High-Fat Diet Reprograms Immune Cells in Mice

A new study from researchers at Portland State University has reported that a diet high in saturated fats – such as the ketogenic or “keto” diet – can alter the immune system in mice.

Some fats have more impact than others

The keto diet is a popular example of a low-carbohydrate, high-fat diet that is used for weight loss. In their research, lead author Dr. Brooke Napier, assistant professor of biology, and colleagues illustrated that mice fed either a Western (high-fat, high-sugar) diet or a ketogenic diet were more susceptible to sepsis than mice fed a normal diet.

The researchers identified one saturated fat that was associated with an increased risk of sepsis when injected into mice fed a normal diet. This fat is palmitic acid, which exists in high proportions in meat and dairy products and can also be found in breast milk.

“It was just exposure to this one saturated fat that made them more susceptible to sepsis mortality,” said Napier. “The idea that you could have a specific fat in your diet that would cause such a drastic outcome in disease is kind of incredible.”

In the mice fed Western or ketogenic diets, and the mice injected with palmitic acid, levels of inflammatory cytokines in the blood increased, which can result in systemic inflammation and fever during sepsis, suggesting palmitic acid affects the immune system by causing inflammation.

However, palmitic acid also reprograms the innate immune system by triggering trained immunity. Trained immunity is the “learned” part of the innate immune response, where an incident of high inflammation alters stem cells in the bone marrow to enable increased production of inflammatory innate immune cells in response to inflammation stimuli afterward.

Napier reported that, “The fat is reprogramming [the mouse] stem cells to produce more inflammatory innate immune cells, and those innate immune cells – when they're put in this sepsis disease model – produce more cytokines, more fever and higher mortality rates.”

A delicate balance

Inflammatory immune cells can be helpful in response to infection, but a response that is too strong can result in sepsis.

Mice that had been injected with palmitic acid were also able to fight off a Candida yeast infection more effectively than untreated mice, the researchers found.

“It's this double-edged sword where if you have exposure to high fat and then exposure to a disease where more inflammation exacerbates the disease, then it's a bad thing,” said Napier. “But if you're in the context where you eat high fat and then you get an infection and more inflammation helps you clear infection quicker, it's a good thing.”

The research team also found that oleic acid, a polyunsaturated fat, could counteract the inflammation produced by the high-palmitic acid diet. Oleic acid can prevent the synthesis of ceramide, a molecule that induces a stress response in cells and may be involved in the overactive inflammatory response in sepsis.

In the study, the higher risk of sepsis in mice fed a ketogenic diet for two weeks was reversed by adding oleic acid to their diets for the last three days, which Napier described as “absolutely shocking.”

In the future, this research could help guide changes in diets for tube-fed patients or in people at higher risk of contracting infections or sepsis.

Napier’s lab is now looking into the relationship between palmitic acid in breast milk and the immune responses of breastfed babies. They hypothesize that “palmitic acid in breast milk is protecting neonates from infection during weaning.”

This article is a rework of a press release issued by Portland State University. Material has been edited for length and content.

Reference: Seufert AL, Hickman JW, Traxler SK, et al. Enriched dietary saturated fatty acids induce trained immunity via ceramide production that enhances severity of endotoxemia and clearance of infection. eLife. 2022;11:e76744. doi: 10.7554/eLife.76744.