Food, Flora, and Function

Research Hints that Diet Choices May Affect Health by Modulating the Immune System

BY MICHAEL TABASKO, THE NIH CATALYST

If the saying “you are what you eat” holds true, the same might be said for our immune system, according to new research. Scientists from NIAID and NIDDK and their collaborators found that vegan and ketogenic diets remodeled the human microbiome and immune system, and each diet was found to have its own unique implications (PMID: 38291301). The results could open the door to a new era of research aimed at using dietary interventions as a way to modulate the body’s immune response.

At NIDDK, Kevin Hall’s Integrative Physiology Section has a long-standing interest in understanding how the body and brain are affected by different kinds of diets. They conducted a clinical trial at the NIH CC in which 20 participants consumed either a high-fat, low-carbohydrate ketogenic diet, or a low-fat, high-carbohydrate vegan diet for two weeks, followed by the opposite diet for another two weeks, in random order.

As it turned out, diet changed the immune system significantly and rapidly, according to multi-omics analyses conducted by Yasmine Belkaid’s team at NIAID’s Laboratory of Host Immunity and Microbiome.

“It was quite remarkable that such a short dietary intervention could remodel the immune system of all participants independently of their age, gender, BMI, ethnicity, or race,” said Belkaid, who in January began a six-year term as president of the Institut Pasteur (Paris).

Diverging effects of diet

Cells of the adaptive immune system recognize specific antigens as a result of being exposed to outside elements such as a certain pathogen or vaccine. This exposure generates antibodies and orchestrates the immune system to respond in a very directed way that includes activation of T cells as well as enrichment of B cells, plasma cells, and natural killer cells. The ketogenic diet upregulated pathways linked to this adaptive immunity.

In contrast, the vegan diet activated pathways associated with innate immunity, the body’s immediate first line of defense against any invading virus or pathogen. This includes quick-acting enzymes and defense cells in the skin and mucous membranes.

The authors note, however, that they measured immune system changes—overall markers on which cells were being upregulated and which proteins were being expressed—and not function, as in someone’s immune response to a vaccine.

Each diet differentially shifted the species of microbes colonizing the gut, an expected result based on prior studies (PMID: 24336217). For example, microbes that thrive on fiber proliferated on the vegan diet. Those types of microbes are known to release short chain fatty acids, a process thought to be beneficial in maintaining digestive health.

The ketogenic diet, which was relatively low in fiber, was associated with a strong downregulation of most microbial pathways, particularly those related to amino acid metabolism. However, that diet also upregulated the amino acid processes of the host. The investigators think that the higher amount of protein consumed during the ketogenic diet might make those participants less reliant on microbe-derived amino acids.

Although we know that the microbiome plays a role in regulating our immune system, exactly how it does that and what differences in microbial communities mean are largely unexplored. "We are at early stages of understanding what the microbiome does, especially over long periods of time and how it interacts with the immune system in humans,” said Hall.

In the future, precision nutrition interventions could be used to modulate the immune system and help manage chronic inflammatory disorders, according to Belkaid, but more controlled clinical studies are needed. “Based on the large number of possible dietary interventions, the opportunity to harness nutrition has an enormous potential for human health,” she said.

The metabolic effects of diet

The research builds off a 2021 clinical trial in which Hall’s team sought to determine each diet’s effect on the participants’ voluntary energy intake (PMID: 33479499). Notably, both diets included foods that were minimally processed and provided a foundation of one kilogram of nonstarchy vegetables daily. The scientists found that participants on the vegan diet chose to consume nearly 700 calories fewer per day than when on the ketogenic diet.

Those unexpected results were at odds with the prevailing carbohydrate-insulin model of obesity, which posits that diets high in carbohydrates drive excess insulin production and increase energy storage in fat cells. In turn, that process would thereby deprive the rest of the body of energy, resulting in increased hunger and food intake.

The average American diet is high in ultraprocessed foods, which has been associated with increased energy consumption and weight gain (PMID: 31105044), so the shift to either whole food diet was beneficial. “Both the vegan and ketogenic diets were quite healthy and both diets resulted in weight loss and metabolic improvements compared to baseline,” said Hall.

Netflix Series Features NIH Grantee Research on Diet and Health

Belkaid and Hall’s findings come on the heels of a NHLBI-funded clinical trial that also discovered differing cardiometabolic effects of an omnivorous versus vegan diet in identical twins (PMID: 38032644) featured in the Netflix docuseries You Are What You Eat: A Twin Experiment.

In that study, the vegan diet emerged as the most beneficial to human health, at least in the short term. By studying 22 sets of healthy identical twins, the researchers controlled for confounding factors such as age, sex, and genetics. One twin was randomly assigned to follow one diet, while the other twin followed the opposite diet. Participants were provided with meals for four weeks, after which they prepared their own meals, maintaining the assigned diet for the final four weeks.

Compared with twins on the omnivorous diet, the twins randomized to the vegan diet experienced significant decreases in low-density lipoprotein cholesterol concentration, fasting insulin concentration, and body weight. As in the NIH immune study, the authors note that both diets had healthy servings of vegetables and whole grains, and decreased sugars, and were likely an improvement over the participant’s eating habits before study participation.