A new study by Portland State University researchers is the first to show that a diet high in saturated fat alone can reprogram the immune system of mice, making them better at fighting infection but more susceptible to systemic inflammatory conditions, including sepsis. Brooke Napier, assistant professor of biology at PSU, led the study, which was published in eLife.
The ketogenic or “keto” diet is a popular high-fat diet used for weight loss or to control epileptic seizures. This study shows that when mice eat a ketogenic diet high in saturated fat, it can have a significant impact on their immune system.
A previous study by Napier and colleagues found that mice fed a Western diet high in fat and sugar were more susceptible to sepsis and had a higher mortality rate than mice fed a standard diet. In the current study, the researchers found similar effects in mice fed a high-fat ketogenic diet, suggesting that dietary fat may play a role in sepsis.
The researchers focused on one particular fat found in the blood of mice fed a ketogenic diet: palmitic acid, which is commonly found in animal fats and dairy products. Remarkably, mice fed a normal diet that were injected with palmitic acid also became more susceptible to sepsis.
“It was just exposure to this single saturated fat that made them more susceptible to sepsis mortality,” Napier says. “The idea that you could have a specific fat in your diet that would cause such a drastic outcome in disease is pretty incredible.”
Napier and his team then probed how high levels of palmitic acid could trigger sepsis. Their first clue came when they noticed that mice fed the Western diet, mice fed the ketogenic diet, and mice treated with palmitic acid all had high levels of inflammatory cytokines, immunological hormones that can cause fever and systemic inflammation during sepsis.
The presence of the inflammatory cytokines suggested that palmitic acid could affect the immune system by causing inflammation, but Napier soon discovered that the story was more complicated and interesting than that.
A DOUBLE-EDGED SWORD
The mammalian immune system has two main components: the more primitive, short-lived innate immune system and the longer-lived adaptive immune system.
When you get sick or get a vaccine, your adaptive immune system makes antibodies, preparing your body to fight off a future infection. It is a form of biological “memory” that can last for months, years or even a lifetime.
Biologists have recently learned that the innate immune system can also retain memory, despite the fact that its cells only last a week to a month in the blood. The “memory” of the innate immune system comes from modifying bone marrow stem cells that make future innate immune cells, a response called trained immunity.
In this study, Napier and his colleagues learned that palmitic acid can trigger trained immunity. The fat acts as a “short burst of inflammation” that alters the function of stem cells in mouse bone marrow so that they produce more inflammatory innate immune cells in the future. This means that when the innate immune system encounters a second inflammatory stimulus later, it responds much more strongly. Sometimes, as with sepsis, this response is too strong.
“Our model is the first time anyone has shown that a food constituent can provide that first push for inflammation,” Napier says. “Fat reprograms their stem cells to produce more inflammatory innate immune cells, and these innate immune cells – when placed in this sepsis model – produce more cytokines, more fever, and higher death rates.”
But that’s not all, because inflammation isn’t always a bad thing.
“If you only have one infection, it’s better to have more inflammation because you can clear the infection faster,” Napier says.
The researchers found this to be the case in mice treated with palmitic acid. They were better able to fight off a Candida yeast infection than the untreated mice.
“It’s this double-edged sword where if you’re exposed to high fat and then exposed to a disease where more inflammation exacerbates the disease, then that’s a bad thing,” Napier says. “But if you’re in a setting where you’re eating a lot of fat and you get an infection and more inflammation helps you clear the infection faster, that’s a good thing.”
NOT ALL FATS ARE CREATED EQUAL
Napier and his colleagues also discovered that another type of fat may be able to counteract the harmful effects of palmitic acid. Oleic acid, a polyunsaturated fat found in many vegetable oils, including olive oil, can block the synthesis of ceramide, a fatty substance that can initiate a stress response in cells and may play a role in the hyperinflammatory response that causes sepsis.
When researchers fed mice a ketogenic diet for two weeks, but also gave them oleic acid for the last three days, they no longer showed increased susceptibility to sepsis.
“It was absolutely shocking,” Napier says.
Although more research is needed to see how the results of this study might extend to humans, these findings could suggest that the types of fats a person eats could impact how their immune system works and their susceptibility. to diseases.
“If you’re on a keto diet high in dairy and red meats, you’ll get a very high level of palmitic acid. Without countering that with polyunsaturated fats from something like olive oil, it would seem very reasonable. that you may make yourself more susceptible to sepsis,” Napier says, noting that this study is by no means a red mark against a ketogenic diet. “Similarly, if you eat a lot of palmitic acid, you might also help you clear the infection in times of global pandemic.”
These results may also be relevant for hospitals. They could lead to changes in the diet of people fed through feeding tubes, for example, or inform how best to administer fatty acid-solubilized drugs. Health care providers may one day increase or decrease the ratios of oleic acid and palmitic acid for a patient based on their particular risk of infection or sepsis.
“We’re definitely looking at ways to apply this new science to clinical problems,” says Napier.
The lab is also exploring the effects of palmitic acid in breast milk. “We are now trying to understand whether the level of fat the mother eats affects the innate immune response of the weaned child, because it is clear that such a response to fat must be conserved through evolution,” says -she. “Our hypothesis is that palmitic acid in breast milk protects newborns from infection during weaning.”
Reference: Seufert AL, Hickman JW, Traxler SK, et al. Enriched dietary saturated fatty acids induce trained immunity via the production of ceramides which increases the severity of endotoxemia and clearance of infection. eLife. 2022;11:e76744. doi: 10.7554/eLife.76744
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