The epigenetic legacy of ICU feeding and its consequences

Abstract

Purpose of review: Many critically ill patients face physical, mental or neurocognitive impairments up to years later, the etiology remaining largely unexplained. Aberrant epigenetic changes have been linked to abnormal development and diseases resulting from adverse environmental exposures like major stress or inadequate nutrition. Theoretically, severe stress and artificial nutritional management of critical illness thus could induce epigenetic changes explaining long-term problems. We review supporting evidence.

Recent findings: Epigenetic abnormalities are found in various critical illness types, affecting DNA-methylation, histone-modification and noncoding RNAs. They at least partly arise de novo after ICU-admission. Many affect genes with functions relevant for and several associate with long-term impairments. As such, de novo DNA-methylation changes in critically ill children statistically explained part of their disturbed long-term physical/neurocognitive development. These methylation changes were in part evoked by early-parenteral-nutrition (early-PN) and statistically explained harm by early-PN on long-term neurocognitive development. Finally, long-term epigenetic abnormalities beyond hospital-discharge have been identified, affecting pathways highly relevant for long-term outcomes.

Summary: Epigenetic abnormalities induced by critical illness or its nutritional management provide a plausible molecular basis for their adverse effects on long-term outcomes. Identifying treatments to further attenuate these abnormalities opens perspectives to reduce the debilitating legacy of critical illness.

Box 1

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FIGURE 1

Early parenteral-nutrition (PN) during pediatric critical illness evokes alterations in leukocyte DNA-methylation which statistically explain part of the long-term neurodevelopmental harm by early parenteral nutrition. Early use of PN in the PICU was shown to cause long-term developmental harm to critically ill children, evidenced by worse executive functioning (inhibition, working memory, meta-cognition and overall executive functioning), externalizing behavior, and visual-motor integration observed 2 years later as compared with children who did not receive PN in the first week of intensive care [9]. The early use of PN was also shown to contribute to part of the changes in leukocyte DNA-methylation that arose after PICU-admission and remained present until PICU-discharge, more particularly changes at the level of 37 of the identified differentially methylated positions (“CpG-sites”) [85]. The changes in DNA-methylation evoked by early-PN were subsequently shown to statistically explain part of the long-term neurodevelopmental harm evoked by early-PN, visually illustrated by the heatmap in this figure (adapted from [85]). Each row corresponds to 100 bootstrap replicates of multivariable nonlinear models for the neurocognitive outcomes harmed by early-PN, adjusting for risk factors and the 37 differentially methylated CpG-sites evoked by early-PN. The columns correspond to those 37 differentially methylated sites. Color intensity of the boxes reflects the frequency with which a CpG-site was found to be independently and significantly associated with the outcomes in the 100 bootstrapped replicated analyses, with darker colors corresponding to a higher frequency. The dendrograms show the hierarchical clustering, revealing that distinct groups of CpG-sites were explanatory for the negative impact of early-PN on the four executive functions, on externalizing behavior and on visual-motor integration. The base of the column dendrogram is color-coded according to the CpG-sites’ functional classes. PICU, pediatric-ICU.

FIGURE 2

The epigenetic legacy of critical illness and ICU feeding. Several studies have demonstrated abnormalities at the level of different epigenetic mechanisms in adult and pediatric critically ill patients as compared with matched controls. Most of these studies focused on peripheral blood samples, but epigenetic abnormalities have also been documented in different organs including muscle, brain and lung. Some of the documented epigenetic abnormalities may have already been present upon ICU-admission, due to premorbid conditions of the patients, but at least part of them were shown to arise de novo during the ICU stay. Furthermore, part of the epigenetic abnormalities appeared to be evoked by intensive care treatment, illustrated by the adverse impact of early initiation of supplemental PN on DNA-methylation in critically ill children. Several lines of evidence suggested that the epigenetic abnormalities that are documented in critical illness could form a plausible biological basis to explain part of the adverse long-term outcomes of the patients. First, many of the documented epigenetic abnormalities appeared to be located in genes with functions highly relevant for adverse long-term outcomes, such as physical development, neurocognitive development or dysfunction, psychiatric problems, and muscle weakness, among others. Second, several studies found associations between the identified epigenetic abnormalities and adverse long-term outcomes of the patients. In particular, abnormalities in DNA-methylation that arose de novo due to critical illness and due to early use of PN statistically explained part of the adverse impact of an episode of critical illness and of early-PN on long-term physical and neurocognitive development of pediatric patients. Finally, several studies also demonstrated the presence of epigenetic abnormalities in the long-term, up to years after the critical illness, in genes and pathways of high relevance for the adverse long-term outcomes, where part of the abnormalities identified during ICU stay may remain present in the long term or may have triggered other changes. PN, parenteral nutrition.