Immunometabolism – How we fuel the fight against disease

Have you ever wondered why we lose our appetite and feel so tired when we’re fighting off a cold or flu? It may seem as though this distinctive fatigue and disinterest in food is just a side-effect of illness. In reality, these changes in behaviour, termed sickness-behaviours, have evolved to aid our survival when facing infection [1]. Less obvious to us when we’re sick is the vital activity being carried out by our immune systems to fight the infection. Our immune systems are very powerful and effective barriers against disease, and when challenged by infectious agents (pathogens) all eyes turn to our immune cells to clear the menacing microbes. These immune cells require a great deal of energy to meet this demand, and we need nutrients to make this energy. Let’s have a look at immunometabolism.

Where do you get your energy?

All of our cells need fuel to survive and carry out their important functions, and our immune cells are no exception. Metabolism is the way in which we process nutrients obtained from the food we eat to fuel the production and activity of our cells [2]. The many reactions involved in metabolism are tightly regulated to ensure efficient use of the products of digestion. An example of these products is glucose, a key molecule used to generate energy in our cells.

Generally, metabolism is split into two terms: anabolism and catabolism, which are fancy words for ‘building up’ or ‘breaking down’ molecules respectively. Anabolic reactions occur to store the nutrients we’ve consumed and, when food is scarce, catabolic reactions will break down what we have stored away. The storage of molecules obtained from food (e.g. glucose) and the synthesis of cell components is essential to the growth of cells, but it’s energetically costly [2]. The energy for these processes is provided by the breakdown of the nutrients we consume (catabolism). Our survival and functioning requires a finely tuned balance between these metabolic reactions, but there are instances that cause particular metabolic strain.

Fueling the fight without an appetite

When faced with an infection, our immune cells have to grow and expand in number to fight off the invading pathogen (think expansion of a fleet of stormtroopers, or any sci-fi clone army). This rapid increase in cells is accompanied by the synthesis of antibodies and signalling chemicals, which, you may have guessed, all require a lot of energy [3]. Another defence mechanism we have is fever, which helps by increasing our body temperature so it’s inhospitable to pathogens, but generating this heat also requires energy [4]. The fight against infection clearly requires plenty of energy, so why do we often lose our appetite when sick?

This question is often looked at from an evolutionary perspective, because we know that many species exhibit similar behaviours to us when ill, such as loss of appetite and tiredness [1]. To an animal in the wild or a hunter-gatherer human, fatigue and loss of appetite are arguably advantageous when fighting an infection [2]. Abstaining from foraging and other energy expensive activities reduces exposure to other potential threats like predators and food-borne pathogens and conserves our energy while in this vulnerable state [3]. The last thing I’d want to do when sick is walk for miles to find food or worse yet, accidentally eat something that has gone off. So, these changes in mood and behaviour have likely evolved to keep us from getting kicked when we’re already down. But the question remains, how do we fuel our immune response with a decreased desire for food?

Our immune system is a powerful and vital force in defending against disease, so we have adapted ways of providing energy for immune cells even when nutrients are scarce. You may remember that glucose is a breakdown product from the food we eat, and it’s also a very important molecule for providing energy to our cells [5]. When the immune system is activated by inflammation, some immune cells shift their cellular metabolism to a catabolic process that rapidly generates energy by breaking down glucose [6]. This happens in order to meet the energetic demand of the immune response, but it means these cells need a whole lot of the sugary substance [7]. You might think with our loss of appetite, our immune cells would have trouble obtaining the glucose they need. Well, it turns out our immune cells are able to increase their uptake of glucose while also signaling to the body to reduce the amount of glucose taken up by our other cells [8].

Immune cells meddling in metabolism

Glucose, being one of those precious products vital to our cells, is under tight metabolic regulation in our bodies. We use hormones to control the storage and release of glucose in our system. Insulin, an important hormone in regulating our body glucose levels, causes our cells to uptake and store glucose molecules [8]. During an infection, however, our immune cells release chemical signals which cause temporary insulin resistance in our less important cells [7]. This means our immune cells are able to temporarily hijack our glucose control system and reduce the uptake of glucose by less important non-immune cells [8]. This metabolic hijacking increases the glucose available for our immune cells and partially explains how we fuel our immune system, even in nutrient scarcity.

This influence of our immune cells over systemic metabolism is nothing to scoff at, as we’ll remember the importance of metabolism in all of our cells. Although a crucial adaptation to fight acute infection, long term disruption of metabolism caused by our immune cells could pose some serious problems [8]. The extent of the relationship between our metabolism and immunity is being uncovered in the aptly named field of immunometabolism, and as it happens, there seem to be a host of ways in which the two influence each other.

References

1. Hart, B.L. (1988). Biological basis of the behavior of sick animals. Neuroscience & Biobehavioral Reviews, 12(2), pp.123–137.
2. Wang, A., Luan, H. and Medzhitov, R. (2019). An Evolutionary Perspective on Immunometabolism. Science (New York, N.Y.), [online] 363(6423).
3. van Niekerk, G., Isaacs, A.W., Nell, T. and Engelbrecht, A.-M. (2016). Sickness-Associated Anorexia: Mother Nature’s Idea of Immunonutrition? Mediators of Inflammation, [online] 2016, pp.1–12.
4. Best, E.V. and Schwartz, M.D. (2021). Fever. Evolution, Medicine, and Public Health, [online] 2014(1), pp.92–92.
5. Troha, K. and Ayres, J.S. (2020). Metabolic Adaptations to Infections at the Organismal Level. Trends in Immunology, 41(2), pp.113–125.
6. O’Neill, L.A.J., Kishton, R.J. and Rathmell, J. (2016). A guide to immunometabolism for immunologists. Nature Reviews Immunology, [online] 16(9), pp.553–565.
7. Wensveen, F.M., Šestan, M., Turk Wensveen, T. and Polić, B. (2019). “Beauty and the beast” in infection: How immune–endocrine interactions regulate systemic metabolism in the context of infection. European Journal of Immunology, 49(7).
8. Buck, M.D., Sowell, R.T., Kaech, S.M. and Pearce, E.L. (2017). Metabolic Instruction of Immunity. Cell, 169(4), pp.570–586.