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BMC Pediatr. 2019 Jul 22;19(1):247. doi: 10.1186/s12887-019-1564-x.

Study of Environmental Enteropathy and Malnutrition (SEEM) in Pakistan: protocols for biopsy based biomarker discovery and validation.

Author information

1
Department of Paediatrics and Child Health, Aga Khan University, Karachi, Pakistan.
2
Department of Biological and Biomedical Sciences, Aga Khan University, Karachi, Pakistan.
3
Department of Pediatrics, University of Virginia, Charlottesville, VA, USA.
4
Department of Public Health Sciences, University of Virginia, Charlottesville, VA, USA.
5
Division of Pediatric Gastroenterology, Hepatology, and Nutrition, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA.
6
Division of Infectious Diseases, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA.
7
Clinical Mass Spectrometry, Division of Pathology and Laboratory Medicine, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA.
8
Department of Pediatrics, Baylor College of Medicine, USDA/ARS Children's Nutrition Research Center, Houston, TX, USA.
9
Department of Pathology, University of Virginia, Charlottesville, VA, USA.
10
Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO, USA.
11
Department of Pathology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.
12
Koch Institute for Integrative Cancer Research at MIT and Department of Biology, Massachusetts Institute of Technology, Cambridge, MA, USA.
13
Data Science Institute, University of Virginia, Charlottesville, VA, USA.
14
Center for Genome Sciences and Systems Biology, Washington University School of Medicine, St. Louis, MO, USA.
15
Department of Pediatrics, University of Virginia, Charlottesville, VA, USA. sean.moore@virginia.edu.
16
Department of Paediatrics and Child Health, Aga Khan University, Karachi, Pakistan. asad.ali@aku.edu.

Abstract

BACKGROUND:

Environmental Enteropathy (EE), characterized by alterations in intestinal structure, function, and immune activation, is believed to be an important contributor to childhood undernutrition and its associated morbidities, including stunting. Half of all global deaths in children < 5 years are attributable to under-nutrition, making the study of EE an area of critical priority.

METHODS:

Community based intervention study, divided into two sub-studies, 1) Longitudinal analyses and 2) Biopsy studies for identification of EE features via omics analyses. Birth cohorts in Matiari, Pakistan established: moderately or severely malnourished (weight for height Z score (WHZ) < - 2) children, and well-nourished (WHZ > 0) children. Blood, urine, and fecal samples, for evaluation of potential biomarkers, will be collected at various time points from all participants (longitudinal analyses). Participants will receive appropriate educational and nutritional interventions; non-responders will undergo further evaluation to determine eligibility for further workup, including upper gastrointestinal endoscopy. Histopathological changes in duodenal biopsies will be compared with duodenal biopsies obtained from USA controls who have celiac disease, Crohn's disease, or who were found to have normal histopathology. RNA-Seq will be employed to characterize mucosal gene expression across groups. Duodenal biopsies, luminal aspirates from the duodenum, and fecal samples will be analyzed to define microbial community composition (omic analyses). The relationship between histopathology, mucosal gene expression, and community configuration will be assessed using a variety of bioinformatic tools to gain better understanding of disease pathogenesis and to identify mechanism-based biomarkers. Ethical review committees at all collaborating institutions have approved this study. All results will be made available to the scientific community.

DISCUSSION:

Operational and ethical constraints for safely obtaining intestinal biopsies from children in resource-poor settings have led to a paucity of human tissue-based investigations to understand and reverse EE in vulnerable populations. Furthermore, EE biomarkers have rarely been correlated with gold standard histopathological confirmation. The Study of Environmental Enteropathy and Malnutrition (SEEM) is designed to better understand the pathophysiology, predictors, biomarkers, and potential management strategies of EE to inform strategies to eradicate this debilitating pathology and accelerate progress towards the 2030 Sustainable Development Goals.

TRIAL REGISTRATION:

Retrospectively registered; clinicaltrials.gov ID NCT03588013 .

KEYWORDS:

Childhood undernutrition; Duodenal biopsies; Endoscopy; Environmental enteropathy; Gut barrier function; Low- middle income countries; Mucosal gene expression; Small intestinal microbiota

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