Abstract
BackgroundA genome-wide study identified de novo DNA methylation alterations in leukocytes of children at paediatric intensive care unit (PICU) discharge, offering a biological basis for their impaired long-term development. Early parenteral nutrition (early-PN) in PICU, compared with omitting PN in the first week (late-PN), explained differential methylation of 23% of the affected CpG-sites. We documented the time course of altered DNA methylation in PICU and the impact hereon of early nutritional management.ResultsWe selected 36 early-PN and 36 late-PN matched patients, and 42 matched healthy children. We quantified DNA methylation on days 3, 5 and 7 for the 147 CpG-sites of which methylation was normal upon PICU admission in this subset and altered by critical illness at PICU discharge. Methylation in patients differed from healthy children for 64.6% of the 147 CpG-sites on day 3, for 72.8% on day 5 and for 90.5% on day 7 as revealed by ANOVA at each time point. Within-patients methylation time course analyses for each CpG-site identified different patterns based on paired t test p value and direction of change. Rapid demethylation from admission to day 3 occurred for 76.2% of the CpG-sites, of which 67.9% remained equally demethylated or partially remethylated and 32.1% further demethylated beyond day 3. From admission to day 3, 19.7% of the CpG-sites became hypermethylated, of which, beyond day 3, 34.5% remained equally hypermethylated or partially demethylated again and 65.5% further hypermethylated. For 4.1% of the CpG-sites, changes only appeared beyond day 3. Finally, for the CpG-sites affected by early-PN on the last PICU day, earlier changes in DNA methylation were compared for early-PN and late-PN patients, revealing that 38.9% were already differentially methylated by day 3, another 25.0% by day 5 and another 13.9% by day 7.ConclusionsCritical illness- and early-PN-induced changes in DNA methylation occurred mainly within 3 days. Most abnormalities were at least partially maintained or got worse with longer time in PICU. Interventions targeting aberrant DNA methylation changes should be initiated early.
Highlights
A genome-wide study identified de novo DNA methylation alterations in leukocytes of children at paediatric intensive care unit (PICU) discharge, offering a biological basis for their impaired long-term development
Studied CpG‐sites We performed this study on the 147 CpG-sites of which methylation status was previously shown to be altered by critical illness and/or its intensive care management [10] but normal upon PICU admission in the current participants’ subset
The studied CpG-sites are clinically relevant, since DNA methylation alterations that occur in these CpGsites during PICU stay were shown to play a mediating role in the negative impact of critical illness and, for 36 of them of early-parenteral nutrition (PN) versus late-PN during critical illness, on the long-term neurocognitive development of children [10]
Summary
A genome-wide study identified de novo DNA methylation alterations in leukocytes of children at paediatric intensive care unit (PICU) discharge, offering a biological basis for their impaired long-term development. Children who have been critically ill and required treatment in the paediatric intensive care unit (PICU) often suffer from adverse long-term health and developmental sequelae that are present years after hospital discharge [1]. Impaired neurocognitive development has been most thoroughly documented, and growth retardation, poor physical functioning and long-term health risks have been reported [1,2,3,4]. Part of this long-term legacy appears preventable through altering aspects of the intensive care management. EarlyPN caused more infections and delayed recovery from the illness, it prevented normal development of executive functions and/or caused behavioural problems, as assessed 2 and 4 years later [5, 8, 9]
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