The epigenetic legacy of ICU feeding and its consequences

INTRODUCTION

Thanks to major advances in intensive care medicine, critically ill patients nowadays can survive many insults and medical complications that only a few decades ago would unavoidably culminate in death. With the growing cohort of critical illness survivors, however, it became clear that many face (currently largely unexplained) long-term physical, mental and/or neurocognitive problems, and inherent lower quality-of-life, up to years after hospital-discharge [1–6]. Preadmission disease could be involved [2–4], but also the acute insult necessitating ICU-admission and its complications, or the intensive care management itself, could induce or aggravate part of this legacy [3,6]. Artificial nutrition is one treatment-related factor with impact on short- and long-term outcomes of critical illness [7–10].

Aberrant epigenetic changes have been linked to abnormal development and long-term disease resulting from adverse environmental exposures, such as early-life or other stress and inadequate nutrition [11–16]. Critical illness imposes extreme stress. We provide a brief overview of adverse long-term outcomes of critically ill patients and the impact of in-ICU nutritional management on such outcomes, followed by evidence for critical illness- and nutritional management-induced aberrant epigenetic changes as plausible molecular contributor. 

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LONG-TERM COMPLICATIONS AFTER CRITICAL ILLNESS AND ARTIFICIAL NUTRITION

Patients who have been critically ill can be confronted with a wide range of new or worsening long-term problems up to years after the insult for which they required intensive care. These long-term problems, affecting multiple organs, have been conceptualized in a framework called “postintensive care syndrome” (PICS) [1–3] or “PICS in pediatrics” for children [4–6].

The long-term legacy after critical illness

Adult patients who have been critically ill are at increased risk of long-term cognitive impairments, often comparable with mild Alzheimer's disease [17]. Anxiety, depression and posttraumatic stress disorders are long-term mental problems which often co-occur [18]. Long-term physical problems include persistent muscle weakness, reduced exercise capacity and reduced independency to perform activities of daily living [19–23], accelerated bone loss with higher fracture risk [24,25], and a higher risk of developing chronic kidney failure despite full resolution of acute kidney injury [26]. These complications contribute to a lower quality-of-life, and may hamper swift return to work for patients who were employed before ICU-admission [27]. Also, late mortality of ICU-survivors is higher as compared with controls [2].

The legacy after pediatric critical illness comprises disturbances in crucial developmental processes, with impairments in physical, neurocognitive, and emotional/behavioral domains. Physically, children who have been critically ill show impaired growth and worse physical performance, with less handgrip-strength, dynamic balance, exercise capacity and overall daily physical activity as compared with healthy children [9,10,28▪]. A substantial proportion of children who acquired acute kidney injury in ICU develop chronic kidney disease [29]. Former pediatric-ICU (PICU) patients also show more problems with clinically assessed neurological functioning and perform worse for many neurocognitive functions, including intelligence, visual-motor integration, motor-coordination, alertness, executive functioning and memory [9,10,30,31]. Parents of former PICU-patients report more emotional/behavioral problems for their children [9,10,30,31], who also show a worse long-term health-related quality-of-life [32]. A within-individual longitudinal study from 2 to 4 years after PICU-admission revealed a rather pessimistic picture, since most developmental deficits remained unaltered or got worse, whereas only a few memory functions partially improved [33▪].

The long-term legacy of ICU feeding

Optimizing nutritional support, an essential component of the care of critically ill patients, remains a major challenge. The patients are unable to feed orally and often show intolerance to enteral feeding. As a result, prescribed caloric targets are often not reached and a macronutrient deficit rapidly accumulates. Observational studies associated such assumed macronutrient deficit with adverse short-term outcomes, including new infections, ICU-acquired muscle weakness, prolonged mechanical ventilation, and delayed recovery [34–41]. These associations have instigated the design of strategies to enhance macronutrient provision from early on, for instance via more energy-dense enteral-nutrition (EN) formulae or supplemental parenteral-nutrition (PN) completing insufficient EN [7,8,42–47]. Other studies focused rather on initial trophic feeding or permissive underfeeding by which the risk of hyperglycemia and associated adverse outcome may be attenuated [48,49]. Thus, even the appropriate caloric goal to set as target for the patients, either guided by equations or resting energy expenditure, remains unclear [50,51]. Several strategies have been compared in a randomized controlled trial (RCT)-design [7,8,42–46,48–51], though mostly focusing only on short-term outcomes. We summarize those RCTs that included long-term follow-up. Overall, these studies showed that early enhanced nutrition is not beneficial for long-term outcome and, particularly in children, actually may cause long-term harm.

Long-term follow-up studies have mostly been performed for adult ICU-patients. The EPaNIC-RCT demonstrated that initiating PN within 48 h after ICU-admission (early-PN) to reach early full feeding when EN was insufficient did not affect mortality, but delayed recovery and increased the risk of new infections and other complications as compared with withholding PN in the first week in ICU (late-PN) [7]. Five years later, the former ICU-patients showed lower muscle strength, shorter 6-min walk-distance and lower aerobic exercise capacity, and reported worse physical function than controls [20,23]. Prolonged ICU-stay and ICU-acquired neuromuscular complications, which occurred more frequently in early-PN than in late-PN patients, were identified as risk factors for worse long-term outcomes [20–22,52]. The EDEN-RCT found no differences between initial trophic versus full enteral feeding in short-term outcomes, nor in measures of long-term physical performance or cognitive impairment 6–12 months after ICU-admission [48,53]. Early goal-directed nutrition with estimation of nutritional requirements by indirect calorimetry in the EAT-ICU-RCT did not affect short-term outcomes or physical quality-of-life at 6 months [44]. Finally, also higher calorie delivery with energy-dense as compared with routine EN in the TARGET-RCT did not affect short-term outcomes, and did not beneficially affect survival, quality-of-life, participation in work or other key life activities, disability, physical function, or muscle layer thickness 6 months later [45,54,55].

Only one study investigated the long-term impact in children of a nutritional intervention during PICU-stay. As the EPaNIC-RCT in adults, the PEPaNIC-RCT demonstrated that early-PN (initiated within 24 h), as compared with late-PN, also delayed recovery and increased the risk of new infection and organ dysfunction of critically ill children [8]. Follow-up showed long-term harm by early-PN, since children in the early-PN group scored worse for executive functioning (inhibition, working-memory, meta-cognition, total executive functioning), visual-motor integration, and emotional/behavioral problems 2 and/or 4 years after PICU-admission than late-PN children [9,10]. Children aged 29 days to 11 months at exposure appeared most vulnerable to the developmental harm evoked by early-PN [56▪]. Unfortunately, the neurocognitive harm by early-PN only showed limited and partial catch-up from 2 to 4 years after PICU-admission [33▪].

THE EPIGENETIC LEGACY OF CRITICAL ILLNESS AND ICU FEEDING

Epigenetic mechanisms lead to functionally relevant changes in gene-expression without altering the genetic code [57]. The most stable epigenetic change is DNA-(de)methylation. Others include histone-modification and expression of noncoding RNAs (miRNA, lncRNA). Epigenetic involvement in the long-term legacy after critical illness appears plausible, as aberrant epigenetic changes have been linked to abnormal development and disease resulting from adverse environmental exposures/stressors [11–16].

The epigenetic legacy of critical illness

Epigenetic research found its way to the field of critical illness only recently. Whereas initial studies focused on animal models, the last few years epigenetic abnormalities have also been documented in adult and pediatric patients with different types of critical illness, including sepsis [58–66], transplant and other major surgery [67,68▪,69,70▪], traumatic brain injury (TBI) or other major trauma [71▪,72,73▪,74], acute pancreatitis [75], and COVID-19 [76–79,80▪,81,82,83▪], as well as in heterogeneous cohorts [84▪,85–86]. Most studies focused on DNA-methylation [58–60,63–65,67,68▪,69,70▪,71▪,72,73▪,80▪,83▪,84▪,85–86], but also histone-modification/chromatin-accessibility [58,69,82] and noncoding RNAs [61,62,66,69,74,81] have been investigated.

Epigenetic research in the critical illness context holds several challenges. First, access to biopsies of organs of interest for patient research is cumbersome or impossible. Thus, peripheral blood samples are most often used [58–60,63,64,67,68▪,74,77–79,80▪,81,82,83▪,85,86]. This holds risk of confounding by the typical critical illness-induced changes in leukocyte composition [87–89], which is often ignored. Strategies to reduce such bias include adjusting for cell heterogeneity [68▪,77], purifying leukocyte subpopulations [58], or discarding any DNA-methylation differences potentially explained by changes in leukocyte composition [85,86]. Scarce studies used other samples and also found epigenetic abnormalities in muscle of adult critically ill patients [84▪], muscle stem cells of children after TBI [73▪], cerebrospinal fluid or surgically-resected brain biopsies of adult TBI patients [71▪,72], or airway epithelial cells from lung-transplant patients [70▪]. Second, due to the frequent urgency of ICU-admission, it is difficult to establish to what extent epigenetic abnormalities were already preexisting before ICU-admission or occurred de novo. Importantly, at least part of them do arise de novo as demonstrated in a genome-wide DNA-methylation analysis in longitudinal blood samples of PEPaNIC-patients, in comparison with healthy children [85]. Here, we first excluded all DNA-methylation differences between patients upon PICU-admission and healthy children, as these reflect premorbid conditions and illness-induced alterations in leukocyte composition. We next identified 159 DNA-positions that became differentially-methylated after PICU-admission and remained differentially-methylated until PICU-discharge. Most de novo changes occurred rapidly, within the first days after PICU-admission [86]. In patients undergoing major surgery, longitudinal analyses of DNA-methylation in peripheral blood mononuclear cells, starting preoperatively, also revealed rapid de novo changes, which generally persisted until hospital-discharge [67,68▪].

Several studies found associations of epigenetic abnormalities with disease-severity [58,59,75,77,78] or acute adverse outcomes [59,69,72,77] of critically ill patients. As most studies focused on the acute phase of critical illness, in the ICU, it remains difficult to forecast whether the observed epigenetic abnormalities could form a basis to explain part of the adverse long-term patient outcomes. However, several lines of evidence suggest that such contribution is plausible.

A first line of evidence supporting involvement of epigenetic abnormalities in adverse long-term outcomes after critical illness is that the epigenetic abnormalities affect genes with functions relevant for long-term impairments. This is most extensively documented for epigenetic mechanisms underlying alterations in the innate and adaptive immune responses in postsepsis immunosuppression [90]. As another example, many genes associated with the aberrant DNA-methylation signature in muscle of critically ill patients as compared with controls have functions highly relevant for muscle structure and function/weakness, which thus theoretically could provide a biological basis for long-term weakness in ICU-survivors [84▪]. Also, the altered DNA-methylome in surgically-resected brain biopsies of TBI patients affected genes related to cellular/anatomical structure development, cell-differentiation, and anatomical morphogenesis, which may have implications for the neurodegenerative disorders associated with TBI [71▪].

In a second line of evidence, epigenetic abnormalities have been associated with adverse long-term outcomes of critically ill patients. After kidney-transplantation, epigenetic modifications across relevant genes associated with renal graft interstitial fibrosis/tubular atrophy, function and long-term outcome [69]. Among the de novo differentially-methylated positions in peripheral blood DNA of PEPaNIC-patients, many were located in genes involved in brain development, plasticity, and signaling; neuronal differentiation, migration, and growth; and physical development and locomotion [85]. Intriguingly, the DNA-methylation changes together statistically explained part of the disturbed long-term physical and neurocognitive development that was documented 2 years after PICU-admission.

Further corroboration of plausible involvement of an altered DNA-methylome in the developmental impairments of former PICU-patients was provided by a recent study on buccal-mucosa DNA collected at the PEPaNIC 2-year follow-up. Former patients, as compared with healthy children, showed abnormal methylation of DNA-positions and DNA-regions among which many located within genes of pathways known to be important for physical and neurocognitive development [91▪]. A few other studies also focused on samples obtained long after the critical illness phase. Cultured airway epithelial cells isolated at 1-year bronchoscopies from patients with severe primary lung-graft dysfunction revealed a higher epigenetic age and differential methylation in key pathways related to hypoxia, inflammation and metabolism as compared with controls [70▪]. A study on muscle biopsies from ICU-survivors 6 months after admission identified miRNA regulatory networks associated with abnormal muscle repair versus recovery of muscle mass [92▪]. Whole blood DNA of severe coronavirus disease 2019 (COVID-19) patients revealed an accelerated epigenetic aging and telomere length shortening as compared with healthy individuals, which may be only partially reversible and contribute to the post-COVID-19 syndrome among survivors [79]. Indeed, part of the acute illness-induced differentially-methylated regions in leukocyte DNA of COVID-19 patients persisted 1 year later [80▪]. Also, some changes in the chromatin-accessibility pattern of circulating monocytes associated with severe acute respiratory syndrome coronavirus 2 infection were maintained 6 months after hospitalization [83▪].

The epigenetic legacy of ICU feeding

The epigenome can be shaped by nutritional states [93,94]. Susceptibility occurs particularly at the time when critical developmental processes are taking place, but also in adulthood diet can affect epigenetic marks. Thus, interest in nutriepigenomics as “the study of nutrients and their effects on human health through epigenetic modifications” is steadily increasing. We obtained evidence that the epigenome of critically ill patients is affected by the artificial nutritional management in the ICU. Indeed, early administration of supplemental PN to critically ill children, as compared with withholding PN in the first week in the PICU, independently contributed to 23% of the de novo alterations in leukocyte DNA-methylation observed by PICU-discharge [85]. This effect occurred rapidly, mainly within 3 days [86]. Importantly, the aberrant DNA-methylation statistically explained the harm by early-PN on neurocognitive development documented 2 and 4 years after PICU-admission [9,10,85,95▪]. Distinct groups of differentially-methylated DNA-positions were explanatory for the negative impact of early-PN on the children's executive functions, behavior, and visual-motor integration (Fig. 1) [85,95▪]. Interestingly, the altered DNA-methylation induced by early-PN was best explained by the dose of amino acids, rather than that of glucose or lipids [85]. This is in line with the finding that the early administration of amino acids and not of glucose or lipids could explain harm by early-PN on short-term outcomes of the children [96]. Another effect of early-PN in critically ill children, which by extension could be considered an epigenetic change, is the accelerated shortening of leukocyte telomere-length during PICU-stay as compared with late-PN, accounting for changes in leukocyte composition [97]. Whether such telomere-shortening may predispose to long-term developmental impairments should be further investigated. Vitamins have been proposed as epigenetic modifiers, to enhance immunity and reduce inflammatory responses, in COVID-19 patients [98]. Importantly, effects of early-PN versus late-PN on clinical outcome and epigenetic changes in the (P)EPaNIC study could not be explained by differences in vitamin administration as vitamins were equally supplemented to both groups when EN was insufficient [7–10,85,86].

F1FIGURE 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.

Interestingly, supplementing standard PN of critically ill mice with the ketone-body 3-hydroxybutyrate protected against sepsis-induced muscle weakness and enhanced muscle regeneration [99]. This effect appeared not explained by its use as alternative energy substrate, but could possibly be explained by an epigenetic mechanism as the treatment affected histone-deacetylase expression. Considering that impaired muscle regeneration has been invoked as a mechanism contributing to long-term muscle weakness of critically ill patients [100], ketone-body supplementation may thus hold promise for optimizing their longer-term recovery. Therapeutic use of ketone-bodies has also been suggested for neuroprotection in acute brain injury, with implication of epigenetic among other mechanisms [101,102].

CONCLUSION

Aberrant epigenetic changes induced by critical illness or its nutritional management provide a plausible molecular basis for the adverse effects of such environmental stressors on long-term outcomes of these vulnerable patients (Fig. 2). This opens perspectives for identifying treatments able to further attenuate the epigenetic abnormalities to reduce the debilitating legacy of critical illness.

F2FIGURE 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.

Acknowledgements

None.

Financial support and sponsorship

This work was supported by the Methusalem program of the Flemish government (through the University of Leuven to G. Van den Berghe and I. Vanhorebeek, METH14/06); by European Research Council Advanced Grants (AdvG-2012-321670 and AdvG-2017-785809) to G. Van den Berghe, and by the Institute for Science and Technology, Flanders, Belgium (through the University of Leuven to GVdB, IWT-TBM150181 and IWT-TBM110685).

Conflicts of interest

There are no conflicts of interest.

REFERENCES AND RECOMMENDED READING

Papers of particular interest, published within the annual period of review, have been highlighted as:

▪ of special interest

▪▪ of outstanding interest

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