Abstract
BackgroundEnvironmental 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.MethodsCommunity 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.DiscussionOperational 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 registrationRetrospectively registered; clinicaltrials.gov ID NCT03588013.
Highlights
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
The Study of Environmental Enteropathy and Malnutrition in Pakistan (SEEM Pakistan), is a follow up to our phase 1 study titled ‘Identification of Novel Biomarkers for Environmental Enteropathy in Children Using an Evidence Based Approach’ [14, 21,22,23], in which we have studied patterns of malnutrition and prevention in a cohort of children in Matiari, Pakistan and looked at potential biomarkers of EE and at the ethical feasibilities of conducting biopsies in a lowand middle income country (LMIC) setting
SEEM Pakistan is a multi-institutional collaboration between the Aga Khan University Hospital (AKUH), Pakistan, University of Virginia (UVa), Cincinnati Children’s Hospital Medical Center (CCHMC) and Washington University in St
Summary
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. Permeability can lead to translocation of microbes or microbial products which along with the intestinal inflammatory nidus, can produce systemic immune activation. This chronic inflammation along with malabsorption are postulated to be the mechanisms through which EE contributes to undernutrition, especially linear growth faltering [13, 14]. A comprehensive approach incorporating longitudinal surveillance of affected children to identify the impact of EE from other co-morbid conditions is needed to fully capture risk factors for EE. We propose a comprehensive study approach which combines longitudinal surveillance of children from birth until 2 years of age, capturing known and postulated risk factors of EE and applying the most advanced tools for the analysis of the intestinal tissue samples. This report describes the SEEM Pakistan study design, including the materials that are being collected along with proposed analysis including use of machine learning methods
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