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Mucosal Genomics Implicate Lymphocyte Activation and Lipid Metabolism in Refractory Environmental Enteric Dysfunction
- Source :
- Gastroenterology
- Publication Year :
- 2021
- Publisher :
- Elsevier BV, 2021.
-
Abstract
- Background & Aims Environmental enteric dysfunction (EED) limits the Sustainable Development Goals of improved childhood growth and survival. We applied mucosal genomics to advance our understanding of EED. Methods The Study of Environmental Enteropathy and Malnutrition (SEEM) followed 416 children from birth to 24 months in a rural district in Pakistan. Biomarkers were measured at 9 months and tested for association with growth at 24 months. The duodenal methylome and transcriptome were determined in 52 undernourished SEEM participants and 42 North American controls and patients with celiac disease. Results After accounting for growth at study entry, circulating insulin-like growth factor-1 (IGF-1) and ferritin predicted linear growth, whereas leptin correlated with future weight gain. The EED transcriptome exhibited suppression of antioxidant, detoxification, and lipid metabolism genes, and induction of anti-microbial response, interferon, and lymphocyte activation genes. Relative to celiac disease, suppression of antioxidant and detoxification genes and induction of antimicrobial response genes were EED-specific. At the epigenetic level, EED showed hyper-methylation of epithelial metabolism and barrier function genes, and hypo-methylation of immune response and cell proliferation genes. Duodenal coexpression modules showed association between lymphocyte proliferation and epithelial metabolic genes and histologic severity, fecal energy loss, and wasting (weight-for-length/height Z < -2.0). Leptin was associated with expression of epithelial carbohydrate metabolism and stem cell renewal genes. Immune response genes were attenuated by giardia colonization. Conclusions Children with reduced circulating IGF-1 are more likely to experience stunting. Leptin and a gene signature for lymphocyte activation and dysregulated lipid metabolism are implicated in wasting, suggesting new approaches for EED refractory to nutritional intervention. ClinicalTrials.gov, Number: NCT03588013. (https://clinicaltrials.gov/ct2/show/NCT03588013)<br />Graphical abstract
- Subjects :
- Leptin
Male
0301 basic medicine
IGF, insulin-like growth factor
Anthropometrics
medicine.medical_treatment
Lymphocyte proliferation
Lymphocyte Activation
Transcriptome
Epigenome
Insulin-like growth factor
Child Development
Full Report: Basic and Translational—Alimentary Tract
DMRs, differentially methylated regions
0302 clinical medicine
SEEM, Study of Environmental Enteropathy and Malnutrition
IFNG, interferon gamma
Pakistan
Lymphocytes
Ctl, control
Insulin-Like Growth Factor I
Intestinal Mucosa
Wasting
Growth Disorders
Original Research
RNA Sequencing
DNAm, DNA methylation
HAZ, length/height-for-age z score
WGCNA, weighted gene coexpression network analysis
mRNAseq, messenger RNA
Gastroenterology
Genomics
Intestine
Child, Preschool
Creatinine
Female
030211 gastroenterology & hepatology
medicine.symptom
FDR, false discovery rate
EED, environmental enteric dysfunction
Biology
AKU, Aga Khan University
03 medical and health sciences
Immune system
CRFs, conditional random forests
medicine
Humans
Cell Proliferation
rDMR, regulatory DMR
Environmental enteropathy
Hepatology
Malnutrition
Infant, Newborn
Infant
Lipid metabolism
DNA Methylation
Lipid Metabolism
medicine.disease
Celiac Disease
Intestinal Diseases
Oxidative Stress
030104 developmental biology
WAZ, weight-for-age z score
Case-Control Studies
Ferritins
Immunology
WHZ, weight-for- length/height z score
Biomarkers
Subjects
Details
- ISSN :
- 00165085
- Volume :
- 160
- Database :
- OpenAIRE
- Journal :
- Gastroenterology
- Accession number :
- edsair.doi.dedup.....face10582fbc876cf9ff9f4c185d3416