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Plasma Metabolome Alterations Associated with Extrauterine Growth Restriction.

ABSTRACT: Very preterm infants (VPI, born at or before 32 weeks of gestation) are at risk of adverse health outcomes, from which they might be partially protected with appropriate postnatal nutrition and growth. Metabolic processes or biochemical markers associated to extrauterine growth restriction (EUGR) have not been identified. We applied untargeted metabolomics to plasma samples of VPI with adequate weight for gestational age at birth and with different growth trajectories (29 well-grown, 22 EUGR) at the time of hospital discharge. A multivariate analysis showed significantly higher levels of amino-acids in well-grown patients. Other metabolites were also identified as statistically significant in the comparison between groups. Relevant differences (with corrections for multiple comparison) were found in levels of glycerophospholipids, sphingolipids and other lipids. Levels of many of the biochemical species decreased progressively as the level of growth restriction increased in severity. In conclusion, an untargeted metabolomic approach uncovered previously unknown differences in the levels of a range of plasma metabolites between well grown and EUGR infants at the time of discharge. Our findings open speculation about pathways involved in growth failure in preterm infants and the long-term relevance of this metabolic differences, as well as helping in the definition of potential biomarkers.

SUBMITTER: Dudzik D

PROVIDER: S-EPMC7230608 | biostudies-literature | 2020 Apr

REPOSITORIES: biostudies-literature

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Plasma Metabolome Alterations Associated with Extrauterine Growth Restriction.

Dudzik Danuta D Iglesias Platas Isabel I Izquierdo Renau Montserrat M Balcells Esponera Carla C Del Rey Hurtado de Mendoza Beatriz B Lerin Carles C Ramón-Krauel Marta M Barbas Coral C

Nutrients 20200423 4

Very preterm infants (VPI, born at or before 32 weeks of gestation) are at risk of adverse health outcomes, from which they might be partially protected with appropriate postnatal nutrition and growth. Metabolic processes or biochemical markers associated to extrauterine growth restriction (EUGR) have not been identified. We applied untargeted metabolomics to plasma samples of VPI with adequate weight for gestational age at birth and with different growth trajectories (29 well-grown, 22 EUGR) at ...[more]

PMID: 32340341

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Project description:Newborn animals with intrauterine growth restriction (IUGR) are characterized by impaired intestinal structure and function; however, their intestinal microbiota and metabolome profiles have not been fully identified. The present study investigated the differences in colonic microbiota, metabolomics, and barrier function-related gene expression profiles between the IUGR and normal birth weight (NBW) piglets at 7, 21, and 28 days of age. Forty-eight piglets (24 NBW and 24 IUGR) from 24 litters were assigned to assess the differences in colonic microbiota, metabolomics, and gene expression between IUGR and NBW piglets. Compared with the NBW piglets, IUGR piglets showed decreased Shannon index and increased Simpson index at 7 days of age and Chao1 index at 21 days of age (p < 0.05). The IUGR piglets had lower abundances of Firmicutes, Subdoligranulum, Ruminococcaceae_UCG-002, and Ruminococcaceae_UCG-003 at 7 days of age, and Bacteroidetes, Phascolarctobacterium, and Ruminococcaceae_UCG-005 at 21 days of age, when compared with the NBW piglets (p < 0.05). Metabolomics analysis showed significant changes in 147 metabolites mainly involved in organic acids and their derivatives in the colon. Six differential metabolic pathways were significantly enriched, including purine metabolism, amino sugar/nucleotide sugar metabolism, ubiquinone/other terpenoid-quinone biosynthesis, phenylalanine/tyrosine/tryptophan biosynthesis, phenylalanine metabolism, and histidine metabolism. Spearman's correlation analysis further demonstrated significant correlations between colonic microbiota and metabolites. In addition, colonic isobutyrate at 7 days of age, isovalerate and total short-chain fatty acids (SCFAs) at 21 days of age, and acetate, propionate, butyrate, and total SCFAs levels at 28 days of age were lower and isovalerate was higher at 28 days of age in the IUGR piglets than in the NBW piglets (p < 0.05). Furthermore, the mRNA expression of zonula occludens (ZO)-1 at 7 days of age, ZO-1, occludin, and interleukin (IL)-4 at 21 days of age were down-regulated in the IUGR piglets, whereas tumor necrosis factor (TNF)-α and nuclear factor-kappa B (NF-κB) at 28 days of age were up-regulated, when compared with the NBW piglets (p < 0.05). The findings suggest that the IUGR pigs present abnormal microbiota and nutrient metabolism in the colon, which may further affect the intestine barrier function by regulating gene expressions.

Project description:BackgroundExtrauterine growth restriction (EUGR) is common among very low birth weight (VLBW) infants and associated with poor neurodevelopmental outcomes. There are two types of EUGR definitions (cross-sectional and longitudinal) and many growth charts for monitoring postnatal growth. Aims of our study were 1) to compare the rate of small for gestational rate (SGA) and EUGR in a population of VLBW infants, both according to different growth charts (Fenton, INeS charts and Intergrowth-21) and different definitions; 2) to identify risk factors for EUGR.MethodsThis is a single centre retrospective observational study, including all VLBW infants born between January 2009 and December 2018. Anthropometric measures were obtained at birth and at discharge and presented as z-scores according to three growth charts (Fenton, INeS charts, Intergrowth-21). Maternal, clinical and nutritional data were retrieved from clinical records.Results228 VLBW were included. Percentage of SGA did not change significantly according to the three different growth charts (Fenton 22.4%, INeS charts 22.8%, Intergrowth 28.2%, p 0.27). Prevalence of EUGR was significantly higher when INeS and Fenton charts were used, compared to Intergrowth charts regardless of EUGR-definition (cross sectional-EUGR: Fenton 33.5%, INeS charts 40.9%, Intergrowth-21 23.8%, p 0.001; longitudinal-EUGR (loss of 1SDS): Fenton 15%, INeS charts 20.4%, Intergrowth 4%, p <0.001). In our population a longer time to reach 100 ml/kg/day of enteral feeding increased of 18% the risk of longitudinal EUGR. Late onset sepsis and retinopathy of prematurity were associated with an increased risk of longitudinal EUGR, although not significantly, while having a preeclamptic mother was associated with a reduced risk.ConclusionsWe confirmed a wide variability of EUGR rates when using different charts and definitions, highlighting that Intergrowth-21 charts identify less EUGR when compared to INeS and Fenton charts. Standardized criteria for defining EUGR are warranted in order to facilitate comparisons between studies and to improve the nutritional management of VLBW infants.

Project description:ObjectiveEarly postnatal life is considered as a critical time window for the determination of long-term metabolic states and organ functions. Extrauterine growth restriction (EUGR) causes the development of adult-onset chronic diseases, including pulmonary hypertension. However, the effects of nutritional disadvantages during the early postnatal period on pulmonary vascular consequences in later life are not fully understood. Our study was designed to test whether epigenetics dysregulation mediates the cellular memory of this early postnatal event.Methods and resultsTo test this hypothesis, we isolated pulmonary vascular endothelial cells by magnetic-activated cell sorting from EUGR and control rats. A postnatal insult, nutritional restriction-induced EUGR caused development of an increased pulmonary artery pressure at 9 weeks of age in male Sprague-Dawley rats. Methyl-DNA immune precipitation chip, genome-scale mapping studies to search for differentially methylated loci between control and EUGR rats, revealed significant difference in cytosine methylation between EUGR and control rats. EUGR changes the cytosine methylation at approximately 500 loci in male rats at 9 weeks of age, preceding the development of pulmonary hypertension and these represent the candidate loci for mediating the pathogenesis of pulmonary vascular disease that occurs later in life. Gene ontology analysis on differentially methylated genes showed that hypermethylated genes in EUGR are vascular development-associated genes and hypomethylated genes in EUGR are late-differentiation-associated and signal transduction genes. We validated candidate dysregulated loci with the quantitative assays of cytosine methylation and gene expressions.ConclusionThese results demonstrate that epigenetics dysregulation is a strong mechanism for propagating the cellular memory of early postnatal events, causing changes in the expression of genes and long-term susceptibility to pulmonary hypertension, and further providing a new insight into the prevention and treatment of EUGR-related pulmonary hypertension.

Project description:IntroductionPreterm birth is a leading cause of infant mortality and morbidity. Despite the improvement in the overall mortality in premature infants, the intact survival of these infants remains a significant challenge. Screening the physical growth of infants is fundamental to potentially reducing the escalation of this disorder. Recently, machine learning models have been used to predict the growth restrictions of infants; however, they frequently rely on conventional risk factors and cross-sectional data and do not leverage the longitudinal database associated with medical data from laboratory tests.MethodsThis study aimed to present an automated interpretable ML-based approach for the prediction and classification of short-term growth outcomes in preterm infants. We prepared four datasets based on weight and length including weight baseline, length baseline, weight follow-up, and length follow-up. The CHA Bundang Medical Center Neonatal Intensive Care Unit dataset was classified using two well-known supervised machine learning algorithms, namely support vector machine (SVM) and logistic regression (LR). A five-fold cross-validation, and several performance measures, including accuracy, precision, recall and F1-score were used to compare classifier performances. We further illustrated the models' trustworthiness using calibration and cumulative curves. The visualized global interpretations using Shapley additive explanation (SHAP) is provided for analyzing variables' contribution to final prediction.ResultsBased on the experimental results with area under the curve, the discrimination ability of the SVM algorithm was found to better than that of the LR model on three of the four datasets with 81%, 76% and 72% in weight follow-up, length baseline and length follow-up dataset respectively. The LR classifier achieved a better ROC score only on the weight baseline dataset with 83%. The global interpretability results revealed that pregnancy-induced hypertension, gestational age, twin birth, birth weight, antenatal corticosteroid use, premature rupture of membranes, sex, and birth length were consistently ranked as important variables in both the baseline and follow-up datasets.DiscussionThe application of machine learning models to the early detection and automated classification of short-term growth outcomes in preterm infants achieved high accuracy and may provide an efficient framework for clinical decision systems enabling more effective monitoring and facilitating timely intervention.

Dataset Information

Plasma Metabolome Alterations Associated with Extrauterine Growth Restriction.

Publications

Plasma Metabolome Alterations Associated with Extrauterine Growth Restriction.

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