Sometimes, food is also medicine. Increasing clinical trials reveal the health benefits of dietary interventions. Traditionally, nutrition scientists have focused on the long-term effects of broad dietary patterns, such as the Mediterranean or Western diet, on population health. However, over the past five years, they have developed innovative approaches in nutritional immunology, narrowing their research to specific food categories and dietary components. This has allowed them to explore the short-term effects of food on the immune system and uncover its molecular mechanisms.

While there is still a long way to go in fully understanding how specific diets affect the immune systems of different individuals, many scientists remain optimistic.

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As the saying goes: “Illness enters through the mouth,” this not only warns people to pay attention to food hygiene but also carries another meaning: many diseases are related to our diet. Conversely, this suggests that improving dietary habits may help prevent and combat diseases.

On the other hand, our bodies are equipped with an innate defense and combat mechanism—the immune system. Scientists are therefore striving to connect diet, immunity, and health through interdisciplinary research. Some researchers believe that modern diets, particularly Western dietary habits, have weakened immune capabilities and need to be reformed. Meanwhile, optimistic scientists suggest that dietary changes could aid in treating a range of health issues, including cancer, metabolic disorders, and autoimmune diseases.

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The Evolution of Nutritional Immunology

Nutritional immunology, the study of the relationship between food and the immune system, is gaining significant attention. As a branch of immunology, it is both an ancient and emerging field. Its roots can be traced back to the classical texts of various ancient civilizations, which contain scattered observations about the connections between food, health, and disease. The Greek physician Hippocrates believed that environmental factors, diet, and lifestyle were the primary causes of human disease. He emphasized the importance of evaluating dietary habits to better understand illnesses. Similarly, in China, archaeologists have identified oracle bone inscriptions about diet and disease, reflecting ancient understanding of the relationship between nutrition and health. These early texts also reveal the conscious use of certain foods for healing and wellness.

However, direct scientific evidence of the impact of nutrition on immune function only emerged in the 19th century. In 1810, British physician J.F. Menkel was the first to describe thymus atrophy in malnourished individuals, establishing a link between nutrition and immune health and laying the groundwork for nutritional immunology. Nearly a century later, in the early 20th century, German physician Paul Ehrlich developed foundational concepts in immunology, while German physiologist Max Rubner defined the basic principles of energy expenditure and metabolism in nutrition.

In the 1920s and 1930s, the discovery of vitamins and a deeper understanding of nutrients led to further advancements. In 1941, American physicians David Perla and Jessie Marmorston co-authored Natural Resistance and Clinical Medicine, a book that covered the immune system and other host defense mechanisms. It also reviewed the roles of proteins, energy, vitamins, and minerals in the body's resistance mechanisms, making it a critical reference for nutritional immunology at the time.



However, with the outbreak of World War II, the progress of nutritional immunology came to a halt. It wasn't until the 1960s and early 1970s that the field experienced a revival, largely driven by the efforts of the World Health Organization. During this period, many scientists, both individually and in teams, contributed significantly to the advancements in this area. Research initiatives spanned countries such as India, Thailand, South Africa, and Nigeria, as well as institutions in the UK and the US. At the University of Pittsburgh, Abraham E. Axelrod conducted extensive studies on the impact of vitamins on the immune system.

At the time, most fundamental research focused on the effects of protein-energy malnutrition and iron deficiency (or excess) on the immune system and other host defense mechanisms. On the clinical front, advances included the introduction of new surgical techniques to provide parenteral nutrition to malnourished patients. Additionally, the organization of international conferences on nutritional immunology, the publication of related academic books and journals, and the establishment of international organizations dedicated to the field provided a significant boost to its development.

After more than half a century of progress, the advent of the 21st century marked a turning point for nutritional immunology, fueled by emerging biotechnologies and tools. Scientists developed novel approaches to the field, aiming to pinpoint the precise effects of food on immune function. Whereas nutritionists traditionally studied the long-term impacts of vaguely defined dietary patterns, such as the Mediterranean or Western diets, the widespread adoption of "omics" technologies now allows researchers to classify and analyze the full range of biomolecules within cellular nuclei, including genes and proteins. This advancement has enabled scientists to reveal the short-term beneficial or harmful effects of specific food categories and dietary components, as well as to explore the molecular mechanisms through which food influences immunity and health.


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Nutrients That Influence the Immune System
After decades of development in modern nutritional immunology, what nutrients have scientists identified as having an impact on the immune system?

It is well-known that a standard human diet includes vegetables, eggs, milk, dairy products, and meat. These foods can be metabolized into micronutrients and macronutrients, ensuring the body's proper functioning. For example, a new study presented at the 2024 Food and Nutrition Conference and Expo (FNCE) [5] showed that increasing the intake of beans and soy products can improve nutrition and dietary quality among American adults.

Beans and soy products are excellent sources of fiber, folate, potassium, and plant-based protein. They also provide iron and zinc, which are critical for regulating immune responses. These nutrients supply immune cells with the resources needed to launch a robust defense against invading pathogens.


Specific Nutrients and Their Roles in Immune Regulation
Different nutrients participate in various biochemical reactions in the body, helping regulate the immune system. For instance, as shown in the figure, macronutrients like arginine and tryptophan are involved in cell proliferation and macrophage activity. Macrophages are vital components of the innate immune system, capable of identifying, engulfing, and eliminating pathogenic bacteria, parasites, and other foreign invaders.

Arginine aids macrophages in producing nitric oxide (NO), which, under the action of nitric oxide synthase, determines macrophage cytotoxicity against antigens like bacteria and parasites.
Tryptophan, essential for protein synthesis, also regulates the anti-inflammatory activities of macrophages through initiation factors. [6]
Micronutrients such as vitamin A and zinc serve more diverse functions. They not only promote cell proliferation but also help suppress the NF-kB signaling pathway, associated with inflammation, autoimmune diseases, viral interference, immune developmental disorders, and cancer. [7]

These nutrients reduce pro-inflammatory cytokines like IL-1β and tumor necrosis factor-α (TNF-α), regulate the differentiation of helper T cells (Th17 and Th19), and stimulate the growth of regulatory T cell populations.
Besides vitamin A, B vitamins, vitamin C, and vitamin D also play roles in reducing inflammation.
Cholesterol is another crucial element, though often linked to health risks like heart disease, hypertension, and diabetes. Cholesterol-rich lipid rafts recruit receptors and signaling molecules essential for forming immune synapses and triggering immune responses. However, excessive cholesterol can negatively affect immune responses. [8]

Lastly, polyunsaturated fatty acids (PUFAs), found in oils like safflower, tea, olive, sunflower, corn, and soybean oils, also influence immunity. [9]

PUFAs are classified into two main types: Omega-3 and Omega-6. Both play roles in immune regulation. Omega-3, in particular, exerts anti-inflammatory effects by inhibiting arachidonic acid (ARA) in cell membranes.
Omega-3 can suppress natural killer cell activity and lymphocyte proliferation, while also reducing levels of IL-6, IL-2, and TNF-α.

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Food as Medicine
Given the close relationship between nutrients in food and the immune system, and with the recent rise of immunotherapy, scientists are exploring its application beyond cancer treatment. A primary target is obesity, one of today’s most pressing global health issues.

At Washington University School of Medicine in St. Louis, immunologist Steven Van Dyken and his team studied a dietary fiber called chitin (also known as chitosan), which can activate type 2 immune responses. They aimed to investigate the metabolic effects of a chitin-rich diet. [10]

When laboratory mice were fed such a diet, the team observed that their stomachs expanded more rapidly compared to mice on a normal diet. This triggered a type 2 immune response, promoting the production of an enzyme capable of digesting chitin. Through genetic engineering, the researchers prevented some mice from producing this enzyme. When fed a chitin-rich diet, these modified mice gained less weight, had lower body fat, and displayed higher insulin sensitivity compared to normal mice. Moreover, chitin increased levels of glucagon-like peptide-1 (GLP-1), which helps suppress appetite. Van Dyken's findings open up new possibilities for developing appetite-suppressing drugs and obesity treatments.

In addition to obesity, autoimmune diseases might also benefit from dietary interventions. For example, the autoimmune disease psoriasis is more prevalent among obese individuals, who are two to three times more likely to develop the condition than those with a normal weight. At Emory University School of Medicine in Atlanta, Georgia, immunologist Chaoran Li and his team investigated the connection between high-fat diets, obesity, and the skin immune system. [11]

Using RNA sequencing, they analyzed skin immune cells in lean mice and identified a specific group of T cells capable of suppressing inflammation associated with psoriasis. However, in obese mice, the same T cell population was significantly reduced, leading to heightened psoriasis-related inflammation. While the study primarily focused on the cellular mechanisms underlying the disease, the team hopes their findings will guide the design and implementation of new therapeutic strategies.


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The Hunger Games of the Immune System
If improving dietary content can enhance the immune system and boost the efficacy of immunotherapy, could changing dietary habits also aid in disease treatment? The scientific community remains divided on this question.

In contrast to the health risks of overeating, fasting has gained popularity in recent years for its potential health benefits. Increasing evidence suggests that fasting can reduce the risk of various diseases, including hypertension, atherosclerosis, diabetes, and asthma.

In some cases, fasting exerts its positive effects through the immune system. In 2019, a study by Stefan Jordan’s team from the Icahn School of Medicine at Mount Sinai, published in Cell [12], demonstrated that fasting reduces the number of circulating monocytes (a type of white blood cell in the immune system) in healthy humans and mice. This decrease lowers the metabolic and inflammatory activity of monocytes, improving inflammation-related diseases without compromising antimicrobial immunity. Similarly, a 2023 study published in Immunity and Aging [13] showed that short-term intensified fasting, commonly known as "Qi-cleansing," activates the complement system on red blood cell membranes. This enhances immune responses against pathogens without impairing oxygen transport or cell longevity.

However, some research suggests fasting may weaken immune responses in specific situations. A 2023 study published in Immunity by Filip Swirski’s team, also from the Icahn School of Medicine, found that fasting reduced circulating monocytes in mice by 90% [14]. This was because monocytes retreated to their "birthplace," the bone marrow, where they entered a state of dormancy to conserve energy and prolong their lifespan [15]. Swirski concluded that when fasting depletes the body's energy reserves, it preserves monocytes as a protective mechanism. However, prolonged fasting may cause more harm than good. Additionally, after 24 hours of fasting, refeeding caused an abnormal surge of monocytes into the bloodstream, potentially leading to monocytosis—a condition linked to infectious and autoimmune diseases. The study highlights the risks of excessive or prolonged fasting.

Taking a different approach, Francesco Siracusa, an immunologist at the University Medical Center Hamburg-Eppendorf in Germany, investigated the effects of cyclic dietary changes on immune function [16]. His team subjected mice to a three-day cycle of low-fiber, high-fat indulgent meals followed by three days of normal diet, repeating the pattern. They found that just three days of high-fat eating suppressed the mice’s immune systems, making them more susceptible to bacterial infections. The number and functionality of T cells decreased, while a lack of fiber disrupted gut microbiota. These rapid shifts in nutrient intake temporarily weakened both mucosal and systemic immunity, providing an opening for pathogens.

“What surprised me,” Siracusa noted, “was how significantly immune system cells were affected by just three days of dietary change.”


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Human Trials Still to be Explored
Currently, the findings mentioned above mainly come from experimental observations in model animals, and it is quite challenging to confirm whether the same effects occur in humans. First, there is the difficulty of precisely controlling the diets of study participants over a long period of time, as they may sometimes consume foods outside the scope of the research. Additionally, getting participants to accurately recall and record their daily diets is also a significant challenge.

For over a decade, Kevin D. Hall, a physiologist at the US National Institute of Diabetes and Digestive and Kidney Diseases, has focused on the impact of different diets on metabolism and body composition. In 2024, he collaborated with Yasmine Belkaid, who is now the Director of the Pasteur Institute in Paris, and other researchers to publish a paper on the effects of different diets on the immune system [17]. The team recruited 20 adults who were hospitalized for four weeks. After randomizing the participants, they followed strict ketogenic or plant-based, low-fat diets for the first two weeks, followed by alternative diets in the last two weeks. Blood samples were collected to analyze the relationship between different diets, immune cell counts, and gene activation changes. The results showed that participants on the ketogenic diet had higher levels of T and B cells, with enhanced activity that helped recognize specific "foreign invaders" through a more targeted immune response. In contrast, vegans had enhanced innate immunity, but with lower specificity. Belkaid was pleased with the clear results and the clinical potential but, given the differences in age, genetics, and weight between individuals, she refrained from providing dietary recommendations based on these findings. However, she added, "The next step is to test the impact of dietary interventions on specific diseases in clinical trials" [4].

Other teams have already undertaken similar preliminary studies. A 2018 study published in Diabetic Medicine explored the effects of the ketogenic diet on adults with type 1 diabetes [18], proving for the first time that a ketogenic diet is associated with smaller changes in blood sugar levels, but it may also be linked to lipid abnormalities and frequent hypoglycemia. A 2020 paper published in the Journal of Proteome [19] indicated that a low-calorie ketogenic diet could effectively improve metabolic disorders associated with psoriasis, correcting overall metabolic and inflammatory states. This suggests that a low-calorie ketogenic diet could serve as an adjunctive treatment strategy.

In addition to diabetes and psoriasis, a 2021 paper from a team at the National Cancer Institute, published in Science [20], revealed that melanoma patients with high dietary fiber intake had better responses to checkpoint inhibitor immunotherapy, leading to higher survival rates. Moreover, melanoma mice on a low-fiber diet had fewer cytotoxic T cells near their tumors, making it harder to attack the cancer cells effectively.

In fact, thoroughly understanding the effects of specific diets on the immune systems of individuals with different health conditions still requires much more exploration. However, more and more immunologists are joining this field, and most are optimistic. Each new mechanism or insight discovered by scientists is bringing us closer to personalized dietary recommendations for disease management. Perhaps in the near future, we will have health nutrition advice backed by solid scientific evidence, continually strengthening our immune defenses while holding great clinical potential.

References:

[1]https://www.sciencedirect.com/science/article/abs/pii/S0022316623048253

[2]https://yizhe.dmu.edu.cn/article/doi/10.12014/j.issn.1002-0772.2023.17.16?viewType=HTML

[3]https://www.nejm.org/doi/abs/10.1056/NEJM194112252252617

[4]https://www.nature.com/articles/d41586-024-03334-0

[5]https://scitechdaily.com/this-simple-change-to-your-diet-could-significantly-improve-nutrient-intake-and-health/

[6]https://pmc.ncbi.nlm.nih.gov/articles/PMC9772031/#S1

[7]https://zh.wikipedia.org/wiki/NF-%CE%BAB

[8]https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2022.1057546/full

[9]https://www.cdctj.com.cn/system/2020/12/24/030041622.shtml

[10]https://www.science.org/doi/10.1126/science.add5649

[11]https://www.cell.com/immunity/fulltext/S1074-7613(23)00278-9?_returnURL=https%3A%2F%2Flinkinghub.elsevier.com%2Fretrieve%2Fpii%2FS1074761323002789%3Fshowall%3Dtrue

[12]https://www.cell.com/cell/fulltext/S0092-8674(19)30850-5?_returnURL=https%3A%2F%2Flinkinghub.elsevier.com%2Fretrieve%2Fpii%2FS0092867419308505%3Fshowall%3Dtrue

[13]https://immunityageing.biomedcentral.com/articles/10.1186/s12979-023-00359-3

[14]https://www.cell.com/immunity/fulltext/S1074-7613(23)00036-5?_returnURL=https%3A%2F%2Flinkinghub.elsevier.com%2Fretrieve%2Fpii%2FS1074761323000365%3Fshowall%3Dtrue

[15]https://www.nature.com/articles/s41423-023-01033-w

[16]https://www.nature.com/articles/s41590-023-01587-x

[17]https://www.nature.com/articles/s41591-023-02761-2

[18]https://onlinelibrary.wiley.com/doi/abs/10.1111/dme.13663

[19]https://pubs.acs.org/doi/10.1021/acs.jproteome.0c00646