Autophagy flux in critical illness, a translational approach

Abstract

Recent clinical trials suggest that early nutritional support might block the induction of autophagy in critically ill patients leading to the development of organ failure. However, the regulation of autophagy, especially by nutrients, in critical illness is largely unclear. The autophagy flux (AF) in relation to critical illness and nutrition was investigated by using an in vitro model of human primary myotubes incubated with serum from critically ill patients (ICU). AF was calculated as the difference of p62 expression in the presence and absence of chloroquine (50 µM, 6 h), in primary myotubes incubated for 24 h with serum from healthy volunteers (n = 10) and ICU patients (n = 93). We observed 3 different phenotypes in AF, non-altered (ICU non-responder group), increased (ICU inducer group) or blocked (ICU blocker group). This block was not associate with a change in amino acids serum levels and was located at the accumulation of autophagosomes. The increase in the AF was associated with lower serum levels of non-essential amino acids. Thus, early nutrition during critical illness might not block autophagy but could attenuate the beneficial effect of starvation on reactivation of the autophagy process. This could be of clinical importance in the individual patients in whom this process is inhibited by the critical illness insult.

Enteral Feeding Intolerance: Updates in Definitions and Pathophysiology

“…73 Autophagy is an ubiquitous cellular pathway of recycled cytoplasmic material and is considered essential to facilitate adaption to a changing environment. 74,75 Although present at low levels in almost all cells, autophagy is markedly upregulated in response to stress. 74,75 However, the provision of nutrient suppresses the autophagy pathway.…”

“…74,75 Although present at low levels in almost all cells, autophagy is markedly upregulated in response to stress. 74,75 However, the provision of nutrient suppresses the autophagy pathway. 75 It has, therefore, been suggested that EFI may represent an adaptive physiological response to critical illness, with evolution favoring GI dysmotility as a protective response to limit nutrient intake and preserve the autophagy pathway during a time of stress.…”

“…One of the underlying, proposed mechanistic pathways that EFI promotes a physiological response to reduce nutrients is the body's attempt to preserve autophagy (or ‘self‐eating’) 73 . Autophagy is an ubiquitous cellular pathway of recycled cytoplasmic material and is considered essential to facilitate adaption to a changing environment 74,75 . Although present at low levels in almost all cells, autophagy is markedly upregulated in response to stress 74,75 .…”

Enteral feeding, even when the gut does not feel very good?

“…There is a discussion, whether EFI could be an adaptive mechanism in critical illness [22], for protecting the body by preserving autophagy [52,53] and avoiding increased metabolic demand during hypoperfusion [43]. A study in mice showing dose-dependent decrease in food intake after being infected with Listeria monocytogenes and increased mortality with forced enteral feeding still clearly below normal daily intake supports this hypothesis [54].…”

Amino acids in acute-on-chronic liver failure: Another piece of the puzzle?

“…Defective autophagy is known to be associated with outcome in sepsis and critical illness. 7,8 Another common feature between patients with ACLF and other groups of critically ill patients is the presence of skeletal muscle loss or sarcopenia, a condition commonly associated with poor outcome in different conditions. [9][10][11] In cirrhotic patients, sarcopenia has been associated with development of ACLF.…”