Final Report Summary - NUTRI-CARE (Nutri-CARE: Nutrient restriction during Critical illness: from induction of Autophagy to Repression of aberrant Epigenetic alterations)
Modern intensive care medicine enables survival from previously lethal illness or trauma. However, patients who require intensive care for more than a few days continue to have a high risk of death mostly due to lack of recovery from organ failure. This condition affects millions of patients annually worldwide and consumes a large fraction of health care resources. Although intensive care has been practiced for over 6 decades, the understanding of the mechanisms and pathways determining why certain patients recover and others do not remains very limited. Organs and tissues from patients who do not recover swiftly and for whom it is ultimately decided to withdraw care for futility do not reveal overt signs of cell death. Instead, cells accumulate damaged organelles and protein aggregates, show signs of oxidative and inflammatory stress, and appear to reprogram towards other cell lineages. Even when patients survive, are weaned from invasive support and are discharged from the ICU, many continue to suffer from morbidity after hospital discharge, referred to as the legacy of critical illness. Examples are weakness, loss of bone mass and increased fracture risk, neurocognitive impairment and posttraumatic stress disorders, and increased risk of chronic renal failure despite successful recovery from acute renal injury. This indicates that acute life-threatening illnesses, and/or the intensive care management, induce “carry-over” effects with long-term consequences. In large randomized controlled studies, we demonstrated that tolerating a macronutrient deficit early during the course of critical illness in adult and pediatric patients unexpectedly accelerated recovery from organ failure and enhanced rehabilitation far beyond the time window of the intervention. These data radically contradicted the traditional dogma that early anabolism is required for recovery from critical illnesses.
Understanding the underlying molecular and cellular mechanisms of the apparent damage-induced “reprogramming” and the benefit of tolerating a macronutrient deficit is crucial in order to develop interventions to prevent and/or treat these consequences of critical illnesses. We hypothesized that activation of autophagy and repression of aberrant epigenetic alterations play a major role. We aimed to investigate (1) the role of autophagy in recovery from critical illness; (2) the degree of genetic predisposition within the mitochondrial genome and nuclear genes controlling mitochondrial turnover and autophagy for recovery from critical illness and its chronic sequellae; and (3) the impact of tolerating a macronutrient deficit early in the course of critical illness on epigenetic alterations (features that modify chromatin structure and/or affect gene expression without changing the primary DNA sequence) during critical illness and how these relate to recovery from organ failure and to long-term sequellae.
We demonstrated that tolerating a substantial macronutrient deficit early during critical illness did not affect muscle wasting, but allowed more efficient activation of autophagic quality control of myofibres and reduced weakness in ICU. With use of experimental models we demonstrated an important protective role of autophagy in critical illness. We are currently analyzing the data we obtained with regard to genetic predisposition. We also linked epigenetic changes to increased formation of active bone-resorbing cells. Further detailed epigenetic studies in different organs/cell types are ongoing. The results of these studies are expected to pave the way towards novel effective interventions to prevent/treat the debilitating legacy of critical illness.
Understanding the underlying molecular and cellular mechanisms of the apparent damage-induced “reprogramming” and the benefit of tolerating a macronutrient deficit is crucial in order to develop interventions to prevent and/or treat these consequences of critical illnesses. We hypothesized that activation of autophagy and repression of aberrant epigenetic alterations play a major role. We aimed to investigate (1) the role of autophagy in recovery from critical illness; (2) the degree of genetic predisposition within the mitochondrial genome and nuclear genes controlling mitochondrial turnover and autophagy for recovery from critical illness and its chronic sequellae; and (3) the impact of tolerating a macronutrient deficit early in the course of critical illness on epigenetic alterations (features that modify chromatin structure and/or affect gene expression without changing the primary DNA sequence) during critical illness and how these relate to recovery from organ failure and to long-term sequellae.
We demonstrated that tolerating a substantial macronutrient deficit early during critical illness did not affect muscle wasting, but allowed more efficient activation of autophagic quality control of myofibres and reduced weakness in ICU. With use of experimental models we demonstrated an important protective role of autophagy in critical illness. We are currently analyzing the data we obtained with regard to genetic predisposition. We also linked epigenetic changes to increased formation of active bone-resorbing cells. Further detailed epigenetic studies in different organs/cell types are ongoing. The results of these studies are expected to pave the way towards novel effective interventions to prevent/treat the debilitating legacy of critical illness.