title: Endomicroscopic and Transcriptomic Analysis of Impaired Barrier Function and Malabsorption in Environmental Enteropathy.
abstract: BACKGROUND
  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.
authors.affiliation: Blizard Institute, Barts and The London School of Medicine, Queen Mary University of London, London, United Kingdom.|Tropical Gastroenterology and Nutrition group, University of Zambia School of Medicine, Lusaka, Zambia.
authors.forename: Paul
authors.initials: P
authors.lastname: Kelly
authors.affiliation: Tropical Gastroenterology and Nutrition group, University of Zambia School of Medicine, Lusaka, Zambia.
authors.forename: Ellen
authors.initials: E
authors.lastname: Besa
authors.affiliation: Tropical Gastroenterology and Nutrition group, University of Zambia School of Medicine, Lusaka, Zambia.
authors.forename: Kanekwa
authors.initials: K
authors.lastname: Zyambo
authors.affiliation: Blizard Institute, Barts and The London School of Medicine, Queen Mary University of London, London, United Kingdom.
authors.forename: John
authors.initials: J
authors.lastname: Louis-Auguste
authors.affiliation: Blizard Institute, Barts and The London School of Medicine, Queen Mary University of London, London, United Kingdom.
authors.forename: James
authors.initials: J
authors.lastname: Lees
authors.affiliation: Tropical Gastroenterology and Nutrition group, University of Zambia School of Medicine, Lusaka, Zambia.
authors.forename: Themba
authors.initials: T
authors.lastname: Banda
authors.affiliation: Tropical Gastroenterology and Nutrition group, University of Zambia School of Medicine, Lusaka, Zambia.
authors.forename: Rose
authors.initials: R
authors.lastname: Soko
authors.affiliation: Tropical Gastroenterology and Nutrition group, University of Zambia School of Medicine, Lusaka, Zambia.
authors.forename: Rosemary
authors.initials: R
authors.lastname: Banda
authors.affiliation: Tropical Gastroenterology and Nutrition group, University of Zambia School of Medicine, Lusaka, Zambia.
authors.forename: Beatrice
authors.initials: B
authors.lastname: Amadi
authors.affiliation: Norwich Medical School, University of East Anglia, Norwich, United Kingdom.
authors.forename: Alastair
authors.initials: A
authors.lastname: Watson
mesh_terms: D001706:Biopsy; D004781:Environmental Exposure; D005767:Gastrointestinal Diseases / Q000473:pathology*; D020869:Gene Expression Profiling; D006651:Histocytochemistry; D007150:Immunohistochemistry; D008070:Lipopolysaccharides / Q000032:analysis; D008853:Microscopy; D010949:Plasma / Q000737:chemistry; D017423:Sequence Analysis, RNA; D015024:Zambia; D015032:Zinc / Q000378:metabolism
chemical_list: D008070:Lipopolysaccharides; D015032:Zinc