Micronutrients for Immune Support

Micronutrient deficiencies, such as vitamins A, D, and C, calcium, iron, zinc, potassium, and magnesium, are prevalent worldwide and may impair immune function, bone health, and cardiovascular health.

Many factors, such as dietary choices, stress, lack of sleep, infections, sweating, increased energy expenditure, health conditions, and pollution, can impact micronutrient levels.

Populations with increased needs, like those with infections or under physical stress, may experience faster depletion of these nutrients. Addressing deficiencies requires meeting the Recommended Dietary Allowances (RDA) and adjusting for factors like bioavailability and individual health circumstances.

Adequate micronutrient intake is essential to aid recovery from infection, made more difficult because food intake may decrease during illness, and antibiotic use can deplete certain micronutrients. For example, levels of vitamin C in plasma rapidly fall to half their original concentration during an infection to levels indicative of a suboptimal status with a risk of deficiency, i.e., ≤ 0.88 mg/dL (50 μmol/L).

For optimal immune protection and resistance to infection, daily intakes may need to be much higher than the RDAs

Micronutrients have key roles at every stage of the immune response

This schematic summarizes important components and processes that are involved in different aspects of the innate and adaptive immune responses. The circles highlight those micronutrients that are known to affect these responses. The significant overlap between micronutrients and processes indicates the importance of multiple micronutrients in supporting proper function of the immune system. Abbreviations: APCs, antigen-presenting cells; C3, complement component 3; CRP, C-reactive protein; Cu, copper; Fe, iron; IFNs, interferons; Igs, immunoglobulins; ILs, interleukins; GI, gastrointestinal; GM-CSF, granulocyte-macrophage colony stimulating factor; MAC, membrane attack complex; MCP-1, monocyte chemoattractant protein-1; Mg, magnesium; MHCs, major histocompatibility complexes; NK, natural killer; NO, nitric oxide; ROS, reactive oxygen species; Se, selenium; TLRs, toll-like receptors; TNF, tumor-necrosis factors; Zn, zinc.

Key nutrients for immunity

Vitamin A

• Vitamin A (retinoic acid) supports gut immunity by guiding T and B cells to the intestines, enhancing the gut barrier.
• Carotenoids, a form of vitamin A, protect cells by reducing oxidative stress and regulating cell communication.
• Vitamin A regulates natural killer (NK) cells, which are crucial for immune defense.
• It supports the development of antibodies and T helper cells, key to immune responses.
• Vitamin A helps control pro-inflammatory molecules like TNF-α, aiding in macrophage activity and the body's immune response.

Deficiency:

• Mucosal epithelium integrity is compromised.
• Intestinal T and B cell activity is impaired, leading to reduced gut immunity.
• Retinoic acid deficiency disrupts microbiota balance and immune function.
• Innate immunity is weakened, affecting neutrophil, eosinophil, and NK cell functions.
• Macrophages have reduced ability to engulf pathogens and diminished oxidative burst activity.
• Inflammation is increased, with elevated IL-12 and TNF-α levels.
• Th1/Th2 balance is altered, impairing antibody production and increasing susceptibility to infections in mucosal tissues like the eye, respiratory, and GI tracts.
• Increased susceptibility to pathogens in mucosal epithelium (e.g., eye, respiratory and GI tracts)

Supplementation:

• Retinoic acid modulates specific microbiota in the gut
• Helps reverse adverse effects on immune functions of neutrophils, eosinophils, NK cells, and macrophages
• Improves antibody titer response to vaccines

Vitamins B6, B12 and folate

All involved in intestinal immune regulation (e.g., by mediating lymphocyte migration into the intestine in the case of vitamin B6, while folate is essential for the survival of regulatory T cells in the small intestine, and human gut microbes use vitamin B12 as a cofactor for metabolic pathways), thus supporting the gut barrier. Immune system effects of vitamin B12 deficiency and folate deficiency are clinically indistinguishable

Vitamin B6

• Maintains or enhances NK cell cytotoxic activity

Deficiency:

• Decreased IL-2 production and reduced lymphoid tissue weight.
• Lymphocytopenia (low lymphocyte count) and weakened cell-mediated immunity.
• Suppression of Th1 cytokine activity and promotion of Th2 activity.
• Impaired maturation and growth of lymphocytes, even with marginal deficiencies.
• Reduced antibody responses and compromised ability to respond to pathogens.

Supplementation:

• Helps to restore cell-mediated immunity
• Can improve lymphocyte maturation and growth, and increase numbers of T-lymphocytes
• Large doses can improve immune response of critically ill patients
• Supplementation in young women in doses up to 2.1 mg/day (i.e., higher than the RDA of 1.3 mg/day for one week increased lymphocyte proliferation in a dose-dependent manner.

Vitamin B12

• May act as immunomodulator for cellular immunity, effects on cytotoxic cells (e.g., NK cells, cytotoxic T cells)

Deficiency:

• Suppressed natural killer (NK) cell activity.
• Impaired delayed-type hypersensitivity (DTH) response.
• Significant reduction in cells involved in cell-mediated immunity.
• Altered proportions of cytotoxic T cells and helper T cells, resulting in a higher helper/cytotoxic T cell ratio.
• Depressed T-cell proliferation.
• Decreased lymphocyte count.
• Impaired antibody response.

Supplementation:

• Increases number of cells with a role in cell-mediated immunity

Folate

• Maintains or enhances NK cell cytotoxic activity
• Is required for an appropriate antibody response

Deficiency::

• Impaired natural killer (NK) cell cytotoxicity.
• Weakened delayed-type hypersensitivity (DTH) response.
• Reduced T-cell proliferation and cytotoxic T-cell activity.
• Impaired thymidine and purine synthesis, affecting DNA, RNA, and immunoglobulin production.
• Decreased antibody response.

Supplementation:

• Can increase innate immunity in older people
• Alters age-associated decrease in NK-cell activity
• Supports Th1 response

Vitamin C

• Supports collagen synthesis, protecting cell membranes from free radical damage and maintaining epithelial barriers.
• Enhances keratinocyte differentiation, lipid synthesis, and fibroblast proliferation for skin healing.
• Aids in the movement and function of immune cells like neutrophils, monocytes, phagocytes, and NK cells.
• Promotes phagocytosis, ROS generation, and microbial killing, and helps clear neutrophils after infection.
• Boosts antimicrobial effects, serum complement proteins, and IFNγ production.
• Increases serum antibody levels.

Deficiency:

• Increased oxidative damage
• Decreased DTH response
• Impaired wound healing
• Increased incidence and severity of pneumonia and other infections

Supplementation:

• High doses stimulate phagocytic and T-lymphocytic activity
• Antioxidant properties protect leukocytes and lymphocytes from oxidative stress
• Enhanced neutrophil chemotaxis
• In high doses, can help severely ill patients in intensive care recover more quickly
• RDA ranges globally between 40 and 110 mg
• However, prophylaxis of infection requires dietary vitamin C intakes of 100–200 mg/day (i.e., higher than the RDA) to provide adequate, if not saturating plasma levels and thus optimize cell and tissue levels.
• Treatment of established infections requires even higher doses (possibly around 6 g/day to compensate for the increased inflammatory response and metabolic demand
• Mostly high-quality evidence demonstrates that vitamin C supplementation (≥2 g/day, or therapeutic doses of 4–8 g/day) in adults and children with a common cold can significantly reduce its duration and severity shorten the time of confinement indoors, and relieve cold symptoms including chest pain, fever, and chills.

Vitamin D

• Vitamin D supports gut, lung, renal, and corneal barrier functions by enhancing tight junction proteins.
• t increases the expression of E-cadherin and connexin 43, which help maintain epithelial integrity.
• The vitamin D receptor, found in immune cells like monocytes and macrophages, promotes their differentiation and phagocytic activity.
• Calcitriol (active form of vitamin D) regulates antimicrobial proteins such as cathelicidin and defensin, which directly kill pathogens.
• It also inhibits IFNγ production, which helps control inflammation.

Deficiency:

• Altered gut microbiota composition
• Reduced number of lymphocytes
• Reduced lymphoid organ weight
• Impaired immune capabilities of macrophages (including antimicrobial functions)
• Especially RTI
• Increased severity, morbidity and mortality
• Increased risk of autoimmune diseases (e.g., type 1 diabetes, multiple sclerosis, systemic lupus erythematosus, rheumatoid arthritis)

Supplementation:

• Calcitriol helps to restore the immune function of macrophages
• No significant effect on biomarkers of systemic inflammation (i.e., TNF-α, IL-6)
• A significant body of work suggests that the RDA for vitamin D is unlikely to raise serum levels needed for adequate function of the immune system
• Approximately 300–3653 IU/day) in adults and children can reduce the risk of respiratory tract infection (RTI).

Vitamin E

• Protects cell membranes from free radical damage, supporting epithelial barrier integrity.
• Enhances or maintains natural killer (NK) cell cytotoxic activity, helping immune defense.
• Inhibits PGE2 production by macrophages, indirectly preserving T-cell function.
• Supports the formation of immune synapses between antigen-presenting cells and CD4+ T-helper cells, essential for immune response coordination.

Deficiency:

• Impaired humoral and cell-mediated aspects of adaptive immunity, including B and T cell function 
• Reduces T cell maturation

Supplementation:

• Improves overall immune function
• In the elderly, enhanced DTH responses and increased antibody titers
• One study has shown that a daily supplementation with 200 IU of synthetic α-tocopherol for one year significantly lowered the risk of contracting upper respiratory tract infections

Copper

• Copper accumulates in macrophage phagolysosomes to help combat infectious agents.
• Enhances the function of macrophages, neutrophils, and monocytes, which are key immune cells.
• Supports the activity of natural killer (NK) cells to fight infections.
• Has intrinsic antimicrobial properties, aiding in defense against pathogens.
• Plays a role in supporting antibody production, crucial for adaptive immunity.

Deficiency:

• Abnormally low neutrophil levels and reduced phagocytic ability
• Reduced IL-2 and decreased T-cell proliferation even in marginal deficiency
• Ineffective immune response to infections
• Increased viral virulence

Supplementation:

• Increased ability of neutrophils to engulf pathogens
• Too much copper can also negatively impact the immune response

Iron

• Essential for differentiation and growth of epithelial tissue.
• Involved in killing bacteria by neutrophils through highly-toxic hydroxyl radicals.
• Critical for immune cell function through enzymes like ribonucleotide reductase, necessary for DNA synthesis.
• Plays a role in regulating cytokine production and action.
• Iron-rich status promotes an anti-inflammatory M2-like macrophage phenotype while negatively regulating the pro-inflammatory M1 response.
• Contributes to interferon-gamma (IFNγ) production, essential for immune responses.

Deficiency:

• Decreased DTH response
• Decreased NK cell activity
• Impaired intracellular microbial killing by polymorphonuclear leukocytes
• Lower IL-6 levels
• Impaired cellular immunity (e.g., decreased T helper cells, increased cytotoxic T cells)
• Decreased lymphocyte bactericidal activity
• Decreased response to mitogens
• For example, RTI more frequent and last longer in children
• Possible protective effect in malaria in children
• Helps reduce the incidence of diarrhea in children, in combination with vitamin A

Supplementation:

• Improves intracellular microbial killing and cellular immunity

Selenium

• Selenoproteins play a vital role in the antioxidant defense system, protecting immune cells from oxidative damage.
• Selenium is essential for the proper function of leukocytes and natural killer (NK) cells.
• It enhances interferon-gamma (IFNγ) production, boosting the immune system's response to infections.
• Selenium supports antibody production, strengthening overall immune function.

Deficiency:

• Suppression of immune function
• Diminished NK-cell cytotoxicity
• Impaired humoral and cell-mediated immunity
• Decreased immunoglobulin titers
• Impaired cell-mediated immunity
• Increased viral virulence
• Decreased response to vaccination
• Increased risk of RTI in the first 6 weeks of life in children

Supplementation:

• Improves cell-mediated immunity
• Improves T helper cell counts
• Enhances immune response to viruses in deficient individuals
• Studies investigating the role of selenium against viral infection suggest up to 200 μg/day (i.e., higher than the RDA of 55 μg/day in adults can be used as safe adjuvant therapy in viral infections.

Magnesium

• Acts as a cofactor for enzymes involved in nucleic acid metabolism and stabilizes DNA and RNA structure.
• Plays a crucial role in DNA replication and repair.
• Regulates leukocyte activation and is involved in antigen binding to macrophages.
• Supports the regulation of apoptosis, aiding in controlled cell death.
• Functions as a cofactor in antibody synthesis, helping the immune system generate effective responses.

Deficiency:

• Decreased numbers of monocytes
• Decreased NK-cell activity
• Increased oxidative stress after strenuous exercise
• Increased levels of cytokines such as IL-6
• Increased inflammation
• Decreased T-cell ratios
• Recurrent bacterial infection, fungal infections

Supplementation:

• Reduces oxidative damage to the DNA of peripheral blood lymphocytes in athletes and sedentary young men
• Reduces leukocyte activation
• After exercises, increases granulocyte count and post-exercise lymphopenia

Zinc

• Supports the integrity of skin and mucosal membranes by acting as a cofactor for enzymes involved in cell membrane repair.
• Maintains or enhances the cytotoxic activity of natural killer (NK) cells.
• Plays a central role in the growth and differentiation of rapidly dividing immune cells.
• Enhances the phagocytic activity of macrophages and monocytes, improving their ability to combat bacteria.
• Involved in complement activity and supports the production of interferon-gamma (IFNγ), contributing to immune system regulation.

Deficiency:

• Impaired immune responses, including reduced skin reactions and decreased survival, proliferation, and activity of immune cells (monocytes, NK cells, T, and B cells).
• Reduced phagocytosis by macrophages and neutrophils, leading to impaired pathogen clearance.
• Altered cytokine production, increasing oxidative stress and inflammation.
• Decreased lymphocyte function, especially T cells, and an imbalance in Th1/Th2 response.
• Increased susceptibility to infections (bacterial, viral, fungal), impaired wound healing, and higher risk of inflammatory diseases.
• Particularly affects older individuals and children.

Supplementation:

• Beneficial effects in intestinal immune functions
• Increases cytotoxicity of NK cells
• Restores thymulin activity
• Increases numbers of cytotoxic T cells
• Reduces numbers of activated T helper cells (which can contribute to autoimmunity)
• The duration of the common cold may be reduced in adults and children after administration of zinc >75 mg/day, but not at lower doses; the type of zinc salt used can also have an effect, with greater benefits with zinc acetate compared with other zinc salts.

Optimal Takeaways

• The immune system relies on multiple key micronutrients, including
  • Vitamins A, D, C, E, B6, B12, folate, zinc, iron, copper, and selenium.
• These nutrients support immune barriers and cells, often requiring higher intakes than current recommendations.
• Certain populations may have insufficient micronutrient intake, worsened by
  • Stress, pollution, lack of sleep, or infection, potentially weakening immunity.
• Vitamin C, vitamin D, and zinc have the strongest evidence for supporting immune function.
• Available evidence indicates that supplementation with multiple micronutrients with immune-supporting roles may modulate immune function and reduce the risk of infection.

Calcitriol = 1,25-dihydroxyvitamin D3, the active form of vitamin D. Selenoproteins are selenium-dependent enzymes. APC, antigen-presenting cell; DC, dendritic cells; IFN, interferon; IL, interleukin; MHC, major histocompatibility complex; NK, natural killer; PGE2, prostaglandin E2; RNS, reaction nitrogen species; ROS, reactive oxygen species; Th, helper T cell; TGF, transforming growth factor; TNF, tumor-necrosis factor; Tregs, regulatory T cells.

Reference

Gombart, Adrian F et al. “A Review of Micronutrients and the Immune System-Working in Harmony to Reduce the Risk of Infection.” Nutrients vol. 12,1 236. 16 Jan. 2020, doi:10.3390/nu12010236 This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).