When colleagues Andrew Wang, MD, PhD, HS ’13, FW ’17, and Ruslan Medzhitov, PhD, were discussing how they feed their kids when they’re sick, they started to wonder what was behind the old adage, “Starve a fever, feed a cold.”
“All animals—from worms, to flies, to dogs, to us—do this. When we get acutely infected, we lose our appetite, and people have wondered for a long time why that might be,” said Wang, who is an assistant professor of medicine (rheumatology) and of immunology.
The two wanted to find out the potential benefits of fasting during an illness. In their 2016 study, published in Cell, when they force-fed an animal that was fighting listeriosis—a bacterial infection—the animal died. On the other hand, feeding an animal battling the flu—a viral infection—helped nurse it back to health.
When the researchers broke the food down into its key components—protein, fat, and sugar—they found that sugar is the active ingredient. Mice that had viral infections needed glucose to adapt to the stress brought on by antiviral inflammation and to prevent stress-induced cell death. In bacterial infections, however, glucose prevented ketogenesis, which was necessary to counteract the oxidative stress of antibacterial inflammation.
Still, Wang said, “As a doctor, I’m hesitant to simply say, ‘If you think you have a bacterial infection, starve yourself, and if you think it’s viral, don’t.’ ”
And Wang has good reason to hold off doling out that advice. The role of glucose in inflammation is far more complex. New research suggests that glucose deprivation before flu infection may in fact prepare the body to fight it. While glucose after flu infection promotes adaptation to inflammation, a November 2019 study in Science Immunology co-authored by Vishwa Deep Dixit, DVM, PhD, the Waldemar Von Zedtwitz Professor of Comparative Medicine and professor of immunobiology, suggests mice already in ketogenesis are better equipped to fight the flu once it hits.
In the study, mice that were on the high-fat, low-carbohydrate ketogenic diet when they contracted the flu were more likely to survive the illness than those on a normal high-carb diet. The extremely low-carb diet, the study found, activates a group of T cells in the lungs not previously linked to the immune system’s response to influenza. The T cells step up mucus production in airway cells and trap the virus.
While the studies point to opposing roles for glucose in viral inflammation, they also asked different questions.
“Our 2016 study,” said Wang, “asks why animals eat less when they have the flu. So, we fed them after they were infected to see what impact that would have. [This new study] asks, ‘If an animal is in a ketotic state, how does it affect response to flu infection?’ I think what is clear from both studies is that the metabolic state of the organism in an infection—before and during, and probably during recovery—is a critical determinant of the organism’s overall outcome in that infection.”
Glucose has a role in parasitic infections, too. Wang and Medzhitov explored this relationship in a 2018 study published in Proceedings of the National Academy of Sciences (PNAS). When they blocked glycolysis in mice with malaria, the mice didn’t go on to develop cerebral malaria.
The glucose deprivation didn’t make the mice resistant to malaria. In fact, in both groups, parasite burden, neuroinflammation, blood-brain barrier permeability, and anemia were the same. But, blocking glucose made mice more tolerant of the disease. Or maybe, the study authors suggest, glycolysis inhibition made the parasites themselves less harmful. Either way, fewer microthrombi (tiny blood clots) formed in the brains of those mice, preventing the spread of the infection to the brain.