Differential Gene Expression in Peripheral White Blood Cells with Permissive Underfeeding and Standard Feeding in Critically Ill Patients: A Descriptive Sub-study of the PermiT Randomized Controlled Trial

Abstract

The effect of short-term caloric restriction on gene expression in critically ill patients has not been studied. In this sub-study of the PermiT trial (Permissive Underfeeding or Standard Enteral Feeding in Critically Ill Adults Trial- ISRCTN68144998), we examined gene expression patterns in peripheral white blood cells (buffy coat) associated with moderate caloric restriction (permissive underfeeding) in critically ill patients compared to standard feeding. Blood samples collected on study day 1 and 14 were subjected to total RNA extraction and gene expression using microarray analysis. We enrolled 50 patients, 25 in each group. Among 1751 tested genes, 332 genes in 12 pathways were found to be significantly upregulated or downregulated between study day 1 and 14 (global p value for the pathway ≤ 0.05). Using the heatmap, the differential expression of genes from day 1 to 14 in the permissive underfeeding group was compared to the standard feeding group. We further compared gene expression signal intensity in permissive underfeeding compared standard feeding by constructing univariate and multivariate linear regression models on individual patient data. We found differential expression of several genes with permissive underfeeding, most notably those related to metabolism, autophagy and other cellular functions, indicating that moderate differences in caloric intake trigger different cellular pathways.

Role of ketones, ketogenic diets and intermittent fasting in ICU

“…Importantly, autophagy can also be affected by modulating nutrition in critical illness, which may be a more straightforward approach [32]. Indeed, a secondary analysis of the PermiT-RCT revealed differential gene expression in peripheral white blood cells of patients randomized to permissive underfeeding (40–60% of calculated caloric requirements) versus standard feeding, suggestive of autophagy activation by permissive underfeeding [33]. Moreover, autophagy activation has emerged as one potential mechanism explaining why withholding early parenteral nutrition was found to be beneficial.…”