Effect of early parenteral nutrition during paediatric critical illness on DNA methylation as a potential mediator of impaired neurocognitive development: a pre-planned secondary analysis of the PEPaNIC international randomised controlled trial

Güiza, Fabian; Vanhorebeek, Ilse; Verstraete, Sören; Verlinden, Ines; Derese, Inge; Ingels, Catherine; Dulfer, Karolijn; Verbruggen, Sascha; Guerra, Gonzalo Garcia; Joosten, Koen; Wouters, Pieter; Berghe, Greet Van den

doi:10.1016/s2213-2600(20)30046-1

Cited by 35 publications

(71 citation statements)

References 54 publications

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“…The use of the Illumina Infinium MethylationEPIC 850,000 BeadChip facilitates comparisons of data between investigations that employ a shared platform comprising sites that span the genome. This approach, which predominantly captures circulating leukocytes DNA, has been recently used in the intensive care setting [ 25 ]. However, the array is intrinsically biased by a priori selection of regions targeted for interrogation and does not incorporate over 24,000,000 additional CpGs amenable to direct sequencing of the entire methylome.…”

Section: Discussionmentioning

confidence: 99%

“…For example, COVID-19-induced DMRs may persist long after acute care, contributing to the post-ICU syndrome comprising physical and cognitive dysfunction [72][73][74][75]. Recent data indicate that blood DNA methylation profiles mediate worse neurocognitive development in the pediatric ICU population [25], which could be relevant in COVID-19 as well [76,77].…”

Section: Strengths and Limitations Of This Studymentioning

confidence: 99%

“…Moreover, methylation of cytosine residues outside the context of CpG sites may also affect gene transcription [16]. Critically ill patients exhibit altered circulating blood DNA methylation profiles [24,25]. Epigenetic marks affect gene expression profiles and increase individual vulnerability to viral infections [26].…”

Section: Introductionmentioning

confidence: 99%

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Blood DNA methylation and COVID-19 outcomes

et al. 2021

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Background There are no prior reports that compare differentially methylated regions of DNA in blood samples from COVID-19 patients to samples collected before the SARS-CoV-2 pandemic using a shared epigenotyping platform. We performed a genome-wide analysis of circulating blood DNA CpG methylation using the Infinium Human MethylationEPIC BeadChip on 124 blood samples from hospitalized COVID-19-positive and COVID-19-negative patients and compared these data with previously reported data from 39 healthy individuals collected before the pandemic. Prospective outcome measures such as COVID-19-GRAM risk-score and mortality were combined with methylation data. Results Global mean methylation levels did not differ between COVID-19 patients and healthy pre-pandemic controls. About 75% of acute illness-associated differentially methylated regions were located near gene promoter regions and were hypo-methylated in comparison with healthy pre-pandemic controls. Gene ontology analyses revealed terms associated with the immune response to viral infections and leukocyte activation; and disease ontology analyses revealed a predominance of autoimmune disorders. Among COVID-19-positive patients, worse outcomes were associated with a prevailing hyper-methylated status. Recursive feature elimination identified 77 differentially methylated positions predictive of COVID-19 severity measured by the GRAM-risk score. Conclusion Our data contribute to the awareness that DNA methylation may influence the expression of genes that regulate COVID-19 progression and represent a targetable process in that setting.

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Section: Discussionmentioning

confidence: 99%

Section: Strengths and Limitations Of This Studymentioning

confidence: 99%

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Blood DNA methylation and COVID-19 outcomes

et al. 2021

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“…Third (Fig. 1), a multivariate mediation analysis [28][29][30] was then performed on the total study cohort to assess whether any impact of late-PN as compared with early-PN on 3HB could explain its beneficial effects on outcome, adjusted for demographics, baseline risk factors, and type and severity of illness. If so, it was further assessed whether such a mediation role for 3HB was direct or indirect via an effect of late-PN on key regulators of ketogenesis, again adjusted for demographics, baseline risk factors, and type and severity of illness.…”

Section: Patients and Study Designmentioning

confidence: 99%

Effect of withholding early parenteral nutrition in PICU on ketogenesis as potential mediator of its outcome benefit

et al. 2020

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Background: In critically ill children, omitting early use of parenteral nutrition (late-PN versus early-PN) reduced infections, accelerated weaning from mechanical ventilation, and shortened PICU stay. We hypothesized that fasting-induced ketogenesis mediates these benefits. Methods: In a secondary analysis of the PEPaNIC RCT (N = 1440), the impact of late-PN versus early-PN on plasma 3-hydroxybutyrate (3HB), and on blood glucose, plasma insulin, and glucagon as key ketogenesis regulators, was determined for 96 matched patients staying ≥ 5 days in PICU, and the day of maximal 3HB-effect, if any, was identified. Subsequently, in the total study population, plasma 3HB and late-PN-affected ketogenesis regulators were measured on that average day of maximal 3HB effect. Multivariable Cox proportional hazard and logistic regression analyses were performed adjusting for randomization and baseline risk factors. Whether any potential mediator role for 3HB was direct or indirect was assessed by further adjusting for ketogenesis regulators. Results: In the matched cohort (n = 96), late-PN versus early-PN increased plasma 3HB throughout PICU days 1-5 (P < 0.0001), maximally on PICU day 2. Also, blood glucose (P < 0.001) and plasma insulin (P < 0.0001), but not glucagon, were affected. In the total cohort (n = 1142 with available plasma), late-PN increased plasma 3HB on PICU day 2 (day 1 for shorter stayers) from (median [IQR]) 0.04 [0.04-0.04] mmol/L to 0.75 [0.04-2.03] mmol/L (P < 0.0001). The 3HB effect of late-PN statistically explained its impact on weaning from mechanical ventilation (P = 0.0002) and on time to live PICU discharge (P = 0.004). Further adjustment for regulators of ketogenesis did not alter these findings. Conclusion: Withholding early-PN in critically ill children significantly increased plasma 3HB, a direct effect that statistically mediated an important part of its outcome benefit.

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“…This nutritional strategy also appeared to contribute to long-term harm, as 2 years after PICU admission, early-PN patients showed worse parent/caregiver reported executive functioning (inhibitory control, working memory, meta-cognition and total executive functioning), externalizing behavioral problems and visual-motor integration [ 4 ]. Interestingly, a secondary analysis of the PEPaNIC RCT provided a possible molecular basis for the adverse effects of critical illness on long-term development and the role of nutritional management herein [ 5 ]. This large epigenome-wide study has shown that the administration of early-PN during critical illness altered the DNA methylation status of 37 CpG-sites.…”

Section: Introductionmentioning

confidence: 99%

Differential DNA methylation by early versus late parenteral nutrition in the PICU: a biological basis for its impact on emotional and behavioral problems documented 4 years later

et al. 2021

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Background The PEPaNIC multicenter randomized controlled trial (RCT) has shown that early administration of supplemental parenteral nutrition (early-PN) as compared with withholding PN for 1 week (late-PN) induced long-term internalizing, externalizing and total emotional/behavioral problems in critically ill children, as observed 4 years later. Early-PN was further shown to alter the methylation status of 37 CpG-sites in leukocyte DNA between admission and discharge from the pediatric intensive care unit (PICU). In a preplanned subanalysis of the PEPaNIC trial, we now investigated whether the altered methylation of these CpG-sites could statistically explain the negative impact of early-PN on emotion/behavior documented 4 years after PICU admission. Results The combination of DNA methylation data and data on behavior 4 years after PICU admission was available for 403 of the 1440 patients (aged 0–17 years at PICU admission) who were included in the PEPaNIC RCT (192 early-PN and 211 late-PN patients). Mediation analyses with use of bootstrapped multivariable non-linear regression analyses adjusted for baseline risk factors revealed that the adverse alterations by early-PN in methylation of the 37 CpG-sites together statistically explained its harmful impact on internalizing, externalizing and total emotional/behavioral problems. When adding the methylation status of the 37 CpG-sites to the models, the explanatory power improved with a 1.710 to 1.851-fold increase, and the impact of the altered methylation status of the CpG-sites explained the impact of the randomization to early-PN versus late-PN. Conclusions Abnormal DNA methylation induced by the early use of PN in the PICU provides a biological basis for its long-term harmful effect on emotion/behavior of critically ill children 4 years after PICU admission. Trial Registration ClinicalTrials.gov NCT01536275, registered February 17, 2012, https://clinicaltrials.gov/ct2/show/NCT01536275.

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Effect of early parenteral nutrition during paediatric critical illness on DNA methylation as a potential mediator of impaired neurocognitive development: a pre-planned secondary analysis of the PEPaNIC international randomised controlled trial

Cited by 35 publications

References 54 publications

Blood DNA methylation and COVID-19 outcomes

Blood DNA methylation and COVID-19 outcomes

Effect of withholding early parenteral nutrition in PICU on ketogenesis as potential mediator of its outcome benefit

Differential DNA methylation by early versus late parenteral nutrition in the PICU: a biological basis for its impact on emotional and behavioral problems documented 4 years later

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