An old saying has to be laid out on the examination table. “Feed a cold and starve a fever” – children in the Anglo-American world learn this from their grandparents. Professor Dr. Ruslan M. Medzhitov is interpreting this with a new slant. “Cold” indicates viral infections, while “fever” suggests bacterial infections.
Medzhitov conducts research as an immunologist at Yale School of Medicine. He based his analysis on the following question: when our body is fighting against pathogens, it reduces our appetite. Is this biological response sensible?
Together with colleagues the scientist designed an experiment. He infected mice with the bacterium Listeria monocytogenes or with a murine influenza-like virus. Subsequently, the rodents were force-fed with either a standard diet or with saline. Animals with bacterial infection died if they received food. In the group given saline at least every other mouse survived.
If they had previously received a virus, the relative ratios were the other way around. Around 78 percent of the food group and ten percent in the saline group survived.
Cells on a sugar rush
Now the foods used have been under the microscope. Ruslan Medzhitov found out that glucose is of central importance. When he used the inhibitor 2-deoxy-D-glucose (2-DG) to prevent the uptake of sugar, animals in the bacteria group survived, whereas there was a high mortality in the virus group. The exact opposite of the first experiment occurred.
Background information: in order to minimise the deleterious effects of reactive oxygen species (ROS), cells need ketones. During fasting the breakdown of fatty acids creates ketone bodies in the liver – an alternative to providing glucose from carbohydrates. This ketogenesis has long been known, but now appears in a completely new contextual interrelationship. Things look quite different in the case of viral infections. Cells respond to the wrong proteins with an unfolded protein response (UPR response). This process requires glucose.
How is Medzhitovs study to be assessed? Since humans and mice are equivalent in their crucial metabolic steps, researchers hope to be better able to treat patients with serious infections in the future. Other studies confirm his assumption that findings can be transferred from animal studies to humans.
Going on the attack against the inflammasome
Already one and a half years ago Vishwa Deep Dixit of the Yale School of Medicine uncovered a connection between fasting and inflammatory processes. When abstinence from food occurs, among other things betahydroxybutyrate (BHB) originates. After prolonged fasting this metabolite in blood plasma reaches relevant concentrations. BHB inhibits inflammatory processes brought about through the NLRP3 inflammasome acting as a target structure. This protein complex is located in cytosol of macrophages and neutrophil granulocytes. It is stimulated among other things by bacteria. Over several stages, active interleukins ultimately arise which trigger inflammatory reactions.
The scientists experimented in this case not only with mice, but also with human cells. They found that both doses of targeted betahydroxybutyrate as well as ketogenic diets decreased inflammatory responses. Thus they found proof, far in advance of Medzhitov’s work, that the metabolism influences inflammatory processes.
Immune cells from the recycling centre
The effect is more complex than expected. If mammals starve, their bodies begin to regenerate cells in the immune system. This finding was arrived at by Valter D. Longo from the University of Southern California, Los Angeles. Intermittent fasting delayed immunosenescence in laboratory animals. This refers to the declining performance of the immune system with increasing age.
Longo then took 19 healthy volunteers into a pilot study. For five days per month they consumed instead of the usual 2,000 to 3,000 kilocalories only 1,090 (one day) or 725 kilocalories (days two to five). Their fasting blood glucose decreased by eleven percent. The ketone bodies increased by a factor of 3.7; IGF-1-levels decreased by 24 percent, and the IGFBP-1-level increased by 50 percent. Through the special program their slightly elevated baseline levels of C-reactive protein normalised. What’s more a slight increase in the stem cell counts of the immune system in the blood were detected by Longo.
Many pieces of the puzzle show that our metabolism affects the immune system. The value of this knowledge for clinical practice is currently unclear. This question can only be answered by further studies.