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Pathogenesis, Clinical and Biological Predictors of Growth in Environmental enteric dysfunction (EED): An Infant Birth Inception Cohort

ABSTRACT: Pathogenesis, Clinical and Biological Predictors of Growth in Environmental enteric dysfunction (EED): An Infant Birth Inception Cohort

PROVIDER: PRJNA663330 | ENA |

REPOSITORIES: ENA

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Project description:Background: Environmental enteric dysfunction (EED) is a major impediment to the Sustainable Development Goals of improved childhood survival and healthy growth worldwide. Few studies have longitudinally and endoscopically examined EED in children, limiting the development of effective interventions. Methods: The Study of Environmental Enteropathy and Malnutrition (SEEM, Pakistan) followed 416 at-risk children prospectively from birth to 24 months of age in a rural district of Pakistan with a high prevalence of undernutrition. The duodenal genome-wide methylome and transcriptome was determined in 52 undernourished SEEM participants refractory to nutritional interventions and 42 North American pediatric controls and coeliac disease patients. Biomarkers were measured at 9 months and tested for association with growth at 24 months. Findings: The EED core transcriptome exhibited suppression of genes regulating antioxidant and detoxification functions and lipid metabolism, and induction of genes encoding anti-microbial responses, interferon signaling, and lymphocyte activation. Relative to coeliac disease, suppression of genes encoding antioxidant and detoxification functions and induction of anti-microbial responses were EED-specific. At the epigenetic level, EED was notable for hyper-methylation of genes involved in epithelial metabolism and barrier function, and hypo-methylation of genes involved in immune responses and cell proliferation. Duodenal co-expression modules revealed associations between genes regulating lymphocyte proliferation and epithelial metabolism with histologic severity, faecal energy loss, and wasting (weight-for-height Z<-2.0), with data supporting epigenetic regulation. Immune response genes were attenuated by Giardia colonization. After accounting for growth at study entry, IGF-1 and ferritin predicted linear growth, whereas leptin correlated with expression of epithelial carbohydrate metabolism and stem cell renewal genes, and weight gain. Interpretation: Data suggest immune and metabolic pathways which may inform more effective interventions to improve outcomes in EED. A validated model may be used to identify infants at greatest risk for future poor growth.

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Pathogenesis, Clinical and Biological Predictors of Growth in Environmental enteric dysfunction (EED): An Infant Birth Inception Cohort

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