The influence of nutrition on the formation and modification of human immunity

INTRODUCTION

The diet provides energy substrates and regulatory factors that influence immune cell function, antibody production, and the immune response. The quality of diet and its role in human health have become topics of scientific research and public interest worldwide. Understanding how nutrition affects immunity has important implications for disease prevention and the­rapy in the context of inflammatory, autoimmune, and infectious conditions [1].
The human immune system is a complex defence system that protects the body against infection and disease. The pace and lifestyle of modern life lead to a weakening of the defence mechanisms due to the following: improper diet and its consequences (e.g. obesity, malnutrition, avitaminosis), chronic sleep deficiency, lack of regular, moderate physical activity, excessive and prolonged alcohol consumption, smoking and drug use.
A diet high in sugar, salt, and highly processed foods, including fried food and refined grains, is associated with higher levels of pro-inflammatory markers. The initiation of inflammation is associated with increased intake of simple carbohydrates with an abnormal ratio of n-3 and n-6 fatty acids, which should be in the range 1 : 4 to 1 : 5. Combinations of products rich in linoleic acid and carbohydrates (with a high glycemic index) are considered unfavourable because insulin-stimulated desaturases catalyse the path of transformation of linoleic acid to pro-inflammatory arachidonic acid. A decrease in anti-inflammatory protective factors is associated with insufficient consumption of n-3 fatty acids and polyphenols [2]. In addition to dietary factors, the environment in which a people live significantly impacts their immunity. People living in cities with high levels of air pollution are more likely to develop respiratory infections. This is due to the damage caused by toxic components of smog to the mucosal barriers of the respiratory system and the weakening of immunity [3].
Another essential factor modifying immunity is the stress accompanying modern living. Short- and long-term, it significantly impedes the destruction of virus-infected cells by lymphocytes. The reason for this is the release of the hormones norepinephrine and cortisol during the stress reaction, inhibiting T lymphocytes.
Immune disorders are particularly common in:
a) people weakened by various chronic diseases (e.g. uncontrolled diabetes, cancer, advanced circulatory failure, severe lung, liver, or kidney disease), b) people taking immunosuppressive drugs (e.g. organ transplant patients and people with autoimmune diseases), c) people who are malnourished (e.g. due to malabsorption, anorexia, or restrictive elimination diets), and d) people after significant surgery.
The prerequisites for improving immunity connected with nutrition are as follows: balanced diet, a predominantly plant-based diet, especially fruit, vegetables, and all kinds of pickles and other fermented products, a diet dominated by plant foods, especially acidic, fresh fruit and vegetables, and all types of pickles and other fermented products, the consumption of probiotic (e.g. yoghurt) and pre­biotic (e.g. chicory, asparagus) products and ingre­dients to strengthen the gastrointestinal microbiome, natu­ral, endogenous opiates, the best known of which are endorphins, which also contribute to reducing the levels of stress hormones, such as cortisol [4].
Plants are source of substances that can influence human immunity through various mechanisms of action. They often contain bioactive constituents such as polyphenols, flavonoids, and saponins that can activate immune cells, especially T and B lymphocytes. These cells are key to the body’s immune response, because T lymphocytes are involved in recognising and fighting infections, while B lymphocytes produce antibodies [5]. Activation of these cells increases their number and activity, which contributes to immune enhancement. Echinacea or ginseng are known to stimulate antibody production by B lymphocytes [6]. Plant stimulants can affect the production of cytokines, which are communication signals between immune cells. Some plant substances, e.g. curcumin or resveratrol, can inhibit the inflammatory process by controlling the production of pro-inflammatory cytokines, which is important in maintaining the balance of the immune system [7]. Selected plant stimulants contain antioxidant components such as vitamin C, vitamin E or beta-carotene, and curcumin (found in turmeric) or flavonoids (found in many fruits and vegetables), and have anti-inflammatory properties to control the severity of inflammation and improve overall immunity. Quercetin (found in onions and apples) may help control allergic reactions by reducing the release of histamine and reducing allergy symptoms. Improving the body’s ability to cope with allergens may enhance immunity [8]. In addition to this, probiotics and pre­biotics found in some plant foods can influence the pro­per functioning of the gut microbiome, which is crucial for immune function. Many plant stimulants contain active ingredients, such as curcumin from turmeric or salicylic acid from willow, which inhibit pro-inflammatory signalling. These substances act on different stages of the inflammatory process, for example inhibiting the activity of enzymes such as cyclooxygenases (COX), which are involved in the production of pro-inflammatory mediators, including prostaglandins. Inhibiting these processes reduces the inflammatory response in the body. Some plant constituents can affect the expression of genes responsible for the production of pro-inflammatory factors such as interleukins and tumour necrosis factor α (TNF-α). For example, resveratrol in red wine is known to inhibit the NF-κB factor, which regulates the expression of many inflammatory genes. Reducing the activity of these transcription factors leads to reduced inflammation [9]. Some plant constituents, such as quercetin or ellagic acid, can affect intracellular signalling in immune cells. These substances can inhibit the activity of protein kinases and transcription factors involved in inflammatory processes, leading to reduced production of inflammatory mediators. The mechanism of anti-inflammatory action of some plant stimulators includes inhibition of pro-inflammatory signalling, regulation of transcription factors, antioxidant activity, and regulation of signalling in immune cells [10].
The aim of this study is to review the available scientific research and literature in medicine, nutrition, and immunology for understanding the effects of diet and nutrients on immune system function.

METHODS

Scientific journals were handpicked online using the keywords plant immunomodulators, immunosti­mulatory drugs, immunostimulatory plants, immunosuppressive drugs, and plants as immunomodulators from the Scopus, PubMed, Google Scholar, and ScienceDirect databases. Sources published in reputable scientific journals and peer-reviewed books were selected. Publications from 2001 to 2023 covering clinical, observational, and effects of dietary components on the immune system were included in the analysis. The quality and reliability of the selected literature sources were assessed. Attention was paid to the study methodology, sample size, control of confounding factors, and the authors’ results and conclusions. Based on the titles and abstracts, articles not related to above mentioned criteria were excluded, and the remaining original and review works were subjected to intensive analysis to select the most relevant publications. All selected articles also had their bibliographies reviewed to identify other potentially useful texts. The search was narrowed to articles published between 2001 and 2023. Finally, a total of 1160 publications were reviewed, of which 69 were used (Diagram 1).

MACRONUTRIENTS AND MICRONUTRIENTS IN DIET

Human immunity is a complex defence system that protects against infection and disease. A key factor influencing the body’s ability to fight pathogens is the spectrum of macronutrients and micronutrients provided by the diet. Nutrients, such as proteins, carbohydrates, and fats, are essential for the functioning of the immune system. Proteins are needed to produce antibodies, which are the body’s key defence factors. Carbohydrates are the primary source of energy for immune system cells, especially lymphocytes. Fats are not only a source of energy but also transport some fat-soluble vitamins important for immune function.

MACRONUTRIENTS

– Proteins play a crucial role in constructing antibodies, enzymes, and other immune proteins. Immune cells, such as lymphocytes, macrophages, and neutrophils, are made up of proteins. Protein deficiency can lead to a weakened immune system [11].
– Carbohydrates are the primary source of energy for immune cells. T lymphocytes, key players in the immune response, use glucose as an energy source for their functions. An adequate amount of carbohydrates is essential to maintain the immune system’s effectiveness [11].
– Fats: adequate fat is essential for the transport and absorption of specific vitamins, such as vitamins A, D, E, and K, which are key to immune function. Fats, especially unsaturated fatty acids, can also have anti-inflammatory effects and influence the regulation of the immune response [11].
Micronutrients:
– Zinc is essential for the proper functioning of immune cells. It is involved in antibody production, phagocytosis, and lymphocyte activation. Zinc deficiency can impair the body’s ability to fight infections [11].
– Selenium plays an important role in the body’s anti­oxidant defence mechanisms. It helps to protect immune cells from oxidative damage and supports antibody function [11].
– Iron is essential for producing haemoglobin, which carries oxygen in the blood. Adequate oxygen is crucial for immune system function. Iron deficiency can lead to anaemia, which impairs the body’s ability to fight infections [11].
– Copper helps to maintain the proper functioning of the immune system because it is involved in the production of antibodies and is involved in enzymatic reactions important for immune health [11].
Macronutrients and micronutrients play a significant role in the functioning of the human immune system. An adequate diet that provides sufficient nutrients is crucial for maintaining a strong and effective immune system. On the contrary, deficiencies in these nutrients can lead to a weakened immune system and increased susceptibility to infection. Therefore, a diet rich in diverse sources of macronutrients and micronutrients is an essential aspect of health care and preventive health care [12].

VITAMINS AND ANTIOXIDANTS

Vitamins and antioxidants play critical roles in maintaining and regulating this immunity.
– Vitamin C is a powerful antioxidant that is key in protecting immune cells from oxidative damage. It helps in the production and function of immune proteins, such as antibodies. It also enhances the body’s ability to fight infection by strengthening defence mechanisms, and it helps wounds and inflammation to heal faster [13].
– Vitamin D is essential for the proper functioning of the immune system. It helps activate T lymphocytes, key players in the immune response. Its deficiency can lead to a weakened immune system and an increased risk of infection. Therefore, vitamin D supplementation may be beneficial, especially during exposure to diseases [14].
– Vitamin E (tocopherol) is an antioxidant, protecting immune cells from oxidative damage. It helps to maintain the integrity of cell membranes. It may improve the immune system’s efficiency by protecting immune cells from damage [15].
– Beta-carotene is a precursor to vitamin A, essential for immune function. It also acts as an antioxidant, protecting cells from oxidative damage. Consuming sources of -carotene, such as carrots and sweet potatoes, can support the body’s ability to fight infection [16].
– Flavonoids and other antioxidants, such as lycopene and resveratrol, neutralize free radicals that can damage cells. A diet rich in sources of flavonoids, such as fruit and vegetables, can boost immunity by protecting immune cells from oxidative damage [17]. Vitamins and antioxidants play critical roles in regulating and strengthening human immunity. It is worthwhile to ensure a balanced diet that provides adequate amounts of these nutrients to maintain the immune system’s effectiveness and increase the body’s ability to defend itself against infection and disease. However, vitamin and antioxidant supplementation should be used in moderation and with constant consultation with a doctor or nutritionist [18].

THE GUT MICROBIOTA

The gut microbiota, a complex community of microorganisms living in the gut, plays a crucial role in regu­lating immune processes. Diet influences the composition of the gut microbiota. Consumption of dietary fibre, probiotics, and prebiotics can support the growth of beneficial gut microbes, increasing the body’s ability to fight infections. The gut microbiota is essential during the first years of life when the immune system is in a developmental phase. Through exposure to various microorganisms, the microbiota helps shape immune responses, which is essential for later immunity. It also acts as a specific antiviral and antimicrobial barrier. The ability of microorganisms to compete with pathogenic bacteria and viruses in the gastrointestinal tract helps protect the body from infection. The microbiota influences the regulation of immune responses. It can have an anti-inflammatory effect. The gut microbiota produces metabolites, such as butyric acid, influencing immune system function. The gut microbiota helps maintain immune homeostasis, i.e. the balance between immune responses to foreign substances and tolerance towards one’s tissues. The mechanism of action of Lactobacillus and Bifidobacterium on the immune system is based on stimulation of T lymphocytes, increased expression of receptors involved in phagocytosis (CR1, CR3, FccRI, FcaR), effects on oxidative stress, and bactericidal properties of neutrophils. Additionally, these strains increase the synthesis of sIgA (secretory immunoglobulin A) and IgG (immunoglobulin G) and modulate the production of the cytokines IL-1, IL-2, IL-6, IL-10, IL-12, IL-18, TNF-α, INF-γ and INF-α [19].
Probiotics also play an important role in maintaining Th1/Th2 cytokine balance and thus may have a beneficial effect on inflammatory and allergic reactions. In the case of allergic reactions, a dose-dependent reduction in the secretion of Th2 cytokines (IL-4, IL-5, IL-13) and an increase in the secretion of INF-γ by Th1 lymphocytes and IL-10 by regulatory T cells are observed in the case of allergic reactions [20]. Abnormalities in the gut microbiota can lead to the development of allergies and autoimmune diseases. There is evidence that the micro­biota composition can influence the outcome of allergic reactions and autoimmune pathologies. Research into microbiota therapy, i.e. manipulation of the gut microbiota, is showing increasing promise for treating some autoimmune diseases and infections. Diet plays a crucial role in shaping the gut microbiota. Consuming fibre, probiotics, and prebiotics can help maintain a healthy microbiota. It has a significant impact on human immunity. Its role is not just limited to digestion but also includes a complex involvement in regulating the immune system. Understanding this complex relationship can lead to better use of the gut microbiota to improve human health and immunity. Research into this issue continues to be intensive, and discoveries may yield new strategies for of treating and preventing many diseases.
Nutritional sources of probiotic bacteria refer to the dietary substances that support the growth and maintenance of beneficial bacteria in the gastrointestinal tract. These sources typically include the following:
• fermented foods: foods like yogurt, kefir, sauerkraut, kimchi, and kombucha are rich in probiotic bacteria due to the fermentation process;
• prebiotics: these are non-digestible dietary fibres that serve as food for probiotic bacteria; examples include inulin, fructooligosaccharides (FOS), and galacto­oligo­saccharides (GOS), which can be found in foods like garlic, onions, leeks, and bananas;
• high-fibre foods: fibre-rich foods such as whole grains, legumes, and certain vegetables (e.g. artichokes) provide a suitable environment for probiotic bacteria to thrive;
• dairy products: as well as yogurt and kefir, other dairy products like buttermilk and some types of cheese can also contain probiotic strains;
• supplements: probiotic supplements are available in various forms, such as capsules, powders, and liquid formulations. These supplements provide concentrated doses of specific probiotic strains;
• fermentation co-factors: certain substances like calcium, magnesium, and various vitamins can enhance the growth and activity of probiotic bacteria during fermentation processes;
• herbal and plant extracts: some plant extracts and herbal supplements, like green tea extracts, may have prebiotic properties that support probiotic bacteria.
It is essential to maintain a balanced diet rich in these nutritional sources to promote the growth and diversity of probiotic bacteria in the gut, which can have positive effects on digestive health and overall well-being [21-27].

MEDITERRANEAN DIET

Research suggests that the Mediterranean diet has a significant impact on human immunity. It is a type of dietary lifestyle characterized by an abundance of fruit and vegetables, fish, and vegetable fats, as well as moderate consumption of red meat and low amounts of processed foods. This diet is rich in fruits, vegetables, and nuts, which are sources of natural antioxidants such as vitamin C, vitamin E, and β-carotene. These substances help fight excess free radicals and protect cells from oxidative damage, which can improve immune function. The Mediterranean diet is dominated by unsaturated fats, especially omega-3 fatty acids, which have anti-inflammatory properties and can help reduce inflammation that weakens immunity. Fish consumption, which is common in the Mediterranean diet, provides valuable sources of protein and omega-3 fatty acids. These substances can support antibody production and immune cell function. The presence of fibre in the Mediterranean diet promotes healthy gut micro­biota. A balanced microbiota is essential for regulating the immune system, and fibre can act as a prebiotic, supporting the growth of beneficial bacteria. The Mediterranean diet is often associated with a healthy lifestyle, including physical activity and eating in pleasant company. Reducing stress and taking care of overall mental well-being can boost immunity. The Mediterranean diet promotes regular and moderate meal consumption and reduced snacking, which can influence the maintenance of a healthy body weight, which is important for immune function. Research into the effects of the Medi­terranean diet on immunity is still ongoing. Still, there is a wealth of evidence to suggest that this dietary style may help to strengthen the immune system [28]. However, it is worth noting that diet is not the only factor influencing immunity, and a healthy lifestyle in general, including physical activity and avoidance of excessive stress, also plays a crucial role in keeping immunity at an adequate level.

BIOLOGICAL RESPONSE MODIFIERS

In some cases, particularly with nutrient deficiencies or during periods of increased pathogen activity, dietary supplements may be indicated [29]. However, supplementation should always be consulted with a doctor or nutritionist to avoid overconsumption or interactions between supplements and medications. Among the key modifiers of the immune response are plant immunostimulants known as biological response modifiers (BMRs) [29]. Polysaccharides, glycoproteins, polyphenols, alkaloids, or quinolines are responsible for the immunomodulatory properties of plants.
>Aloe vera. Natural medicine values the species most highly: Aloe arborescens (tree aloe), Aloe vera (common aloe), and Aloe xerox (spiny aloe) [29].These succulents are the source of gel and yellow-coloured milk, obtained from the leaves’ parenchymal and pericycle cells. Pro­ducts obtained from aloe vera leaves can be used orally and topically. It is known for its antibacterial, anti-inflammatory, analgesic, and immunomodulatory effects. Aloe vera contains many active biological compounds. Among these active substances are B vitamins, C vitamins, folic acid, minerals (Fe, Ca, Mg, Mn, K), salicylic acid, anthraquinones, sterols, saponins, lignins, and enzymes represented by carboxypeptidase, cyclooxygenase, or amylase. Aloe vera also shows high concentrations of polysaccharides, which affect the immune system. The main polysaccharide showing immunomodulatory properties is acemannan [30]. Polysaccharides isolated from Aloe vera support the immune system by affecting the secretion of IL-1, IL-6, TNF-α, and INF-γ, which in turn stimulate fibroblast growth and increase the phagocytosis capacity of macrophages [31]. Glycoproteins are necessary for the immune system, which contain glutamic acid and aspartic acid in the protein parts of the molecules. A lectin P-2 was isolated from Aloe arborescens, which reacts with α2- macroglobulins to activate the C3 component and proactivator of complement. The stimulated C3 component activates B lymphocytes to produce antibodies and stimulates mitotic divisions of B lymphocytes [32]. A strong effect of an orally administered extract on the primary humoral response, in the form of an increase in antibody production, has also been reported [33]. As a biogenic immunomodulator, aloe vera is used in the prevention and treatment of infectious diseases as a normalizer of immune system function.
Another plant used in natural medicine is chokeberry. The ripe fruit is a pharmaceutical and food raw material. The polyphenols in the chokeberry fruit, namely anthocyanins, phenolic acids, and flavonoids, are responsible for its medicinal properties. The chokeberry anthocyanins are mainly cyanidin derivatives: cyanidin-3-O-galactoside, cyanidin-3-O-arabinoside, cyanidin-3-O-xyloside and cyanidin-3-O-glucoside. Their content in the fruit varies from 200 to 1000 mg/100 g of product. Representatives of the plant’s flavonoids are quercetin 3O-quercetin viscyanoside and quercetin 3-O-quercetin robinobioside. Of the phenolic acids, chokeberry contains feluric acid, caffeic acid, chlorogenic acid, and neochlorogenic acid [34]. In addition, chokeberry fruits contain a rich set of vitamins (A, B, C, PP, E) and minerals (Cu, Mn, Ca, Fe), as well as tannins and organic acids [35]. The ripe fruit of black chokeberry is attributed to anti-hepatotoxic, anti-cancer, anti-inflammatory, anti-viral, and anti-bacterial effects [36]. The anti-inflammatory effect is based on blocking the expression of inducible nitric oxide synthase and cyclooxygenase II, leading to the inhibition of the release of pyrogenic PGE2 and nitric oxide. Anthocyanins play a protective role in the inflammatory process by indicating the production of prostacyclin (PGI2) in endothelial cells [37]. In addition, chokeberry anthocya­nins reduce TNF-α activity and inhibit the monocyte chemotactic protein MCP-1 release, resulting in reduced monocyte adhesion to the vascular endothelial surface [38].
A critical plant of medicinal importance is elderberry (Sambucus nigra L.). Elderflowers contain flavonoids such as kaempferol, rutoside, quercetin, isoquercetin, organic acids, triterpenes, and mineral salts (mainly potassium) [39, 40]. Elderberry derivatives are used during colds due to their antipyretic and vasoconstrictor effects. Elderberries, on the other hand, besides flavonoids, are also rich in anthocyanins, among them cyanidin-3-O-glycoside, cyanidin-3-O-5-O-diglycoside, cyanidin-3-O-sambubio­side, and sambucin. Preparations made from Sambuci fructus have antiviral and immunomodulatory properties [41, 42]. Based on the results of in vitro studies, elderberry extracts have been shown to increase the production of cytokines such as IL-1β, IL-6, ILl-8, and TNF-α by bacterial lipopolysaccharide-activated monocytes and inhibit inflammation in a mechanism similar to Aronia melanocarpa anthocyanins [43].
Since ancient times, common garlic (Allium sativum L.) has been used in medicine for its antifungal, antimicrobial, anti-atherosclerotic, anticoagulant, blood pressure and blood sugar lowering, anti-inflammatory, anticancer, and immunomodulatory properties [44, 45]. The most important bioactive garlic substances include organosulphur derivatives such as allicin, diallyl sulphide, diallyl disulphide, and S-allocysteine [46]. Effects on the immune system are manifested by stimulating NK cell activity, enhancing macrophage phagocytosis, and activating lymphocyte responses to myogens and cytokines. Like the aronia and elderberry mentioned earlier, organic sulphur compounds from garlic reduce cyclooxygenase and lipoxygenase activity and nitric oxide synthase expression by macrophages [47]. It was found that an aqueous garlic extract had a positive effect on the intracellular release of the adhesin responsible for leukocyte adhesion ICAM-1 (intercellular adhesion molecule-1) and the vascular factor VCAM-1 (vascular cell adhesion molecule 1) [45]. Garlic compounds show antimicrobial solid properties that include bacteria (Staphy­lococcus, Streptococcus, Salmonella, Escherichia, Klebsiella, Proteus, Helicobacter, Mycobacterium, Clostridium), fungi (Candida albicans, Saccharomyces cere­visiae, Pichia anomala, Hanseniaspora valbyensis, Aspergillus niger), and protozoa (Entamoeba histolytica). Studies conducted to date suggest that the bioactive compound in garlic extracts is allicin, which can penetrate the cell and affect cytoplasmic components and enzymes. In addition to inhibiting the activity of bacterial virulence factors such as proteases, allicin blocks lipid and RNA synthesis in bacteria [47]. In addition, the combination of antibiotic therapy with garlic preparations shows partial or complete synergism in the effects of both substances [48].
Like garlic, a plant with known and long-used medi­cinal properties is ginger (Zingiber officinale Roscoe). It has found use in treating rheumatoid arthritis, sore throat, constipation, indigestion, vomiting, hypertension, fever, infectious diseases, and worms [49]. Ginger contains many biologically active substances. Ginger’s pharmacological effects are attributed to gingerols, which are derivatives of phenols. Among these, [6]-gingerol is the most abundant. During storage and drying of ginger flocs, shogaols, dehydration products of gingerols, are formed. The pharmacological properties of ginger and compounds isolated from it include immunomodulatory, anticancer, anti-inflammatory, anti-inflammatory, anti-inflammatory, and anti-emetic effects. In addition, gingerols have been shown to actively inhibit prostaglandins and leukotrienes of RBL-1 cells, while gingerols with a long alkyl side chain are more potent inhibitors of leukotrienes [49]. Ginger can modulate pathways activated in chronic inflammation. Ginger has been found to inhibit genes involved in the inflammatory response and some genes encoding the enzyme cyclooxygenase-2, cytokines, and chemokines. Gingerols and mainly [8]-paradol inhibit cyclooxygenase-1 more than aspirin. The mechanism of this blockade is based on the carbonyl groups at the C3 position of paradol. It may contribute to the substantial reduction of platelet aggregation and inhibition of COX-1 (cyclooxygenase-1). Gingerol has been shown to inhibit the production of pro-inflammatory cytokines by macrophages selectively and does not affect their antigen presentation function [44]. Ginger and compounds isolated from it have shown the ability to modulate T-lymphocyte proliferation and the cellular immune response. This suggests that ginger extracts may have beneficial effects in treating chronic inflammation and autoimmune diseases [50].
Another plant with beneficial medicinal properties is raspberry (Rubus idaeus L.), which has been used for hundreds of years for its anti-inflammatory, antipyretic, and inflammatory effects. Raspberries are rich in vitamins C, E, B₁, B₂, B₆, and minerals (potassium, calcium, copper, iron, manganese) [51]. In addition, these fruits are a natural source of polyphenols – anthocyanins, phenolic acids, flavones, tannins, and β-sitosterol. The anti-inflammatory effect of Rubus idaeus L. fruit is related to the inhibition of enzymes of the inflammatory process – cyclooxygenase I (COX- 1) and cyclooxygenase II (COX- 2) [52].
Similar properties are found in cranberry fruit. They are a valuable source of vitamins A, C, and E, lutein, and beta-carotene, and rich in minerals such as potassium, sodium, and selenium. The most important group of health-promoting compounds present in cranberry fruit are polyphenols: flavonoids, stilbenes, and phenolic acids. Cranberry juice reduces the number of bacteria during the course of an infection. The antibacterial effect of the treatment is due to the anti-adhesive action of cranberry juice, which involves changing the shape of E. coli bacteria by losing outgrowths that enable them to adhere to the substrate and grow colonies.
The fibre β-glucan contained in cereal products involves repair, detoxification, and metabolic processes. Studies to date have confirmed its ability to increase the body’s resistance to infection and synergize with anti­biotics, and as an adjuvant to anticancer therapy [53].
Citrus fruits are is a rich source of phenolic compounds, vitamins, minerals, essential oils, carotenoids, and fibre. Citrus flavonoids in fruit are present as glycosides and aglycones. Among the flavonoids, juices, and fresh fruit contain hesperidin, neohesperidin, hesperidin, naringenin, naringin, rutin, diosmin, nobilin, quercetin, and apigenin. Apigenin, quercetin, and naringenin, present in lemon fruit, exhibit anti-inflammatory effects, the mechanism of which is based on the inhibition of 5- lipoxygenase and cyclooxygenase-2 activity. By blocking COX-2, these flavonoids reduce the synthesis of PGE2 (prostaglandin 2), LTB4 (leukotriene B4), and TXA2 (thromboxane A2), which consequently inhibits leukocyte influx, regulates capillary tone, and reduces inflammation [54]. Quercetin also reduces the expression of TNF-α and IL-1α. The modulation of NF-κB explains this mechanism in peripheral blood mononuclear cells by quercetin, which in effect inhibits TNF- expression genes [55]. Lemon and other citrus fruits contain the methyl group-rich flavonoid nobiletin. Nobiletin suppresses the production of IL-1 and PGE2 by human synovial membrane cells. In addition, it redu­ces COX-2 expression without affecting COX-1 secretion. Nobiletin also induces the production of the pro-inflammatory cytokines IL-1α, IL-1β, TNF-α, and IL-6 by LPS-induced macrophages. Furthermore, citron essential oils significantly reduce the production of the pro-inflammatory cytokines TNF-α, IL-β, and IL-6 by lipopolysaccharide-stimulated macrophages [55].
The therapeutic properties are demonstrated by bee products. Honey is a bee product made from flower nectar, honeydew, or both. The qualitative and quantitative chemical composition of honey varies greatly and depends, among other things, on the species of plant from which the bees extract nectar or honeydew. Appro­ximately 300 components from different chemical groups have been identified in various types of honey. Organic and 29 inorganic substances include water, monosaccharides and oligosaccharides, polysaccharides, organic acids, globulins, albumins and amino acids, carotenoids, flavonoids, enzymes, as well as vitamins (nicotinic acid, vitamin C and B) and elements (potassium, phosphorus, magnesium, calcium). Research to date shows that bee honey has a beneficial effect on the biochemical and haematological indices of the human body. It improves the functions of the red blood cell system, lipid and carbohydrate metabolism, the cardiovascular and respiratory systems, the kidneys and liver, and the immune system. Liu et al., in a study on the anti-inflammatory properties of multifloral forest honeys, proved that they have a significant effect on IL-8 secretion [56]. Many cell types including monocytes, neutrophils, epithelial cells, fibroblasts, endothelial cells, mesothelial cells, and tumour cells secrete IL-8. The active components of honey are responsible for its immunomodulatory action: royal jelly-1 protein, endotoxins, phenolic acids, flavonoids, and ellagic acid. However, the molecular mechanism of honey’s action is still unclear [56]. Intake of a honey-enriched diet of 2.2 g/kg body weight for a fortnight increased neutrophil, eosinophil, and monocyte pools. Honey also manifested activity in stimulating monocytes to secrete TNF-α, IL-1β, and IL-6. In addition, honey reduces the activity of cyclooxygenases in basophilic granulocytes, leading to a decrease in prostaglandins, which play an important role in allergic reactions [48].
Fatty acids occupy a significant place among immunostimulants. Among essential fatty acids (EFAs), polyunsaturated fatty acids of the n-3 and n-6 family are distinguished. The most important are linoleic acid (LA, n-6) and α-linolenic acid (ALA, n-3), which are not synthesized by the human body and must be supplied externally. Linoleic acid is converted in the body to arachidonic acid (AA) and dihomo-γ-linolenic acid (DGLA, ω-6), while α-linolenic acid is converted to eicosapen­taenoic acid (EPA) and docosahexaenoic acid (DHA). Both transformations involve desaturases and elongases competing with each other for LA and ALA metabolites [57]. From arachidonic acid, prostaglandins and thromboxanes of series 2 and leukotrienes and lipoxins of series 4 are synthesized. Eicosapentaenoic acid is the precursor of prostaglandins and thromboxanes of series 3 and leukotrienes and lipoxins of series 5. In contrast, prostaglandins and thromboxanes of series 1 and leukotrienes and lipoxins of series 3 will be formed from dihomo-γ-linolenic acid. With a high supply of linoleic acid, there is an increase in arachidonic acid, dienes, prostaglandins, and leukotrienes LTB4, LTC4, LTD4, and LTE4. This results in impaired metabolism of the ω-3 series. On the other hand, when α-linolenic acid intake increases, EPA levels in cell membrane phospholipids increase. The result is eicosanoids with weaker chemotactic activity LTB5, PGI3, and TXA3. The competitive use of ω-3 fatty acids in relation to arachidonic acid should reduce inflammation. Synthesis of eicosanoids occurs at the membrane level [58]. Phospholipase A2, which releases arachidonic acid from phospholipids, is involved in their synthesis. Subsequently, prostaglandins and thromboxanes are formed via cyclooxygenases (COX1 and COX2), while leuko­trienes and hydroperoxyeicosatetraenoic (HPETE) and hydroxyeico­satetraenoic (HETE) acids are formed via lipoxyge­nases (LOX). Formed from dihomo-γ-linolenic acid, PGE1 33 causes vasodilation and has anti-inflammatory and anti-aggregation effects. PGE1 causes an increase in intracellular cAMP levels, which contributes to a weaker release of lysosomal enzymes and a reduction in chemotaxis of multinucleated leukocytes. PGE1 also blocks lymphocyte activity. In contrast, 15 HETE is highly active in inhibiting 5-LOX, which is involved in forming the leukotrienes LTB4 and LTC4 from arachidonic acid. Prostaglandin E2 exerts anti-inflammatory effects by blocking lymphocyte proliferation, IL-2 release, and γ-interferon release by Th1 helper lymphocytes. PGE2 also inhibits TNF-α and IL-1β production by macrophages, monocytes, and NK cell activity. PGE3 has similar effects to PGE1. Arachidonic acid-derived leuko­trienes have the strongest pro-inflammatory effects. Leukotriene B4 is the most active factor modulating neutrophil chemotaxis. Leukotrienes C4, D4, and E4 are mediators of inflammatory processes and are involved in allergy. They also belong to the group of slow-acting anaphylaxis (SRS-A) substances. The ultimate response of immune cells depends on the amount of linoleic acid in the diet, the timing of eicosanoid production, and the sensitization of cells to its effects. Quali­tative and quantitative changes in dietary fatty acids affect the composition of fatty acids in the cell membrane and the diversity of eicosanoids formed from arachidonic acid metabolism [59]. Scientific reports suggest that indirect and direct mechanisms that quench inflammation are involved in the area of acute inflammation, in addition to anti-inflammatory cytokines and kinases. Quenching of the inflammatory response can occur passively, i.e. due to reduced activity of pro-inflammatory factors, or actively as a result of activating agonistic anti-inflammatory ‘pro-quenching’ factors. Pro-quenching mediators are synthesized from polyunsaturated fatty acids supplied in the diet, supplemented, and present in the cell membrane. Inflammation-quenching mediators include derivatives of 4 polyunsaturated fatty acids: arachidonic acid (AA; ω-6) lipoxin; eicosapentaenoic acid (EPA; ω-3) resolvin-E; docosahexaenoic acid (DHA; ω-3) resolvin, neuroprotectin, maresin; docosapentaenoic acid ω-6 (DPA-ω-6; ω-6), resolvin oxylipin, and lipoxin. The first group of mediators discovered were lipoxins (LX, LXs), which are arachidonic acid derivatives with anti-inflammatory and immunomodulatory properties [60]. Two lipoxins, LXA4 (5S,6R,15Stri­hydroxy-1,9,13-trans-11-cis-eicosatetraenoic acid) and LXB4 (5S,14R,15S-trihydroxy6,10,12-trans-8-cis-eicosatetraenoic acid), and 2 lipoxin epimers, 15-epi-LXA4 and 15- epi-LXB4, were isolated. Lipoxin A4 and its epimer 15-epi-LXA4 act by activating the ALX membrane receptor, which is present in leukocytes, macrophages, eosinophils, basophils, dendritic cells, fibroblasts, and T lymphocytes. The ALX receptor is cell-specific because the effect of its stimulation varies according to location. Neutrophils show impaired chemotaxis, adhesion, transmigration, and reduced degranulation. In the case of eosi­nophils, migration and degranulation are inhibited, as well as the production of eotaxin and IL-15. Macrophages and monocytes show enhanced chemotaxis and adhesion to laminin and phagocytosis of apoptotic leukocytes, impaired IL-8 release, NF-κB activation, and reactive oxygen radical-nitrite formation. In the case of T lymphocytes, TNF-α secretion is blocked. Dendritic cells release lower amounts of IL-12, and epithelial cells release IL-8, making a distinction between anti-inflammatory and pro-inflammatory effects. In the group of anti-inflammatory effects generated by signals from neutrophils, there would be a reduction in the production of reactive oxygen species, the production of pro-inflammatory cytokines and chemokines, and an increase in the release of anti-inflammatory cytokines and chemo­kines. In contrast, the pro-quenching effects generated by macrophage and monocyte signalling includes increased Ca²⁺ mobilisation, increased adhesion and chemotaxis, and phagocytic activity of macrophages in the area of inflammation [61]. Resolvins are derivatives of eicosapentaenoic acid (E-series resolvins) and docosahexaenoic acid (D-series resolvins). In the group of E-series resolvins, a distinction is made between resolvin E1 (RvE1), i.e. 5S,12R,18R-trihydroxy-6Z,8E, 10E,16Eeicosapentaenoic acid, and the emerging para­llel resolvin E2 (RvE2), i.e. 5S,18Rdihydroxy-eicosapentaenoic acid. The anti-inflammatory action of resolvins is triggered by activating the extinction of the acute inflammatory response. RvE1 and RvE2 lead to the inhibition of infiltration-transendothelial migration of neutrophils to the site of inflammation, stimulate 35 macrophages to phagocytose dying neutrophils, reduce the release of pro-inflammatory cytokines, and promote the inflammation-catabasis or extinction resolution step. Resolvin E1 exerts its effects by stimulating the ChemR23 receptor but can interact with the leukotriene B4 receptor (BLT4 receptor). In contrast, RvE2, which is released in larger quantities by neutrophils, does not stimulate ChemR23. D-series resolvins presumably have a protective effect in oxidative stress-induced inflammation [62]. The beneficial effects of fatty acids of the ω-3 family in maintaining normal brain function have been highlighted for a long time. Hydroxydocosanoids, derivatives of DHA, named protectins, are endowed with these unique properties. Neuroprotectin (NAD1) is synthesized in the CNS, particularly in the retina. The conversion of DHA to NPD1 is probably a response to an inflammatory process or neurodegeneration. Unfortunately, the mechanism of action of neuroprotectin and protectin has not yet been identified. NPD1 and PD1 have been classified as pro-quenching factors in the inflammatory region. Namely, they inhibit the expression of genes encoding pro-inflammatory compounds, e.g. IL-1, COX-2, B94 (a pro-inflammatory element induced by TNF-α), and CEX-1 (a marker of inflammatory response and oxidative stress) [62]. The most recent pro-acute phase inflammation mediator is maresins. Serhan et al. observed that unknown 17S-hydroxyl derivatives of docosahexaenoic acid appeared in the DHA metabolism pathway in addition to the derivatives known so far. The identified compound is maresin (MaR1), a 7S,14S-dihydroxy-docosa4Z,8,10,12,16Z,19Z- hexaenoic acid. The action of MaR1 is multidirectional and leads to a reduction in the accumulation of multi­nucleated leukocytes in the region of inflammation through regulation of the phagocytic capacity of macrophages. MaR1 is another pro-inflammatory factor [63].
The diet’s most important sources of essential fatty acids are vegetable oils and fish fats. Sunflower, soybean, and corn oils are rich in linoleic acid, as well as grape seed oil and cottonseed oil. The primary sources of α-linolenic acid are rapeseed oil, soybean oil, linseed oil, walnut oil, and green vegetables such as spinach, Brussels sprouts, and cabbage. The richest dietary source of ω-3 family acids – EPA and DHA – is the liver and muscles of marine fish, e.g. Atlantic salmon, mackerel, tuna, herring, cod, flounder, and halibut. The microalgae Cryptheocodinum cohnie and Schizochytrium sp. are also sources of DHA. The supply of ω-3 family acids is best supplemented by a diet rich in products containing these acids and by eating fish 1-2 times a week. Many international medical organizations recommend a daily EPA and DHA intake of 400-650 mg/day [64, 65].
Fish fat preparations have been known for many years to be used in treating and preventing many diseases. The first references to the use of shark liver oils in the treatment of infections, hard-to-heal wounds, or general weakness date back to the 11th century in Iceland. The biological activity of shark liver lipids (Centroscymnus crepitater, Etmopterus granulosus, Deania colcea, Centrophorus scalpratus) is related to their content of acylglycerol ethers: diacylglycerols (DAGE), triacylglycerols (TAG), and squalene compounds, as well as docosahexaenoic and eicosapentaenoic acids [66]. 1-O-alkylglycerols (AKGs) are naturally biologically active compounds also found in high amounts in human milk, liver, spleen, bone marrow, and cell membrane of myeloid and red cell lineage cells, but the most increased occurrence of AKGs has been reported in marine fish livers [67]. Clinical studies have demonstrated the effects of compounds in fish oils on immune function. Ingested fish oils trigger mechanisms regulating the body’s immune response, and there are few contraindications to their use. 1-O-alkylglycerols supplied with food are absorbed in the gastrointestinal tract without enzymatic breakdown. They are incorporated into cell membranes in this form [68]. 1-O-alkylglycerols have been found to stimulate the immune response by inducing the synthesis and increasing the release of activated derivatives of platelet-activating factor (PAF) by immunocompetent cells, THP-1. As a result, increased PAF expression leads to non-specific immunity activation through platelet, neutrophil, and macrophage aggregation and increased vascular permeability [68]. In addition, alkylglycerols do not cause more excellent stimulus-specific induced arachidonic acid release through blocking protein kinase. C-squalene, also found in the livers of marine fish, is a precursor of cholesterol and vitamin D synthesis and is also a component of lipids secreted by the sebaceous glands. Squalene’s immunostimulating effect is due to its adherent properties to cell membranes and lipid shields of pathogens. It opsonises pathogens, which in turn improves their presentation to immunocompetent cells. Squalene taken daily with the diet at a dose of 25-100 mg/kg b.w. increased NK cell activity and phagocytic activity of neutrophils and resulted in increased activity of peripheral blood CD3+ lymphocytes [66]. Alkylglycerols and squalene appear to activate monocytes, dendritic cells, and neutrophils to produce cytokines, leading to activation of Th1 lymphocytes. In addition, pro-inflammatory cytokines stimulate the production of complement system components, which explains the increased levels of C4 and TNF-α. This effect is defined by the proximity of the genes encoding the factors on chromosome 6, which causes transcription factors to activate both mediators simultaneously because of the stimulation of immunocompetent cells. Strict recommendations for the use of shark liver oil are not well-defined. Taking 750 mg/day of oil for preventive purposes and 3 g/day for medicinal purposes is recommended. Shark liver oil shows strong immunomodulatory properties when taken in high doses, around 5 g/day [69]. Indeed, high doses of shark liver oil have been found to support the treatment of bacterial infections, viral infections, and cancer and to activate the natural and specific immune system response [67].

CONCLUSIONS

Nutrition plays an important role in shaping and modi­fying the human immune system. Choosing the proper nutrients, attending to the balance of the gut micro­biota, can help strengthen the immune system and increase the body’s ability to defend itself against infection and disease. This is an im­portant aspect of a healthy lifestyle and preventive health care. The action of nutrients on cellular and humoral immune mechanisms signals the possibility of using nutritional immunomodulation mainly in the increased inflammatory response, the prevention and treatment of infectious and chronic diseases, during and after emotional stress, and in old age. Polyunsaturated acids of the ω-3 family have a definite impact on the immune system.

DISCLOSURE

The authors report no conflict of interest.

References