Sickness-Associated Anorexia: Mother Nature's Idea of Immunonutrition?

Abstract

During an infection, expansion of immune cells, assembly of antibodies, and the induction of a febrile response collectively place continual metabolic strain on the host. These considerations also provide a rationale for nutritional support in critically ill patients. Yet, results from clinical and preclinical studies indicate that aggressive nutritional support does not always benefit patients and may occasionally be detrimental. Moreover, both vertebrates and invertebrates exhibit a decrease in appetite during an infection, indicating that such sickness-associated anorexia (SAA) is evolutionarily conserved. It also suggests that SAA performs a vital function during an infection. We review evidence signifying that SAA may present a mechanism by which autophagic flux is upregulated systemically. A decrease in serum amino acids during an infection promotes autophagy not only in immune cells, but also in nonimmune cells. Similarly, bile acids reabsorbed postprandially inhibit hepatic autophagy by binding to farnesoid X receptors, indicating that SAA may be an attempt to conserve autophagy. In addition, augmented autophagic responses may play a critical role in clearing pathogens (xenophagy), in the presentation of epitopes in nonprovisional antigen presenting cells and the removal of damaged proteins and organelles. Collectively, these observations suggest that some patients might benefit from permissive underfeeding.

Figure 1

Autophagy plays a key role in energy homeostasis, immune regulation, and a generic stress response to various insults. Growth factor signalling is known to inhibit autophagy directly but may also influence autophagy indirectly, by controlling the cellular import system for AAs. High levels of AAs (in particular, essential AAs such as the BCAA, leucine) also inhibit autophagy through activation of mTOR. In contrast, low energy status upregulates AMPK, which in turn inhibits mTOR, resulting in an increase in autophagy. Autophagy can also be activated by immune effectors including TLR-4 activation or alarmins or via cytokine such as Il1-b and IFN-γ. Also, autophagy modulates these inflammatory mediators, for example, by degrading the inflammasome. Finally, autophagy as a generic stress response is also upregulated under hypoxic conditions, or in response to oxidative stress.

Figure 2

Autophagy plays a critical role in pathogen clearance and host survival. The fibril response as well as oxidative stress resulting from tissue ischemia or immune activation may damage proteins which in turn form toxic aggregates which are cleared by autophagy (“aggrephagy”). Similarly, damaged and dysfunctional mitochondria are targeted for cellular digestion (mitophagy), thus optimising energy generation while diminishing ROS production. Autophagy is also involved in the clearance of intracellular pathogens (xenophagy) in both immune and nonimmune cells. Not demonstrated, autophagic processes are also involved in epitope expression and may provide an alternative form of cell death in viral-infected cells. Also, autophagy may modulate the inflammatory tone by possessing membrane receptors and singling platforms such as the inflammasome.