Fatty Feasts May Come at an Immune Cost

ABOVE: Transmission electron microscopy shows that T cells from mice eating high fat diets (right) have impaired mitochondrial function compared to T cells from mice on fiber-rich diets (left). Michaela Schweizer

Many people indulge in energy-rich foods that are high in fats and carbohydrates for snacks or during social activities, like eating at a restaurant. While the consequences of a long-term high-calorie, low-nutrient diet on the immune system are well studied, the effects of short-term alterations are not well known.^1,2 Recently, a team of researchers reported how brief dietary changes influence the immune system and showed that at least one type of T cell rapidly responds to this perturbation.³ Their findings, published in Nature Immunology, can help researchers track the early changes that take place in the development of metabolic diseases.

“I've been dealing with how the diet influences our immune system,” said Francesco Siracusa, an immunologist at the University Medical Center Hamburg-Eppendorf and coauthor of the study. However, unlike many studies that look at the effects of high fat diets long-term, after health conditions develop, Siracusa and his team look at much earlier times, such as the influence of only a few days eating a high-calorie diet. “Obesity and chronic metabolic syndrome—all of that is out of the equation. We really focus on short-term dietary intervention,” he said.

To investigate the effects of these acute changes in diet, the team fed animals a feast diet with 60 percent fat and added cholesterol but low fiber content for three days, then switched them to a regular rodent diet for another three days. They alternated between these two diets every three days for a total of 12 days. Using a gene set enrichment analysis, the researchers observed alternating patterns of gene expression with dietary switches; notably, they saw reduced expression of T cell receptor genes when animals ate the feast diet. Consistent with these findings, they observed reduced expression of interleukin (IL)-17 related cytokine genes IL17a, Il17f, and Il22 in mice that were fed a feast diet compared to mice that ate a regular diet for three days. They also found reduced numbers of T helper 17 (T_H17) cells, which produce IL-17 cytokines, in the small intestine and in the intestinal lymphoid compartments in feast diet-fed mice. “We were, to be honest, a bit surprised at first to see that within this very short period of time, adaptive immune cells reacted,” Siracusa said.

These initial results suggested that even a short-term change in diet could alter mucosal T cell responses. To explore this further, the team infected mice with a pathogenic strain of Salmonella and compared the immune responses of mice that ate a normal diet but lacked cytokines IL-17A and IL-17F to those of wild type animals that ate a regular diet or a feast diet. Both feast diet eating mice and IL17A/IL17F-deficient mice exhibited reduced weight and more bacteria in their intestines compared to the normal mice that ate a regular diet. According to Siracusa, these data suggested that the feast diet reduced T_H17 immune responses.

“I am not quite sure I would see it as an impairment of the immune response,” said Sammy Bedoui, an immunologist at the University of Melbourne who was not involved in the study. According to Bedoui, there could be evolutionarily beneficial reasons for these adaptations, such as limiting allergic or autoimmune reactions in response to large amounts of food. However, he thought that the feasting model captured an important and relevant aspect to omnivorous diets, and that the study offered important insights into the relationship between food consumption and immune responses.

Since the feast diet contained limited fiber, which contributes to the production of short chain fatty acids that T cells use in their metabolism, Siracusa’s team explored the effects of this diet on T cell metabolism. They found that the feast diet reduced the presence of acetate and butyrate, two short chain fatty acids, in mouse intestines. This decreased oxidative phosphorylation in T cells, which led to reduced production of cytokines. These altered T cell responses seemed reversible to some extent. When the researchers supplemented mice with acetate and butyrate, they observed restored mitochondrial health, increased production of IL-17A and IL-17F, and increased number of T_H17 cells in the intestines. They also noted improved clearance of Salmonella with either acetate and butyrate supplementation or after returning to a regular diet for three weeks, suggesting that the effects on T cell activity are transient.

“I would like to see more interrogation of that,” said Bedoui. In particular, he is interested in understanding if T cells return completely to their original states, as well as if repeated cycles of this type of feasting diet alter the system’s flexibility. That is something that interests Siracusa as well. “How long can you play this game?” he wondered.