Endomicroscopic and transcriptomic analysis of impaired barrier function and malabsorption in environmental enteropathy

Kelly, Paul, Besa, Ellen, Zyambo, Kanekwa, Louis-Auguste, John, Lees, James, Banda, Themba, Soko, Rose, Banda, Rosemary, Amadi, Beatrice and Watson, Alastair (2016) Endomicroscopic and transcriptomic analysis of impaired barrier function and malabsorption in environmental enteropathy. PLoS Neglected Tropical Diseases, 10 (4). ISSN 1935-2735

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    Abstract

    Introduction: Environmental enteropathy (EE) is associated with growth failure, micronutrient malabsorption and impaired responses to oral vaccines. We set out to define cellular mechanisms of impaired barrier function in EE and explore protective mechanisms. Methods: We studied 49 adults with environmental enteropathy in Lusaka, Zambia using confocal laser endomicroscopy (CLE); histology, immunohistochemistry and mRNA sequencing of small intestinal biopsies; and correlated these with plasma lipopolysaccharide (LPS) and a zinc uptake test. Results: CLE images (median 134 for each study) showed virtually ubiquitous small intestinal damage. Epithelial defects, imaged by histology and claudin 4 immunostaining, were predominantly seen at the tips of villi and corresponded with leakage imaged in vivo by CLE. In multivariate analysis, circulating log-transformed LPS was correlated with cell shedding events (β = 0.83; P = 0.035) and with serum glucagon-like peptide-2 (β = -0.13; P = 0.007). Zinc uptake from a test dose of 25mg was attenuated in 30/47 (64%) individuals and in multivariate analysis was reduced by HIV, but positively correlated with GLP-2 (β = 2.72; P = 0.03). There was a U-shaped relationship between circulating LPS and villus surface area. Transcriptomic analysis identified 23 differentially expressed genes in severe enteropathy, including protective peptides and proteins. Conclusions: Confocal endomicroscopy, claudin 4 immunostaining and histology identify epithelial defects which are probably sites of bacterial translocation, in the presence of which increased epithelial surface area increases the burden of translocation. GLP 2 and other protective peptides may play an important role in mucosal protection in EE.

    Item Type: Article
    Additional Information: This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
    Uncontrolled Keywords: environmental enteropathy,environmental enteric dysfunction,africa,hiv,microbial translocation,zinc,glucagon-like peptide 2,trefoil factor 3,defensin,spink-4
    Faculty \ School: Faculty of Medicine and Health Sciences > Norwich Medical School
    University of East Anglia > Faculty of Medicine and Health Sciences > Research Groups > Gastroenterology and Gut Biology
    Depositing User: Pure Connector
    Date Deposited: 22 Mar 2016 09:37
    Last Modified: 25 Jul 2018 11:55
    URI: https://ueaeprints.uea.ac.uk/id/eprint/57827
    DOI: 10.1371/journal.pntd.0004600

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