Mucosal Genomics Implicate Lymphocyte Activation and Lipid Metabolism in Refractory Environmental Enteric Dysfunction

Yael Haberman; Najeeha T. Iqbal; Sudhir Ghandikota; Indika Mallawaarachchi; Braun Tzipi Braun; Phillip J. Dexheimer; Najeeb Rahman; Rotem Hadar; Kamran Sadiq; Zubair Ahmad; Romana Idress; Junaid Iqbal; Sheraz Ahmed; Aneeta Hotwani; Fayyaz Umrani; Lubaina Ehsan; Greg Medlock; Sana Syed; Chris Moskaluk; Jennie Z. Ma; Anil G. Jegga; Sean R. Moore; Syed Asad Ali; Lee A. Denson

doi:10.1053/j.gastro.2021.01.221

Mucosal Genomics Implicate Lymphocyte Activation and Lipid Metabolism in Refractory Environmental Enteric Dysfunction

Yael Haberman, Najeeha T. Iqbal, Sudhir Ghandikota, Indika Mallawaarachchi, Braun Tzipi Braun, Phillip J. Dexheimer, Najeeb Rahman, Rotem Hadar, Kamran Sadiq, Zubair Ahmad, Romana Idress, Junaid Iqbal, Sheraz Ahmed, Aneeta Hotwani, Fayyaz Umrani, Lubaina Ehsan, Greg Medlock, Sana Syed, Chris Moskaluk, Jennie Z. MaAnil G. Jegga, Sean R. Moore^*, Syed Asad Ali^*, Lee A. Denson^*

^*Corresponding author for this work

Pediatrics

Research output: Contribution to journal › Article › peer-review

43 Scopus citations

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)

Original language	English
Pages (from-to)	2055-2071.e0
Journal	Gastroenterology
Volume	160
Issue number	6
DOIs	https://doi.org/10.1053/j.gastro.2021.01.221
State	Published - May 2021

Funding

Funders	Funder number
Inflammation and Environmental Enteric Dysfunction
National Institutes of Health
Fogarty International Center	K23DK117061, D43TW007585
Fogarty International Center
National Institute of Diabetes and Digestive and Kidney Diseases	P30 DK078392, FIC K43TW010697
National Institute of Diabetes and Digestive and Kidney Diseases
Bill and Melinda Gates Foundation	OPP1144149, OPP1138727
Bill and Melinda Gates Foundation
Leona M. and Harry B. Helmsley Charitable Trust
Engineering Research Centers	758313
Engineering Research Centers

Keywords

Anthropometrics
DNA Methylation
Intestine
RNA Sequencing

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

Access to Document

10.1053/j.gastro.2021.01.221

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Haberman, Y., Iqbal, N. T., Ghandikota, S., Mallawaarachchi, I., Tzipi Braun, B., Dexheimer, P. J., Rahman, N., Hadar, R., Sadiq, K., Ahmad, Z., Idress, R., Iqbal, J., Ahmed, S., Hotwani, A., Umrani, F., Ehsan, L., Medlock, G., Syed, S., Moskaluk, C., ... Denson, L. A. (2021). Mucosal Genomics Implicate Lymphocyte Activation and Lipid Metabolism in Refractory Environmental Enteric Dysfunction. Gastroenterology, 160(6), 2055-2071.e0. https://doi.org/10.1053/j.gastro.2021.01.221

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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)",

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author = "Yael Haberman and Iqbal, {Najeeha T.} and Sudhir Ghandikota and Indika Mallawaarachchi and {Tzipi Braun}, Braun and Dexheimer, {Phillip J.} and Najeeb Rahman and Rotem Hadar and Kamran Sadiq and Zubair Ahmad and Romana Idress and Junaid Iqbal and Sheraz Ahmed and Aneeta Hotwani and Fayyaz Umrani and Lubaina Ehsan and Greg Medlock and Sana Syed and Chris Moskaluk and Ma, {Jennie Z.} and Jegga, {Anil G.} and Moore, {Sean R.} and Ali, {Syed Asad} and Denson, {Lee A.}",

note = "Publisher Copyright: {\textcopyright} 2021 The Authors",

year = "2021",

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doi = "10.1053/j.gastro.2021.01.221",

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Haberman, Y, Iqbal, NT, Ghandikota, S, Mallawaarachchi, I, Tzipi Braun, B, Dexheimer, PJ, Rahman, N, Hadar, R, Sadiq, K, Ahmad, Z, Idress, R, Iqbal, J, Ahmed, S, Hotwani, A, Umrani, F, Ehsan, L, Medlock, G, Syed, S, Moskaluk, C, Ma, JZ, Jegga, AG, Moore, SR, Ali, SA & Denson, LA 2021, 'Mucosal Genomics Implicate Lymphocyte Activation and Lipid Metabolism in Refractory Environmental Enteric Dysfunction', Gastroenterology, vol. 160, no. 6, pp. 2055-2071.e0. https://doi.org/10.1053/j.gastro.2021.01.221

TY - JOUR

T1 - Mucosal Genomics Implicate Lymphocyte Activation and Lipid Metabolism in Refractory Environmental Enteric Dysfunction

AU - Haberman, Yael

AU - Iqbal, Najeeha T.

AU - Ghandikota, Sudhir

AU - Mallawaarachchi, Indika

AU - Tzipi Braun, Braun

AU - Dexheimer, Phillip J.

AU - Rahman, Najeeb

AU - Hadar, Rotem

AU - Sadiq, Kamran

AU - Ahmad, Zubair

AU - Idress, Romana

AU - Iqbal, Junaid

AU - Ahmed, Sheraz

AU - Hotwani, Aneeta

AU - Umrani, Fayyaz

AU - Ehsan, Lubaina

AU - Medlock, Greg

AU - Syed, Sana

AU - Moskaluk, Chris

AU - Ma, Jennie Z.

AU - Jegga, Anil G.

AU - Moore, Sean R.

AU - Ali, Syed Asad

AU - Denson, Lee A.

PY - 2021/5

Y1 - 2021/5

N2 - 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)

AB - 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)

KW - Anthropometrics

KW - DNA Methylation

KW - Intestine

KW - RNA Sequencing

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JF - Gastroenterology

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ER -

Mucosal Genomics Implicate Lymphocyte Activation and Lipid Metabolism in Refractory Environmental Enteric Dysfunction

Abstract

Funding

Keywords

UN SDGs

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