Mice fed a ketogenic diet—in which 90 percent of calories come from fat and less than 1 percent from carbohydrates—were less susceptible to the influenza A virus, according to a study published today (November 15) in Science Immunology. The protective effects seem to be mediated by an increase of so-called gamma-delta T cells in the animals’ lungs that induce the epithelial cells in the airway to make more mucus to trap the virus.
The project began as a discussion between Ryan Molony, at the time a grad student in the Yale School of Medicine lab of Akiko Iwasaki, and Emily Goldberg, a postdoc in Vishwa Dixit’s lab at Yale. Dixit’s group had shown in 2015 in mice and in human cells that a ketogenic diet blocks an inflammation pathway triggered by a protein complex that plays a role in some autoimmune disorders. A year later, Iwasaki’s group published work showing that this protein complex also drives lethal influenza infection. The two groups formed a collaboration to connect the dots and investigate whether or not a ketogenic diet could stop mice from dying of the flu virus.
They started by keeping mice on a normal diet, in which 18 percent of calories come from fat and 58 percent from carbs, or feeding them a ketogenic diet for seven days, and then infecting them intranasally with H1N1 influenza. All animals eating the normal diet were dead by the fourth day after infection, while half of the mice fed the keto diet survived. The keto diet–fed mice also lost less body weight, maintained higher blood-oxygen saturation levels, and had lower levels of the virus in their blood than their counterparts that ate normal chow.
Humans and mice have two types of T cells: alpha-beta T cells, which are well studied and specific to pathogens, and gamma-delta T cells, which detect signs of stress, are more numerous in the lungs, skin, and gut, and are much less well understood. The researchers found that mice fed a ketogenic diet have about four times the number of gamma-delta T cells in the lungs as mice fed a normal diet by the third day after infection. Then they analyzed gene expression in flu-infected lungs from mice fed the keto diet and determined that the gamma-delta T cells were protecting the mice in a surprising way.
“Typically, T cells are thought to control viral infection by killing the infected cells. What we found was that instead of killing, gamma-delta T cells modify the environment . . . to protect the host against the virus,” writes Iwasaki in an email to The Scientist. “These T cells modify the airway epithelial cells to produce more mucus that can trap the virus in its tracks.”
These two ideas—that a diet that the mice are being fed contributes to protection by improving barrier function and that the mechanism of that protection is being mediated by gamma-delta T cells—haven’t received much attention in influenza biology, says Paul Thomas, an immunologist at St. Jude Children’s Research Hospital who did not participate in the study. “Why are gamma-delta T cells an effector of a diet-induced changed in metabolism” is one open question, he adds, and another is “whether or not the same pathways exist in humans, and if they do, how that might affect how we handle influenza infection.”
The findings indicate that the keto diet could have similar protective effects in people.
“Obese and diabetic patients incur more hospitalizations and have increased severity of influenza infections each year,” Julie Jameson, an immunologist at California State University, San Marcos, who did not participate in the work, writes in an email to The Scientist. It’s already known that a ketogenic diet can help these patients lose weight and improve their cholesterol levels and blood pressure, she adds, and this study raises the possibility that it “may have even more health benefits than previously reported.”
According to Jameson, it is still not clear what the consequences of a long-term ketogenic diet are. “This study examines a one-week, acute time point. It is important to know whether gamma-delta T cells would continue to accumulate in the lung and whether this would be beneficial,” she explains.
And it’s probably best to hold off on switching over to a ketogenic diet during flu season for now. “We do not extrapolate the findings in mice to people,” cautions Iwasaki, “but this study provides a rationale for looking into whether people on [a] keto diet have more gamma-delta T cells and whether they are better protected from flu disease.”
E.L. Goldberg et al, “Ketogenic diet activates protective γδ T cell responses against influenza virus infection,” Science Immunology, doi:10:1126/sciimmunol.aav2026, 2019.
