Author
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YU, JINSHENG - Washington University School Of Medicine |
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ORDIZ, M - Washington University School Of Medicine |
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STAUBER, JENNIFER - Washington University School Of Medicine |
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SHAIKH, NURMOHAMMAD - Washington University School Of Medicine |
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TREHAN, INDI - Washington University School Of Medicine |
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BARNELL, ERICA - Washington University School Of Medicine |
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HEAD, RICHARD - Washington University School Of Medicine |
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MALETA, KEN - University Of Malawi |
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TARR, PHILLIP - Washington University School Of Medicine |
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MANARY, MARK - Children'S Nutrition Research Center (CNRC) |
Submitted to: Cellular and Molecular Gastoenterology and Hepatology
Publication Type: Peer Reviewed Journal Publication Acceptance Date: 12/3/2015 Publication Date: 12/11/2015 Citation: Yu, J., Ordiz, M.I., Stauber, J., Shaikh, N., Trehan, I., Barnell, E., Head, R.D., Maleta, K., Tarr, P.I., Manary, M.J. 2015. Environmental enteric dysfunction includes a broad spectrum of inflammatory responses and epithelial repair processes. Cellular and Molecular Gastoenterology and Hepatology. 2(2):158-174. Interpretive Summary: It is not known what responses human cells are exhibiting in the gut to microbes in rural African children. Our lab took a new, existing microarray technology, and applied it to this problem. We found that there were inflammatory responses to all major classes of microbes; viruses, bacteria, fungi and parasites. Future research should explore these potential biomakers. Technical Abstract: 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 the limitation of RNA sequencing to interrogate the host transcriptome in feces in Malawian children with EED. 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. 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. 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. |