Nutrition plays an essential role in supporting the immune system.(De Rosa, Galgani et al. 2015; Hosomi and Kunisawa 2017) Without good nutrition, which provides direct and indirect factors for the complex immune system, the host will be compromised or weakened and subject to more potential harm from pathogenic organisms and infection. Research has documented that there are many nutrients that impact the ability of the immune system to mount an effective response. In addition, there are interdependent nutrient interactions that drive immune response (Kubena and McMurray 1996) positively or negatively.
The development of tolerance, control of inflammation and response to normal mucosal flora are interrelated and linked to specific immune mechanisms. Some nutrients act as antioxidants and as cofactors at the level of cytokine regulation. Chronic undernutrition, including insufficient intake of energy, and micronutrient deficiency compromise cytokine response and affect immune cell trafficking. Undernutrition combined with infection creates even greater challenges to the immune system leading to altered immune responses, cellular populations and an increase in inflammatory mediators. While many clinicians do not see much frank nutrient deficiency, research has clearly shown that the immune system can be significantly impacted by nutrient deficits.
Nutritional Antioxidants are Essential to Prevent Collateral Damage to Healthy Tissue During Bouts of Inflammation
Antioxidants are needed to protect tissue from damage due to the production of free radicals during the inflammatory process. The need for antioxidants is essential to either acute or chronic inflammation(Milenkovic, Jude et al. 2013; Arulselvan, Fard et al. 2016). A balance between reactive oxygen species formation/free radical and endogenous antioxidant defense mechanisms is need to avoid tissue damage to DNA, proteins and membrane lipids.
In addition to the traditional antioxidants found in the diet(Basu and Maier 2016; Hidalgo and Almajano 2017) such as Vitamin E and Vitamin C, carotenoids (lycopene and beta-carotene), plant polyphenols and resveratrol, there are less well known antioxidants found in foods and herbs. Gallic acid (3,4,5-trihydroxybenzoic acid) is a powerful phenolic antioxidant naturally found in foods and herbs. Gallic acid inhibits mast-cell derived inflammatory allergic reactions by blocking histamine release and pro-inflammatory cytokine expression.(Fei, Je et al. 2017) Gallic acid is present in most plants and exhibits bioactivity as an antioxidant, antimicrobial, anti-inflammatory, neuroprotective agent and anti-cancer.(Daglia, Di Lorenzo et al. 2014; Fernandes and Salgado 2016).
Free radicals Reactivity
Superoxide anion Generated in mitochondria, cardiovascular system and other cell type
Hydrogen peroxide Formed in the human body by a large number of reactions and yield potent reactive species
Hydroxyl radical Highly reactive and generated during iron overload and such conditions in the human body
Peroxyl radical Reactive and formed lipid, proteins, DNA, and sugar molecules during oxidate damage
Nitric oxide Neurotransmitter and blood pressure regulation and can yield oxidants during pathological states
Peroxynitrite Highly reactive and formed from NO and superoxide
Ozone Present as an atmospheric pollutant and can react with various molecules
Plant derived phenolic compounds have been shown to inhibit the initiation and progression of cancers by modulating genes regulating key physiologic processes, such as oncogenic transformation of normal cells, growth and development of tumors and angiogenesis and metastasis. Pre-clinical research with plant derived phenolic compounds on cancer cell death have shown down regulation of: transcription factors NF-κB, and NRF2 (nuclear factor erythroid-2 related factor which regulates the expression of antioxidant proteins that protect against oxidative damage triggered by injury and inflammation).
In addition, plant derived phenolic compound down regulate oncogenic survival kinases such as Akt and PI3k, cell proliferation regulators that include Erk1/2, D-type cyclins and cyclin dependent kinases, histone deacetylases and angiogenic factors VEGF, FGFR1 and MIC-1. In addition to inhibiting oncogenic proteins, the phenolic compounds elevate the expression of tumor suppressor proteins, p53, PTEN, p21 and p27.(Anantharaju, Gowda et al. 2016)
Clinical characteristics Primary nutrient deficiency Associated nutrient deficiency Immune system Immune response
↓weight/height, growth, non genetic short stature Protein calorie deficiency (marasmus) Zinc, magnesium, selenium, copper, iron, vitamin A Thymic atrophy,
↓lymph nodes, tonsils, T cells, ↑ IgA, IgG is normal or ↑ ↓ Skin test reactivity;
↓cytokine response; might respond to vaccines, risk of bacterial, viral, parasitic, opportunistic infection
Moon face, edema, apathy, ↓muscle mass, hepatomegaly, anemia Protein deficiency (kwashiorkor) Zinc, magnesium, selenium, copper, iron, Vitamin A Altered T-cell subsets, ↑ IgA, IgG is normal or ↑ ↓ Skin test reactivity;
↓cytokine response; might respond to vaccines, risk of bacterial, viral, parasitic, opportunistic infection
Diarrhea, skin lesions, infections, alopecia, poor wound healing,
Anemia, pallor, spoon-shaped nails, pica, infection Zinc
Rarely iron, copper
Zinc Lymphopenia, thymic atrophy, altered T0cell subsets
↓phagocytic activity ↓ Skin test reactivity;
↓Cytokine response, risk of parasitic and opportunistic Candida species infections
Neutropenia, anemia Copper ↑ Zinc (might be causative) Lymphopenia Reduced IL-2 response
Muscle aches and pains, cardiomyopathy, infections Selenium Not reported ↓Antioxidant defense ↑Viral virulence
Xenophthalmia, keratomalacia, diarrhea and respiratory infections Vitamin A Zinc Lymphopenia ,
↓mucosal barrier function ↓T-cell response, especially TH2,
↓ phogocytic cell and NK cell function
Neurologic symptoms, atopic disease with ↑ IgE Vitamin E Selenium ↓Antioxidant defense, ↑IgE levels ↓PGE2 production,
Scurvy, purpura, petechiae, hyperkeratotic lesions, recurrent furunculosis, stress exercise Vitamin C Not reported ↓ Plasma glutahionine ↓Phagocyte function, risk of infections
Zinc, Iron, Copper, Vitamins E, A and C and Selenium: Integrated Roles in Supporting the Immune System
For instance, vitamin E and selenium have been shown to work together increasing antibody titers and lymphocyte proliferation and antiviral antibody in animals. A deficiency of vitamin E and selenium can result in a decrease in cytolytic T lymphocyte activity and proliferation, impaired thymus and lymph node integrity and decreased neutrophil phagocytic activity. Vitamin E and Vitamin A have been shown to enhance neutrophil function.(Kubena and McMurray 1996)
Magnesium May Reduce hs-CRP and Chronic Inflammation
A meta-analysis and systematic review indicated that dietary magnesium intake is inversely associated with serum C – reactive protein levels.(Moslehi, Vafa et al. 2012; Dibaba, Xun et al. 2014) The authors indicated that the potential beneficial effect of magnesium intake on chronic diseases may be, at least in part, explained by inhibiting inflammation. Researchers have also reported that higher intakes of magnesium are associated with lower risk of metabolic syndrome.(Sarrafzadegan, Khosravi-Boroujeni et al. 2016) The best sources of magnesium from the diet are legumes, nuts, seeds, fish and whole grains.(Canada 2016)
Amino Acids: Arginine and Glutamine May be Essential in Cellular Immunity
Amino acids are the building blocks of all protein. A diet that contains the essential amino acids is necessary for life. Data from the 3rd National Health and Examination Survey (NHANES), a US National Survey, indicated that higher intakes of the amino acid, arginine were associated with lower levels of c-reactive protein.(Wells, Mainous et al. 2005). The authors suggested that individuals may be able to lower their risk for cardiovascular disease by consuming more arginine-rich foods such as nuts and fish. During severe metabolic stress, including sepsis and surgery, another amino acid, glutamine, is typically depleted from muscle stores and is considered to be “conditionally essential” in these conditions.(Kim 2011) Additionally, glutamine has an important role in cell-mediated immunity and maintains the integrity of the intestinal mucosa.(dos Santos, Viana et al. 2010) Protein-rich foods like beef, chicken fish, dairy products, beans, and many other foods are good food sources of glutamine. Recently, glutamine was reported to inhibit micro RNA-23 in animals, thereby protecting myocardial function from ischemia/reperfusion injury.(Kou, Zheng et al. 2016)
Omega-3 Fatty Acids and Oxidized Derivatives Actively Direct Resolution of Inflammation
The role of dietary omega-3 fatty acids, eicosapentaenoic acid (EPA, 20:5n3), docosapentaenoic acid (DPA, 22:5n3) and docosahexaenoic acid (DHA, 22:6n3) and their oxygenated derivatives are emerging as key factors in the active and sequential resolution of inflammation and physiological repair of tissues. Dietary EPA and DHA have been recognized as important modulators of the inflammatory process by shifting the cyclooxygenase-stimulated production of prostaglandins, thromboxanes and leukotrienes from arachidonic acid (AA, 20:4n6) cell-signaling intermediates to the less-inflammatory omega 3 intermediates. However, the understanding of genetic, molecular and cellular mechanisms has led to a new paradigm of science called resolution pharmacology. Research has identified a superfamily of unique stereospecific mediators of inflammation resolution named resolvins or specialized pro-resolving mediators. The resolvins derived from EPA (E-series; RvE1, 2, 3), DHA (D-series;RvD1, 2, 3, 4) and AA (lipoxins. LX) and have been shown in numerous pre-clinical settings to not only orchestrate the self-limiting inflammatory process, but also support repair of tissue affected by inflammation.(Perretti, Leroy et al. 2015; Serhan, Dalli et al. 2015; Serhan 2017). The Figure from Serhan illustrates the lipid mediator biosynthesis in the resolution of acute inflammation. (Serhan, Chiang et al. 2015)There are other mediators such as proteins and peptides (e.g., adrenocorticotropic hormone, annexin A1, short peptides (chemerin) that reduce inflammation, β-galactoside binding proteins that have anti-inflammatory effects (galectin-1) , autocoids (e.g., adenosine, a nucleoside formed by the enzymatic activity of 5’-nucleotidases on intracellular ATP, ADP and AMP) and gases (H2S and CO).(Wallace, Ianaro et al. 2015)All of these mediators, collectively share fundamental properties to terminate the initial inflammatory reaction and organize the “cleaning phase” within the affected tissue in an effort to return to homeostasis. (Perretti, Leroy et al. 2015) The diverse physiological actions of specialized pro resolving mediators are illustrated in the Figure from Serhan (Serhan, Chiang et al. 2015)
The bioactivity identified with the formation of resolving mediators includes the inhibition of granulocyte trafficking, removal of monocytes, promotion of granulocyte cell death (apoptosis), augmentation of phagocytosis and subsequent clearance of cellular debris, activation of macrophage class switching (M1 to M2) resulting in a macrophage that can repair physiology and also promote tissue regeneration and repair.(Perretti, Leroy et al. 2015; Serhan 2017). Perretti et al., illustrate that current pharmacopeia is targeted to blocking inflammation via many classes of drugs that have specific inhibitory functions. However, side effects of many of the therapeutic anti-inflammatory approaches may lead to negative consequences such as immunosuppression, toxicity to tissues and compensation by the body leading to tolerance of the therapy and reduced effectiveness. A pro-resolving strategy with pro-resolving molecules may be the desired therapeutic approach of the future and would deliver actions already “optimized” by nature. (Perretti, Leroy et al. 2015) There are many therapeutic agents that are in various stages of research using the pro-resolving therapeutic approach for a variety of health conditions including, type 2 diabetes, dry eye syndrome, gingival inflammation and pain receptivity via D series resolving receptors in patients with osteoarthritis pain.(Weylandt, Chiu et al. 2012; Huang, Burston et al. 2017)
There is evidence that lymph nodes produce 17-DHDA, where it enhances antibody production. In addition, other D series resolvins have been characterized in other lymphoid tissues (spleen) in mice. These observations suggest that the pro-resolving mediators, in addition to returning tissue to homeostasis, may also play a positive role in supporting acquired immunity.(Ramon, Gao et al. 2012; Dalli, Winkler et al. 2013)
The aging process dysregulates D and E series resolvin activity in modulating cardiosplenic and cardiorenal function following myocardial infarction in experimental animals.(Gangemi, Pescara et al. 2005; Arnardottir, Dalli et al. 2014; Halade, Kain et al. 2016) Resolvin dysregulation may also be a factor in age-associated neurodegenerative conditions such as Alzheimer’s disease. (Dyall 2015). As the formation of resolvins from dietary precursors is reduced with aging, this may signal the need for a direct supplement of resolvins to support dietary intake.
Nucleotides Support Immune Function in Adults and Healthy Infants
Nucleotides are the building blocks of DNA and RNA and play key roles in many biological processes. They serve as nucleic acid precursors, physiological mediators, components of coenzymes and sources of cellular energy.(Carver 1999) A nucleotide consists of a base of either cytosine, thymine or uridine (known as pyrimidines) or adenine and guanine (known as purines) plus a molecule of pentose sugar and one or more phosphate groups. Sources of nucleotides include de novo synthesis, recovery via salvage mechanisms and dietary intake of normal foods, particularly, meats. Nucleotides, found in normal diets, have been determined to be required for normal immune competence, intestinal development and recovery and may be considered “conditionally essential” in periods of rapid growth or in the presence of regulatory or developmental factors which interfere with full expression of the endogenous synthetic capacity.(Uauy 1989; Carver 1999; Schaller, Buck et al. 2007; Hess and Greenberg 2012) In adults fed enteral diets containing nucleotides, immune function was improved compared to a nucleotide-free diet. In addition, post-operative cancer patients fed a nucleotide formula had reduced infectious complications and reduced length of hospital stay compared to the nucleotide free diet.(Van Buren, Kulkarni et al. 1994)
Rapidly proliferating tissues, such as the immune system or the intestine may not be able to fulfil the needs for cell nucleotides exclusively by de novo synthesis. When demand exceeds the ability of the body to synthesize nucleotides, the tissues can utilize the salvage pathway recovering nucleosides and nucleobases from blood and diet and then make additional nucleotides.(Gil 2002) Dietary nucleotides influence lymphocyte maturation, activation and proliferation and affect the lymphocyte population in both the small intestine and blood. Additionally, nucleotides are involved in support of the innate immune system by enhancing macrophage phagocytosis and delayed hypersensitivity as well as allograft and tumor responses.
Prospective randomized trials in infants fed formula supplemented with nucleotides at the level found in human milk (bound and free nucleotides; 72mg/L) demonstrated that humoral immunity was enhanced compared to infants fed control formula with no added nucleotides. Specifically, in the first year of life, infants had higher humoral vaccination response (poliovirus type 1 neutralizing antibody) when given infant formula with nucleotides. (Pickering, Granoff et al. 1998; Schaller, Kuchan et al. 2004) Nucleotide supplemented formulas also provided a better antibody response to immunization with Haemophillus influenza vaccine, diphtheria toxoid and oral polio vaccine and fewer episodes of diarrhea.(Gutierrez-Castrellon, Mora-Magana et al. 2007) Additionally, infants were evaluated for cellular immunity and the cohort fed infant formula supplemented with nucleotides had increased memory/effector T-cell populations and changes in NK cell subtypes compared to infants fed unfortified formula.(Buck, Thomas et al. 2004)The shift in maturation and immunoregulatory subsets of the group fed the nucleotide formula had similar results as those fed human milk.