title: Environmental Enteric Dysfunction Includes a Broad Spectrum of Inflammatory Responses and Epithelial Repair Processes.
abstract: OBJECTIVE
  Environmental enteric dysfunction (EED), a chronic diffuse inflammation of the small intestine, is associated with stunting in children in the developing world. The pathobiology of EED is poorly understood because of the lack of a method to elucidate the host response. This study tested a novel microarray method to overcome limitation of RNA sequencing to interrogate the host transcriptome in feces in Malawian children with EED.
  
  
  METHODS
  In 259 children, EED was measured by lactulose permeability (%L). After isolating low copy numbers of host messenger RNA, the transcriptome was reliably and reproducibly profiled, validated by polymerase chain reaction. Messenger RNA copy number then was correlated with %L and differential expression in EED. The transcripts identified were mapped to biological pathways and processes. The children studied had a range of %L values, consistent with a spectrum of EED from none to severe.
  
  
  RESULTS
  We identified 12 transcripts associated with the severity of EED, including chemokines that stimulate T-cell proliferation, Fc fragments of multiple immunoglobulin families, interferon-induced proteins, activators of neutrophils and B cells, and mediators that dampen cellular responses to hormones. EED-associated transcripts mapped to pathways related to cell adhesion, and responses to a broad spectrum of viral, bacterial, and parasitic microbes. Several mucins, regulatory factors, and protein kinases associated with the maintenance of the mucous layer were expressed less in children with EED than in normal children.
  
  
  CONCLUSIONS
  EED represents the activation of diverse elements of the immune system and is associated with widespread intestinal barrier disruption. Differentially expressed transcripts, appropriately enumerated, should be explored as potential biomarkers.
authors.affiliation: Genome Technology Access Center, Department of Genetics, Washington University School of Medicine, St. Louis, Missouri.
authors.forename: Jinsheng
authors.initials: J
authors.lastname: Yu
authors.affiliation: Department of Pediatrics, Washington University School of Medicine, St. Louis, Missouri.
authors.forename: M Isabel
authors.initials: MI
authors.lastname: Ordiz
authors.affiliation: Department of Pediatrics, Washington University School of Medicine, St. Louis, Missouri.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Stauber
authors.affiliation: Department of Pediatrics, Washington University School of Medicine, St. Louis, Missouri.
authors.forename: Nurmohammad
authors.initials: N
authors.lastname: Shaikh
authors.affiliation: Department of Pediatrics, Washington University School of Medicine, St. Louis, Missouri.
authors.forename: Indi
authors.initials: I
authors.lastname: Trehan
authors.affiliation: Department of Pediatrics, Washington University School of Medicine, St. Louis, Missouri.
authors.forename: Erica
authors.initials: E
authors.lastname: Barnell
authors.affiliation: Genome Technology Access Center, Department of Genetics, Washington University School of Medicine, St. Louis, Missouri.
authors.forename: Richard D
authors.initials: RD
authors.lastname: Head
authors.affiliation: Department of Community Health, College of Medicine, Blantyre, Malawi.
authors.forename: Ken
authors.initials: K
authors.lastname: Maleta
authors.affiliation: Department of Pediatrics, Washington University School of Medicine, St. Louis, Missouri.
authors.forename: Phillip I
authors.initials: PI
authors.lastname: Tarr
authors.affiliation: Department of Pediatrics, Washington University School of Medicine, St. Louis, Missouri; Department of Community Health, College of Medicine, Blantyre, Malawi; Children's Nutrition Research Center, Baylor College of Medicine, Houston, Texas.
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Manary
keywords: %L, lactulose permeability; EED, environmental enteric dysfunction; Environmental Enteropathy; FARMS, factor analyses for robust microarray summarization; Fecal Transcriptome; G-CSF, granulocyte colony–stimulating factor; HAZ, height-for-age z score; IRON, iterative rank order normalization; Intestinal Inflammation; KEGG, Kyoto Encyclopedia of Genes and Genomes; RMA, robust multi-array average; Stunting; dHAZ, change in height-for-age z score; mRNA, messenger RNA; qPCR, quantitative polymerase chain reaction