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Anorexia and the Acute Phase Response

During sickness it is very common to lose one’s appetite (anorexia) and reduce energy intake. The anorexia during illness is one of a group of symptoms collectively known as sickness behaviors. Whether anorexia and other sickness behaviors are adaptive is uncertain and the optimal amount of nutrition to provide during illness is an unanswered question in medicine. However, various authors have speculated that anorexia of illness has benefits by assisting host defense during infection or by changing energy provisioning in the body.  If true, it is possible that providing fewer than normal nutrients during illness might speed recovery and improve survival.

Over 50 years ago, Brobeck (1960) reported that anorexia is caused by fever. More recently, bacterial products have been shown to cause anorexia by activating toll like receptors and affecting neurotransmitters and neuropeptides involved in appetite and food intake (Von Meyenburg et al. 2004; Langhans 2007). Bacterial lipopolysaccharide (LPS) is a potent stimulant of anorexia by reducing appetite-stimulating orexin in the hypothalamus and by increasing pro-inflammatory cytokines, such as IFN-γ and TNF α, that inhibit feeding behavior (Langhans 2007).

Exton (1997) postulated that anorexia may be beneficial by limiting the availability to pathogens of essential trace metals, notably iron; and he presented evidence that dietary restriction can enhance certain immune functions. Straub et al. (2010) proposed that anorexia is beneficial by redirecting stored energy from the needs of the gut toward meeting the high metabolic costs of fighting infection. LeGrand and Alcock (2012) proposed an alternative view, that anorexia is a costly nutritional stress that tends to disproportionately harm invading pathogens more than the host. In this brinksmanship model, anorexia is a gamble on the part of the host that the host can better withstand the nutritional deprivation better than the invading organism. Because the host has stored energy reserves, anorexia may disproportionately affect gut pathogens and make infected intestinal epithelial cells more susceptible to apoptosis (LeGrand and Alcock 2012).

In an early example, Murray et al. (1978) force-fed Listeria-infected mice back to their preinfection food intake levels and found increased mortality after replacement of “normal” nutrient requirements. Similarly, Adamo et al. (2007) reported that force-feeding bacterially infected caterpillars with a high lipid diet increased mortality.

In humans, patients with higher illness severity were found to have longer stays in the ICU when feeding was initiated early, versus late (Huang et al 2012). Krishnan and colleagues (2003) showed that higher calorie delivery was associated with worse ICU outcomes, although other observational trials have had opposite results (Elke et al.  2013). In a recent randomized trial, Arabi and colleagues (2011) compared underfeeding (60%) vs. normal (100%) replacement of calorie needs in critical illness, and reported fewer deaths in the underfeeding group. A recent review concluded that underfeeding is not harmful compared to full feeding, and replacing complete calorie requirements with parenteral (intravenous) nutrition tends to worsen outcomes (Schetz 2013). In March of 2017, a large scale trial undertaken by Arabi’s group found no harm associated with underfeeding in critical illness.

The results of human trials support the view of Zaloga and Roberts (1994) that maximizing nutrition “may adversely affect the host response to injury, especially when given in excess of energy and protein needs.” Increasing evidence suggests that some degree of calorie restriction during illness might be protective. Future work will be needed to define the optimal degree of nutrition for differing conditions, e.g. cancer versus infection. Overall, these observations provide support for the hypothesis that anorexia of illness is an adaptation that is beneficial to the host during infection.


Adamo, S. A., T. L. Fidler, and C. A. Forestell. 2007. Illness-induced anorexia and its possible function in the caterpillar, Manduca sexta. Brain, Behavior, and Immunity, 21:292-300.

Arabi YM, Haddad SH, Tamim HM, Rishu AH, Sakkijha MH, Kahoul SH, Britts RJ: Near-target caloric intake in critically ill medical–surgical patients is associated with adverse outcomes. J Parenter Enteral Nutr 2010,34: 280-288.

Arabi, Yaseen M., et al. “Permissive Underfeeding or Standard Enteral Feeding in High–and Low–Nutritional-Risk Critically Ill Adults. Post Hoc Analysis of the PermiT Trial.” American journal of respiratory and critical care medicine 195.5 (2017): 652-662.

Brobeck JR. Food and temperature. Recent Prog Horm Res 16: 439 – 466, 1960

Elke, Gunnar, et al. “Close to recommended caloric and protein intake by enteral nutrition is associated with better clinical outcome of critically ill septic patients: secondary analysis of a large international nutrition database.” Crit Care 18 (2014): R29.

Exton, M. S. 1997. Infection-induced anorexia: active host defence strategy. Appetite, 29:369-83.

Huang HH, Hsu CW, Kang SP, Liu MY, Chang SJ: Association between illness severity and timing of initial enteral feeding in critically ill patients: a retrospective observational study. Nutr J 2012, 11:30.

Krishnan JA, Parce PB, Martinez A, Diette GB, Brower RG: Caloric intake in medical ICU patients: consistency of care with guidelines and relationship to clinical outcomes. Chest 2003, 124: 297-305.

LeGrand, Edmund Kenwood, and Joe Alcock. “Turning up the heat: immune brinksmanship in the acute-phase response.” The Quarterly review of biology 87.1 (2012): 3-18.

Murray, J., A. Murray, and N. Murray. “Anorexia: sentinel of host defense?.” Perspectives in biology and medicine 22.1 (1978): 134-42

Schetz, Miet, Michael Paul Casaer, and Greet Van den Berghe. “Does artificial nutrition improve outcome of critical illness.” Crit Care 17.1 (2013): 302.

Straub, R. H., M. Cutolo, F. Buttgereit, and G. Pongratz. 2010. Energy regulation and neuroendocrine-immune control in chronic inflammatory diseases. Journal of Internal Medicine, 267:543-60.

Von Meyenburg, C., et al. “Role for CD14, TLR2, and TLR4 in bacterial product-induced anorexia.” American Journal of Physiology-Regulatory, Integrative and Comparative Physiology 287.2 (2004): R298-R305.

Zaloga, G. P., and P. Roberts. “Permissive underfeeding.” New horizons (Baltimore, Md.) 2.2 (1994): 257-263.

Categories: Uncategorized

Joe Alcock

Emergency Physician, Educator, Researcher, interested in the microbiome, evolution, and medicine

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