A little change on the table may enhance your immunity

Sometimes, food is also medicine, and more and more clinical trials are showing the benefits of dietary interventions on health. Traditionally, nutrition scientists have often studied the long-term effects of broad Mediterranean or Western diets on population health; in the past five years, they have developed innovative nutritional immunology methods that can focus on the short-term effects of narrower food categories and specific dietary components, and explore the molecular mechanisms of food's effects on immunity.

Scientists still have a long way to go to fully understand how specific diets affect different people's immune systems, but many of them are hopeful.

Compiled by Xiaoye

As the saying goes: Diseases come from the mouth, which not only warns people to pay attention to dietary hygiene, but also contains another meaning: many diseases are related to our diet. Conversely, it can also show that improving one's eating habits may help prevent and fight diseases.

On the other hand, our bodies are naturally equipped with a complete disease defense and fighting mechanism - the immune system. Therefore, scientists strive to link diet, immunity and health and conduct interdisciplinary research. Some researchers believe that modern diet, especially Western eating habits, has weakened immunity and needs to be changed. Other optimistic scientists say that diet can help treat a series of health problems, including cancer, metabolic disorders and autoimmune diseases.

The development of nutritional immunology

Nutritional immunology, which studies the relationship between food and the immune system, is gaining momentum. As a branch of immunology, it is an ancient yet emerging field. It can be traced back to the documents of many ancient civilizations in the East and the West, which record simple observations about food, health, and disease. The ancient Greek physician Hippocrates advocated that the main causes of human disease are environmental factors, diet, and living habits, so he gave clear guidance, saying that physicians must carefully evaluate dietary habits to better understand diseases [1]. Chinese archaeologists have identified oracle inscriptions about diet and disease from ancient oracle bone rubbings unearthed, which to a certain extent reflects the level of understanding of the relationship between diet and disease in ancient times, and that people consciously chose certain foods for disease treatment and health preservation [2].

However, direct scientific evidence of the effects of food nutrition on immune function did not appear until the 19th century. In 1810, British physician JF Menkel first described the problem of thymus atrophy in malnourished people, linking the two aspects and establishing the prototype of nutritional immunology from a scientific perspective [1]. Nearly a century later, in the early 20th century, German physician Paul Ehrlich developed the basic concepts of immunology, and another German physiologist Max Rubner clearly defined the basic laws of energy consumption and metabolism in nutrition [1]. In the 1920s and 1930s, with the discovery of vitamins and the increasing understanding of nutrients, American doctors David Perla and Jessie Marmorston jointly published the book Natural Resistance and Clinical Medicine in 1941 [3]. The content covers the immune system and other host defense mechanisms, and reviews the role of protein, energy, vitamins and minerals in the body's resistance mechanism. It can be said that it became an important reference book for immune nutrition at the time.

However, with the outbreak of the World War, nutritional immunology stagnated for a time. It was not until the 1960s and early 1970s that the field experienced a revival. Under the impetus of the World Health Organization, many scientists devoted themselves to research. Both individuals and research teams from India, Thailand, South Africa, Nigeria, and several research institutions in the United Kingdom and the United States have made great contributions to the progress of nutritional immunology. Abraham E. Axelrod of the University of Pittsburgh has long been committed to the effects of vitamins on the immune system. At that time, most basic research focused on the effects of protein-energy malnutrition and iron deficiency (or excess) on the immune system and other host defense mechanisms, while clinical nutritional immunology progress included the introduction of new surgical techniques to provide parenteral nutrition to malnourished patients. Various international conferences on nutritional immunology, the publication of related academic books and journals, and the establishment of the International Nutritional Immunology Organization have also injected a "boost" into the development of this discipline [1].

After more than half a century of development, after entering the 21st century, with the emergence and development of various emerging biotechnologies and tools, scientists have pioneered new nutritional immunology methods, dedicated to clarifying the specific effects of food on immunity. For example, nutritionists have traditionally studied the long-term effects of vaguely defined Mediterranean or Western diets. Today, with the popularization of various "omics" technologies, researchers are able to classify and analyze complete biological molecular species in cell nuclear tissues, such as genes and proteins, to reveal the beneficial and harmful effects of different food categories and specific dietary ingredients in the short term, in order to explore the molecular mechanisms by which food affects immunity and health [4].

Nutrients that affect the immune system

So, after nutritional immunology has developed for so long in the context of modern science, what nutritional elements have scientists found that can affect the immune system?

As we all know, the normal standard human diet includes vegetables, eggs, milk, dairy products and meat. These foods can be converted into micronutrients and macronutrients in the body to ensure the normal functioning of the body. For example, a new study published at the 2024 Food and Nutrition Conference and Expo (FNCE) showed [5] that increasing the intake of beans and soy products can improve malnutrition and improve the quality of diet among American adults. Beans and soy products are excellent sources of fiber, folic acid and potassium, and plant protein. They also provide iron and zinc. These nutrients are precisely important elements for regulating immune responses, providing sufficient nutrition for immune cells, thereby launching a powerful counterattack when facing pathogen invasion.

Diagram showing the relationship between nutrients and the immune system | Source: Paper [6]

Specifically, different nutrients participate in different biochemical reactions in the body and regulate the immune system. For example, as shown in the figure above, macronutrients such as arginine and tryptophan participate in cell proliferation and various biological activities of macrophages. Macrophages are an important part of the human innate immune system and can identify, engulf, and eliminate pathogenic bacteria, parasites, and foreign pathogens. Arginine helps macrophages produce nitric oxide, which is then determined by the action of nitric oxide synthase. The nitric oxide produced determines the cytotoxicity of macrophages when fighting pathogenic bacteria, parasites, and other antigens. Tryptophan is necessary for protein synthesis and regulates the anti-inflammatory activity of macrophages through initiation factors [6].

Micronutrients such as vitamin A and zinc have more diverse functions. They not only promote cell proliferation, but also help inhibit the nuclear factor-kappa light-chain enhancer of activated B cells (NF-kB) pathway, which is associated with inflammation, autoimmune diseases, viral interference, immune development abnormalities, cancer, etc. [7]. In addition, they can reduce the proinflammatory cytokines IL-1β and tumor necrosis factor-α (TNF-α), regulate the differentiation of helper T cells 17 and helper T cells 19, and initiate the growth of regulatory T cell populations. In addition to vitamin A, B vitamins, vitamin C, and vitamin D all contribute to the anti-inflammatory effect in the body.

In addition, we are all familiar with cholesterol. When we hear this word, we may immediately associate it with a series of health risks such as heart disease, high blood pressure, and diabetes. However, cholesterol-rich lipid rafts can recruit receptors and signal transduction molecules, which are crucial for the formation of immune synapses and the triggering of immune responses. However, excessive cholesterol concentrations can in turn have a negative impact on immune responses[8].

Finally, we need to mention polyunsaturated fatty acids, which are mostly found in safflower oil, tea oil, olive oil, sunflower oil, corn oil, soybean oil, etc. [9]. These fatty acids are mainly divided into two categories: Omega-3 and Omega-6. Both are involved in immune regulation, among which Omega-3 participates in anti-inflammatory effects by inhibiting arachidonic acid (ARA) in the cell membrane. They can block the activity of natural killer cells and lymphocyte proliferation to exert anti-inflammatory effects, and can also inhibit IL-6, IL-2 and TNF-α6.

Food is the cure

Source: Pixabay

Since the nutrients in food are closely related to the immune system, and with the rise of immunotherapy in recent years, scientists hope to expand immunotherapy to areas beyond cancer. The first to bear the brunt is the most pressing health problem plaguing the world today: obesity. Here, Steven Van Dyken, an immunologist at Washington University School of Medicine in St. Louis, and his team have observed that a dietary fiber called chitin (also known as chitosan) can activate type 2 immune response, so they want to continue to explore the impact of a diet rich in chitin on metabolism [10].

After arranging such a diet for laboratory mice, the team observed that the stomachs of these mice stretched faster than those of mice on a normal diet, which activated the type 2 immune response and prompted the production of an enzyme that can digest chitin. Subsequently, the team genetically engineered the mice to be unable to produce this enzyme. After feeding them a chitin-rich diet, they gained less weight, had less body fat, and were more insulin sensitive than normal mice. In addition, chitin can increase the level of glucagon-like peptide-1 (GLP-1), which helps to further suppress appetite. The research of Van Dyken's team provides new ideas for the development of appetite suppressant drugs and obesity treatments.

In addition to obesity, autoimmune diseases may also be improved through diet therapy. Take psoriasis, an autoimmune disease, for example. The prevalence of psoriasis in obese people is two to three times that of non-obese people. Therefore, Chaoran Li, an immunologist at Emory University School of Medicine in Atlanta, Georgia, and his team wanted to understand the relationship between high-fat diet, obesity, and the skin immune system [11]. They used RNA sequencing technology to analyze skin immune cells in lean mice and found a type of T cell population that can inhibit the inflammation caused by psoriasis. However, in obese mice, the researchers found that the level of the same T cell population was low, followed by an increase in psoriasis inflammation. This study focuses on the cellular basis mechanisms involved in the disease, but the team also hopes to provide reference significance for the design and practice of treatment methods.

The Hunger Games of the Immune System

If improving diet can strengthen the immune system and make immunotherapy more effective, then can changing eating habits also help treat diseases? There is no consensus in the academic community.

The opposite of overeating, which is harmful to health, is fasting. In recent years, different types of fasting have become increasingly popular due to their potential health benefits. More and more research evidence shows that fasting can reduce the risk of a variety of diseases such as high blood pressure, atherosclerosis, diabetes and asthma.

In some cases, fasting can have beneficial effects through the immune system. In 2019, Stefan Jordan's team from the Department of Oncology at the Icahn School of Medicine at Mount Sinai published an article in Cell[12], stating that fasting can reduce the number of circulating monocytes (a type of white blood cell in the human immune system) in healthy humans and mice, reduce the metabolism and inflammatory activity of monocytes, thereby improving inflammatory diseases without impairing antimicrobial immunity. A study published in Immunity and Aging in 2023[13] showed that short-term intensive fasting, also commonly known as fasting, can activate the complement system through complement receptors on the red blood cell membrane, allowing red blood cells to continue to function and enhance the immune response against pathogens without damaging their oxygen transport capacity and survival.

However, there is also research evidence that fasting may weaken the immune response in some cases. In a study published in the journal Immunity in 2023, immunologist Filip Swirski's team from the Icahn School of Medicine at Mount Sinai found that the number of monocytes circulating in the blood of fasting mice decreased by 90% [14]. The reason is that during fasting, monocytes migrate back to their "birthplace" - the bone marrow, where they "hibernate" to extend their lifespan and save energy [15]. Therefore, Swirski believes that when fasting causes the body's energy reserves to be low, the body will retain monocytes as a protective mechanism. If the fasting is extended afterwards, the damage may outweigh the benefits. In addition, when mice eat again after fasting for 24 hours, monocytes will abnormally flow into the blood, causing mononucleosis, which is usually associated with infectious diseases and autoimmune diseases. Therefore, one of the purposes of this study is to tell everyone not to fast excessively or for a long time.

Francesco Siracusa, an immunologist at the University Medical Center Hamburg-Eppendorf in Hamburg, Germany, took a different approach and explored the effects of diet on immunity by constantly changing the diet [16]. His team had mice eat a low-fiber, high-fat indulgence for three days, then returned to a normal diet for three days, and then continued to overeat for three days, and so on. The results showed that a high-fat diet of just three days suppressed the immunity of mice, making them more susceptible to bacterial infection. At the same time, the number of T cells in the body was reduced and their function was weakened. Lack of fiber can damage the intestinal microbiota. In short, drastic changes in nutrient intake in the short term can lead to a temporary decrease in mucosal immunity and systemic immunity, creating opportunities for pathogen infection.

"What surprised me was that just three days of changing the diet was enough to see a significant effect on immune system cells," Siracusa said.

Human trials are yet to be explored

At present, the above findings mainly come from experimental observations of model animals. It is quite difficult to determine whether the same situation occurs in humans. First of all, it is challenging to accurately control the diet of research participants over a long period of time, because they sometimes eat other foods that are not within the scope of the study. In addition, it is not easy to get participants to accurately recall and record their daily diet.

For more than a decade, Kevin D. Hall, a physiologist at the US National Institute of Diabetes and Digestive and Kidney Diseases, has been focusing on the effects of different diets on metabolism and body composition. In 2024, he collaborated with researchers such as Yasmine Belkaid, now director of the Pasteur Institute in Paris, to publish a paper reporting the effects of different diets on the immune system.[17] The team recruited 20 adults to be hospitalized for four weeks. After randomization, they strictly followed a ketogenic diet or a vegan, low-fat diet for the first two weeks, and adopted an alternative diet for the last two weeks. Blood samples were then taken to analyze the relationship between different diets and changes in the number of different immune cells and gene activation. The results showed that participants who followed a ketogenic diet had increased levels of T cells and B cells, and enhanced activity, which helped to identify specific "foreign enemies" with precise immune responses, while vegans had enhanced innate immune responses, but with low specificity. Belkaid was delighted to see such obvious results and was delighted with its clinical potential. However, given the differences in age, genetics, and weight among individuals, she did not provide corresponding dietary recommendations based on these results. However, it states: “The next step is to test the effects of dietary interventions on specific diseases in clinical trials.”[4]

However, other teams have already conducted such preliminary research: a study published in the journal Diabetic Medicine in 2018 explored the effects of a ketogenic diet on the health of adults with type 1 diabetes [18], proving for the first time that a ketogenic diet is associated with smaller changes in blood sugar, but it may also be associated with dyslipidemia and frequent hypoglycemia. A paper published in the Journal of Proteome in 2020 showed [19] that a nutritional regimen based on a low-calorie ketogenic diet for patients with psoriasis can effectively improve disease-related metabolic disorders and correct overall metabolic conditions and inflammatory states, indicating that a low-calorie ketogenic diet has the potential to be used as an adjuvant treatment strategy.

In addition to diabetes and psoriasis, a team from the National Cancer Institute of the National Institutes of Health (NIH) published a paper in the journal Science in 2021 [20], revealing that melanoma patients with high dietary fiber intake have a better response to checkpoint inhibitor immunotherapy and therefore have a higher survival rate. In addition, the number of cytotoxic T cells near the tumor in melanoma mice that were fed a low-fiber diet was also relatively small, and they were unable to effectively attack tumor cells.

In fact, scientists still have a long way to go to fully clarify the impact of specific diets on the immune system of people with different health conditions. However, more and more immunologists are now involved, and most of them are optimistic. The new mechanisms and insights discovered by each scientist are moving more and more towards the goal of personalized diet customization for disease care. Perhaps, in the near future, we can all get healthy eating recommendations with more solid scientific evidence, continuously strengthen the body's immune shield, and bring huge clinical potential.

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