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Transcriptomic analysis of enteropathy in Zambian children with severe acute malnutrition
Mubanga Chama1, Beatrice C Amadi1, Kanta Chandwe1
1Tropical Gastroenterology and Nutrition group, University of Zambia School of Medicine, Nationalist Road, Lusaka, Zambia.
Insights
Severe acute malnutrition (SAM) enteropathy involves specific gene expression changes in nutrient transporters and gut barrier function. These molecular insights may guide new therapeutic strategies for affected children.
Area of Science:
- Molecular Biology
- Genomics
- Pediatric Gastroenterology
Background:
- Children with severe acute malnutrition (SAM) often develop enteropathy, complicating treatment.
- Limited molecular data exists to guide novel therapeutic development for SAM-associated enteropathy.
Purpose of the Study:
- To identify specific transcriptional changes in intestinal biopsies from children with SAM.
- To improve understanding of SAM enteropathy and identify potential therapeutic targets.
Main Methods:
- Intestinal biopsies were collected from children with SAM and persistent diarrhea.
- mRNA sequencing and transcriptomic analyses (NOIseq, GSEA, correlation analysis) were performed.
Main Results:
- 66 differentially expressed genes (DEGs) were identified, including those related to mucins, nutrient absorption, and antimicrobial defense.
- Increased cell cycling gene expression correlated with villus height; amino acid and zinc transporters were elevated in severe enteropathy.
- Reduced transcripts for xenobiotic metabolizing enzymes were observed.
Conclusions:
- Transcriptomic analysis revealed novel pathological elements in SAM enteropathy, including altered nutrient transporters and xenobiotic metabolism.
- Gene expression patterns showed similarities to pediatric Crohn's disease and celiac disease, but to a lesser extent.
- Findings provide molecular insights for potential new therapies for SAM enteropathy.
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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