Sickness behaviors are a coordinated suite of behavioral changes that accompany illness. These evolved behaviors include lethargy, decreased sociality, reduced eating, disinterest in sex, and increased sleep.
Many of these are evolutionarily conserved, seen across the tree of life. For instance lethargy, social withdrawal, and eating less are seen in sick mice and sick humans alike. We shared a common ancestor with mice 75 -100 million years ago, indicating that evolution has preserved these responses for some time, and for some reason.
One prominent sickness behavior is disinterest in eating, or illness anorexia, sometimes reinforced by nausea and vomiting. The hypothesis that illness anorexia is adaptive has led clinical researchers to test the idea of intentionally reducing nutrition provided to critically ill human patients. The idea, called permissive underfeeding, was first proposed by Zaloga and Roberts (1994). Huang et al 2012 then showed that when feeding was initiated later in the ICU, they had a shorter stay in the ICU. Arabi and colleagues found that giving more calories to ICU patients was associated with worse outcomes (2010). A subsequent randomized controlled trial by Arabi and colleagues (2011), showed that underfeeding (60% of calorie needs) resulted in improved survival in ICU patients. More recently, a 2023 randomized trial of 3044 patients failed to show an overall survival benefit to underfeeding, although patients with underfeeding spent less time in the ICU. A 2024 meta analysis that included this 2023 trial along with 22 other RCTS, showed that permissive underfeeding had a modest survival benefit to patients while in the ICU, fewer gastrointestinal adverse events, shorter ICU length of stay, and less time on the mechanical ventilator. However, this study had a null result in overall mortality. This leaves us almost in the same place as a decade ago, when LeGrand and I suggested in an 2015 article that the idea of underfeeding critically ill patients awaits a definitive trial.
On the other hand, RCT evidence to date shows no harm from underfeeding, which would argue against anorexia as an evolved adaptive trade-off. The totality of evidence from clinical trials, along with the indirect evidence from comparative studies, supports the idea that, like fever, illness anorexia evolved because it enhances survival during infection.
If anorexia is beneficial, how would it work? Anorexia of illness seems paradoxical because it limits calories at the same time that energy requirements are increased from the immune system. Ed LeGrand and I tackled this paradox in a clinical brief published in Evolution Medicine and Public Health. I described our ideas about this ‘puzzling feature of sickness – loss of appetite and interest in food, sometimes along with nausea and vomiting’ in a previous post, paraphrased here:
During illness, energy demands from the immune system are elevated. Since energy spend is constrained, requiring tradeoffs in how energy is allocated, physical activity is reduced when sick to compensate. So why doesn’t appetite also increase to compensate? LeGrand and I proposed that sickness anorexia (loss of appetite) happens because of a life and death contest with invading pathogens over energy. We eat less because starving pathogens is a host defense. Unfortunately a byproduct of this strategy is self-starvation. We speculated that this tradeoff is worth it, especially from threats coming from the microbiome – since we feed our microbiomes at the same time that we feed ourselves. If this notion is true, we would expect greater weight loss and more profound illness anorexia when we have a GI infection versus a non GI infection.
Along with a contest over calories, we undergo an intense struggle over micronutrients with pathogens and potential pathogens. During infection, the body scavenges micronutrients using molecules such as transferrin, lactoferrin and calprotectin. The bound micronutrients, specifically iron and zinc, are necessary for pathogen growth. For example, oral iron promoted bacterial growth in human serum ex vivo, causing markedly higher growth of gram negative Escherichia coli, Yersinia enterocolitica and Salmonella enterica and gram-positive Staphylococcus epidermidis. These observations have clinical implications. Supplemental iron, especially by the intravenously route, was linked with an increased risk of infection in this JAMA meta-analysis. The advice for pediatric iron supplementation endorsed by the WHO in locations with high childhood anemia could have a downside. Oral iron supplementation resulted in pathogen overgrowth in the gut microbiota and intestinal inflammation in anemic Ivory Coast and Kenyan children.
You’d think those observations might generate some interest for a strategy of “permissive hypoferritinemia” in some patients with anemia. Apparently not, since Google returned zero results for a search with that phrase. On the other hand, the opposite strategy has been tried experimentally. Janelle Ayers has argued for flooding the zone with iron in an effort to reduce virulence by pathogens. A test of that idea in mice improved survival, showing that giving high levels of supplemental iron can experimentally improve virulence and lethality of an enteric infection. While intriguing, it tells us only that virulence is costly – when microbes have unlimited access to iron, they can replicate at lower cost without destroying host tissues to get it. When the free iron runs out, the host is left with a higher pathogen burden, limiting the clinical utility of such an approach. The underlying evolutionary contest is an ongoing tug of war over micronutrients. This competition provides an attractive explanation for why iron deficiency anemia and other nutrient deficiencies are so common in populations with a high burden of pathogens and chronic diseases. Better perhaps to treat anemia by focusing on eradicating infections and reducing pathogens in the microbiota.
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Joe Alcock
Emergency Physician, Educator, Researcher, interested in the microbiome, evolution, and medicine
EvolutionMedicine 
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