphological change, malabsorption, mucosal inflammation, microbial translocation (MT), systemic inflammation, and changes in the microbiome.…”

“…There is a spectrum of morphological change, ranging from subtle increases in lamina propria infiltrates to total villus atrophy. 25,38 It is not possible to specify an absolute value of villus height that is normal, partly in view of the paucity of morphometric data available from industrialized countries free of EED. 38 Increased intestinal permeability, measured by monosaccharide and disaccharide probes, is also considered a diagnostic hallmark of EED.…”

“…25,38 It is not possible to specify an absolute value of villus height that is normal, partly in view of the paucity of morphometric data available from industrialized countries free of EED. 38 Increased intestinal permeability, measured by monosaccharide and disaccharide probes, is also considered a diagnostic hallmark of EED. 39,43,44 The principle of the test is that larger sugars (such as lactulose) cross the epithelium paracellularly, through dysfunctional tight junctions, while smaller monosaccharides (such as mannitol and rhamnose) are absorbed transcellularly and reflect the absorptive capacity of the epithelium.…”

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

“…Endoscopic duodenal biopsies from four cohorts were analyzed: (1) Hospitalized 6-36 month olds with SAM and persistent diarrhea in Lusaka, Zambia [39]; (2) children 18-22 months with non-edematous wasting not requiring hospitalization recruited from a community-based birth cohort in rural Pakistan, and undergoing endoscopy if unresponsive to 2 months of outpatient nutritional intervention [40]; (3) children <18 years with clinically suspected GSE; and (4) children <18 years with normal tissue transglutaminase (tTG) IgA concentrations, no known inflammatory bowel disorders or prior GSE diagnosis, and in whom a diagnostic upper endoscopy was indicated ( Table 1). The latter two groups underwent endoscopy as part of routine clinical care at the Washington University School of Medicine/St.…”