Yael Haberman1, Najeeha T Iqbal2, Sudhir Ghandikota3, Indika Mallawaarachchi4, Phillip J Dexheimer5, Najeeb Rahman6, Rotem Hadar7, Kamran Sadiq6, Zubair Ahmad8, Romana Idress8, Junaid Iqbal2, Sheraz Ahmed6, Aneeta Hotwani6, Fayyaz Umrani6, Lubaina Ehsan9, Greg Medlock9, Sana Syed10, Chris Moskaluk9, Jennie Z Ma4, Anil G Jegga11, Sean R Moore9, Syed Asad Ali6, Lee A Denson12. 1. Department of Pediatrics, Cincinnati Children's Hospital Medical Center and the University of Cincinnati College of Medicine, Cincinnati, Ohio; Department of Pediatrics, Sheba Medical Center, Tel-HaShomer, affiliated with the Tel-Aviv University, Israel. 2. Department of Pediatrics and Child Health, Aga Khan University, Karachi, Pakistan; Department of Biological and Biomedical Sciences, Aga Khan University, Karachi, Pakistan. 3. Department of Computer Science, Cincinnati Children's Hospital Medical Center and the University of Cincinnati College of Engineering, Cincinnati, Ohio. 4. Department of Public Health Sciences, University of Virginia, Charlottesville, Virginia. 5. Department of Pediatrics, Cincinnati Children's Hospital Medical Center and the University of Cincinnati College of Medicine, Cincinnati, Ohio. 6. Department of Pediatrics and Child Health, Aga Khan University, Karachi, Pakistan. 7. Department of Pediatrics, Sheba Medical Center, Tel-HaShomer, affiliated with the Tel-Aviv University, Israel. 8. Department of Pathology and Laboratory Medicine, Aga Khan University, Karachi, Pakistan. 9. Department of Pediatrics, University of Virginia, Charlottesville, Virginia. 10. Department of Pediatrics and Child Health, Aga Khan University, Karachi, Pakistan; Department of Pediatrics, University of Virginia, Charlottesville, Virginia. 11. Department of Pediatrics, Cincinnati Children's Hospital Medical Center and the University of Cincinnati College of Medicine, Cincinnati, Ohio; Department of Computer Science, Cincinnati Children's Hospital Medical Center and the University of Cincinnati College of Engineering, Cincinnati, Ohio. 12. Department of Pediatrics, Cincinnati Children's Hospital Medical Center and the University of Cincinnati College of Medicine, Cincinnati, Ohio. Electronic address: lee.denson@cchmc.org.
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 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.
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 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.
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