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Transcriptomic analysis of enteropathy in Zambian children with severe acute malnutrition

BACKGROUND: Children with severe acute malnutrition (SAM), with or without diarrhoea, often have enteropathy, but there are few molecular data to guide development of new therapies. We set out to determine whether SAM enteropathy is characterised by specific transcriptional changes which might impro...

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Autores principales: Chama, Mubanga, Amadi, Beatrice C., Chandwe, Kanta, Zyambo, Kanekwa, Besa, Ellen, Shaikh, Nurmohammad, Ndao, I. Malick, Tarr, Philip I., Storer, Chad, Head, Richard, Kelly, Paul
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Elsevier 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6642221/
https://www.ncbi.nlm.nih.gov/pubmed/31229436
http://dx.doi.org/10.1016/j.ebiom.2019.06.015
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author Chama, Mubanga
Amadi, Beatrice C.
Chandwe, Kanta
Zyambo, Kanekwa
Besa, Ellen
Shaikh, Nurmohammad
Ndao, I. Malick
Tarr, Philip I.
Storer, Chad
Head, Richard
Kelly, Paul
author_facet Chama, Mubanga
Amadi, Beatrice C.
Chandwe, Kanta
Zyambo, Kanekwa
Besa, Ellen
Shaikh, Nurmohammad
Ndao, I. Malick
Tarr, Philip I.
Storer, Chad
Head, Richard
Kelly, Paul
author_sort Chama, Mubanga
collection PubMed
description BACKGROUND: Children with severe acute malnutrition (SAM), with or without diarrhoea, often have enteropathy, but there are few molecular data to guide development of new therapies. We set out to determine whether SAM enteropathy is characterised by specific transcriptional changes which might improve understanding or help identify new treatments. METHODS: We collected intestinal biopsies from children with SAM and persistent diarrhoea. mRNA was extracted from biopsies, sequenced, and subjected to a progressive set of complementary analytical approaches: NOIseq, Gene Set Enrichment Analysis (GSEA), and correlation analysis of phenotypic data with gene expression. FINDINGS: Transcriptomic profiles were generated for biopsy sets from 27 children of both sexes, under 2 years of age, of whom one-third were HIV-infected. NOIseq analysis, constructed from phenotypic group extremes, revealed 66 differentially expressed genes (DEGs) out of 21,386 mapped to the reference genome. These DEGs include genes for mucins and mucus integrity, antimicrobial defence, nutrient absorption, C-X-C chemokines, proteases and anti-proteases. Phenotype – expression correlation analysis identified 1221 genes related to villus height, including increased cell cycling gene expression in more severe enteropathy. Amino acid transporters and ZIP zinc transporters were specifically increased in severe enteropathy, but transcripts for xenobiotic metabolising enzymes were reduced. INTERPRETATION: Transcriptomic analysis of this rare collection of intestinal biopsies identified multiple novel elements of pathology, including specific alterations in nutrient transporters. Changes in xenobiotic metabolism in the gut may alter drug disposition. Both NOIseq and GSEA identified gene clusters similar to those differentially expressed in pediatric Crohn's disease but to a much lesser degree than those identified in coeliac disease. FUND: Bill & Melinda Gates Foundation OPP1066118. The funding agency had no role in study design, data collection, data analysis, interpretation, or writing of the report.
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spelling pubmed-66422212019-07-29 Transcriptomic analysis of enteropathy in Zambian children with severe acute malnutrition Chama, Mubanga Amadi, Beatrice C. Chandwe, Kanta Zyambo, Kanekwa Besa, Ellen Shaikh, Nurmohammad Ndao, I. Malick Tarr, Philip I. Storer, Chad Head, Richard Kelly, Paul EBioMedicine Research paper BACKGROUND: Children with severe acute malnutrition (SAM), with or without diarrhoea, often have enteropathy, but there are few molecular data to guide development of new therapies. We set out to determine whether SAM enteropathy is characterised by specific transcriptional changes which might improve understanding or help identify new treatments. METHODS: We collected intestinal biopsies from children with SAM and persistent diarrhoea. mRNA was extracted from biopsies, sequenced, and subjected to a progressive set of complementary analytical approaches: NOIseq, Gene Set Enrichment Analysis (GSEA), and correlation analysis of phenotypic data with gene expression. FINDINGS: Transcriptomic profiles were generated for biopsy sets from 27 children of both sexes, under 2 years of age, of whom one-third were HIV-infected. NOIseq analysis, constructed from phenotypic group extremes, revealed 66 differentially expressed genes (DEGs) out of 21,386 mapped to the reference genome. These DEGs include genes for mucins and mucus integrity, antimicrobial defence, nutrient absorption, C-X-C chemokines, proteases and anti-proteases. Phenotype – expression correlation analysis identified 1221 genes related to villus height, including increased cell cycling gene expression in more severe enteropathy. Amino acid transporters and ZIP zinc transporters were specifically increased in severe enteropathy, but transcripts for xenobiotic metabolising enzymes were reduced. INTERPRETATION: Transcriptomic analysis of this rare collection of intestinal biopsies identified multiple novel elements of pathology, including specific alterations in nutrient transporters. Changes in xenobiotic metabolism in the gut may alter drug disposition. Both NOIseq and GSEA identified gene clusters similar to those differentially expressed in pediatric Crohn's disease but to a much lesser degree than those identified in coeliac disease. FUND: Bill & Melinda Gates Foundation OPP1066118. The funding agency had no role in study design, data collection, data analysis, interpretation, or writing of the report. Elsevier 2019-06-20 /pmc/articles/PMC6642221/ /pubmed/31229436 http://dx.doi.org/10.1016/j.ebiom.2019.06.015 Text en © 2019 The Authors http://creativecommons.org/licenses/by/4.0/ This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Research paper
Chama, Mubanga
Amadi, Beatrice C.
Chandwe, Kanta
Zyambo, Kanekwa
Besa, Ellen
Shaikh, Nurmohammad
Ndao, I. Malick
Tarr, Philip I.
Storer, Chad
Head, Richard
Kelly, Paul
Transcriptomic analysis of enteropathy in Zambian children with severe acute malnutrition
title Transcriptomic analysis of enteropathy in Zambian children with severe acute malnutrition
title_full Transcriptomic analysis of enteropathy in Zambian children with severe acute malnutrition
title_fullStr Transcriptomic analysis of enteropathy in Zambian children with severe acute malnutrition
title_full_unstemmed Transcriptomic analysis of enteropathy in Zambian children with severe acute malnutrition
title_short Transcriptomic analysis of enteropathy in Zambian children with severe acute malnutrition
title_sort transcriptomic analysis of enteropathy in zambian children with severe acute malnutrition
topic Research paper
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6642221/
https://www.ncbi.nlm.nih.gov/pubmed/31229436
http://dx.doi.org/10.1016/j.ebiom.2019.06.015
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