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

ABSTRACT: Environmental enteric dysfunction (EED) is a major impediment to the Sustainable Development Goals of improved childhood survival and healthy growth worldwide. Few studies have directly examined the affected intestine, limiting the development of effective interventions. 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 healthy controls and celiac disease patients. Biomarkers were measured at 9 months and tested for association with growth at 24 months in training (n=166) and validation (n=84) groups within SEEM.

ORGANISM(S): Homo sapiens

PROVIDER: GSE157914 | GEO | 2021/05/19

REPOSITORIES: GEO

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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.

Project description:Transcriptomics and functional bioinformatics were used to investigate the potential interactions of undernutrition and the presence of the conceptus at the time of maternal recognition of pregnancy on uterine indicators of metabolism and reproduction. Adult Rasa Aragonesa ewes were allocated to one of two planes of nutrition during 28 days: maintenance energy intake (control; 5 cyclic, 6 pregnant ewes) providing 7.8 MJ of metabolisable energy per ewe and 0.5 maintenance intake (undernourished; 6 cyclic, 7 pregnant ewes) providing 3.9 MJ of metabolisable energy per ewe. RNA from uterine tissue was harvested at slaughter on day 14 of estrus or pregnancy, and hybridized to the Agilent 15K Sheep Microarray chip. Functional bioinformatics analyses were performed using the Dynamic Impact Approach (DIA) and Ingenuity Pathway Analysis. Among metabolic pathways, citrate cycle, oxidative phosphorylation, pentose and glucuronate interconversions and biosynthesis of unsaturated fatty acids were upregulated in control pregnant compared with control cyclic ewes. However, these pathways were not altered in undernourished ewes. The presence of an embryo in undernourished ewes upregulated fatty acid and glycogenic amino acid metabolism. RIG-I and Toll like receptors and chemokine signaling pathways were upregulated by the presence of the embryo in both control and undernourished ewes, but in the latter group the impact was lower. Undernutrition alone upregulated carbohydrate metabolism, but different pathways were altered in cyclic versus pregnant ewes. Citrate cycle, glycolysis/gluconeogenesis, and pentose and glucuronate interconversions were upregulated in undernourished cyclic compared with control cyclic ewes. Glycolysis/gluconeogenesis, pyruvate and propanoate metabolism, beta-alanine and phenylalanine metabolism were upregulated in undernourished pregnant compared with control pregnant ewes, whereas biosynthesis of unsaturated fatty acids and replication and repair were downregulated. Undernutrition alone led to an overall weak activation of immune system pathways both in cyclic and pregnant ewes. However, undernourished cyclic compared with control cyclic ewes had a high activation of NOD-like and RIG-1 like receptor signaling pathways, whereas undernourished pregnant compared with control pregnant ewes only had a weak upregulation of T cell receptor signaling pathways. Overall, data revealed that metabolic and immune adaptations of the uterus to nutrient restriction are dependent on the presence of the conceptus.

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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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