Micronutrients in the prevention of chronic inflammatory diseases

Inflammation is a normal reaction of the body intended to remove harmful internal or external irritants and create conditions conducive to repair processes. An inflammatory reaction is a complex process involving numerous elements of the immune system. An excessive immune response or an immune system that attacks the body’s own structures (e.g. certain cells or tissues) can lead to persistent (chronic) inflammation. In this case, the immune system not only attacks pathogenic factors but also damages healthy structures, thus forming the basis for many chronic diseases. In recent years the incidence of chronic inflammatory diseases has greatly increased, especially in industrialized countries. A major cause of this increase, apart from genetic factors, is an unhealthy lifestyle, in particular an unbalanced diet and lack of exercise. A diet with plenty of micronutrients, some of which possess anti-inflammatory properties, can help prevent the development of chronic inflammatory diseases.

The field of chronic inflammatory diseases includes health disorders of the nerv-ous system, respiratory system, intestine, skin and joints, as well as diabetes and atherosclerosis, with their associated risks of heart attack and stroke. Many stu-dies have investigated how regular consumption of particular foodstuffs and different micronutrients can help prevent and even treat these diseases. One focus of such investigations has been micronutrients that can influence immune functions and/or reduce inflammation. Studies have provided evidence that the nutrients directly intervene in immunological regulatory systems and participate in the regulation of inflammatory reactions, hence combating the incidence and progress of disease. In addition to the immunomodulatory potential of beta-carotene and the anti-inflammatory properties of omega-3 fatty acids and vitamin D, the antioxidant vitamins C and E could be important, since there appears to be a connection between oxidative stress and inflammation, as well as cardiovascular diseases and neurode-generative processes.

Vitamins C and E

Atherosclerosis is a chronic inflammatory disease of the blood vessels. In the early phase of the condition, certain cells of the immune system (e.g. monocytes) adhere to the vessel lining (endothelium). Even in the early stages of the disease, immune cells penetrate ever deeper into the layers of the vessel wall and ac-cumulate fats (e.g. LDL cholesterol) to form foam cells which produce characteristic deposits (plaques). This leads to frequent tears in the blood vessels and inflammatory reactions in the body, with the formation and release of pro-inflammatory proteins such as the cytokines interleukin-1 (IL-1) and tumor necrosis factor (TNF) alpha (1). The inflammatory processes in the lining of the vessel can be detected through the increase in the concentration of certain indicator molecules in the bloodstream (C-reactive protein, CRP), which are released primarily where cell damage occurs. A raised CRP value that cannot be explained by other inflam-matory diseases indicates a risk of vascular disease (2). Deposits and/or inflammation in the blood vessels can cause a reduction in blood flow and hence restrict blood supply to the brain or coronary arteries, leading to stroke or heart attack.

Oxidative stress plays an important part in the onset and persistence of chronic inflammatory processes which can damage blood vessels and other tissues in the long term: a high concentration of oxygen radicals (reactive oxygen species) leads to activation of several pro-inflammatory enzymes. Thus, substances that induce an immune response can, for instance, release oxygen radicals from the membrane of immune cells, which in turn activates enzymes (e.g. phospholipase A2) that release the polyunsaturated fatty acid arachid-onic acid from the cell membrane (3). Other activated enzymes convert arachidonic acid into pro-inflam-matory messenger substances (eicosanoids). Antioxidant micronutrients can bind and neutralize oxygen radicals – especially when acting synergistically – and thus combat the initiation of inflammation.

As a fat-soluble antioxidant found in cell membranes, vitamin E might play a special role in reducing inflam-mation. Among the various forms of vitamin E consumed, only alpha-tocopherol can be detected in signifi-cant amounts in plasma and tissues, whilst the other forms are metabolized fairly rapidly (4). Vitamin E does not appear to prevent radical formation in the cell membrane itself or to prevent the initial oxidation of fatty acids. Rather, it appears to interrupt the chain reaction of membrane-damaging lipid peroxidation (5). Studies have shown that concentrations of vitamin E (alpha-tocopherol) in the blood of patients with inflam-matory rheumatic diseases are distinctly lower than those in healthy people (6). It has also been shown that people with low plasma vitamin E levels develop rheumatic joint diseases much more frequently than people with an adequate intake. In one randomized controlled trial with patients suffering from rheumatoid arthritis, twice daily administration of 600 mg of vitamin E led to a clear decrease in pain parameters, although other indices of inflammation were not affected (7). While population studies uniformly indicate that a sufficient intake of vitamin E can prevent the onset of atherosclerosis-related cardiovascular diseases, results from studies with vitamin E dietary supplements were sometimes contradictory: some were positive (8–11), others showed no effects (12) and some investigations even reported possible negative activity (13, 14). Meta-analyses showed that daily doses of 400 or 800 IU had no harmful effects (15). The recommended daily intake for vitamin E is currently 15 mg (22 IU) of alpha-tocopherol (16), an amount consumed by less than 96% of women and 93% of men in the US (17). The food-based average intake of vitamin E in the US is only around 6 mg of alpha-tocopherol (18). In short, the study results indicate that dietary supplementation with vitamin E could prevent inflammatory diseases, especially in people whose antioxidant protection is less than optimal (5) or who are exposed to high levels of (in some cases genetically caused) oxidative stress over long periods of time (19).

Water-soluble vitamin C (ascorbic acid) is active both intra- and extracellularly as a radical scavenger. It potentially neutralizes oxygen radicals before these can develop membrane-damaging and pro-inflammatory lipid peroxidation activity in plasma and LDL particles and hence promote the onset of chronic diseases like cardiovascular and neurodegenerative diseases or diabetes (20). As an antioxidant, vitamin C is able to regenerate oxidized vitamin E. Studies on dietary supplements with vitamin C have shown that increased intakes can lead to lower plasma C-reactive protein (CRP) levels (21). CRP is a marker for chronic inflam-mation and an independent risk factor for coronary heart diseases. Compared to healthy people, patients with peripheral arterial occlusive disease have significantly lower serum vitamin C concentrations and higher CRP levels (22). A randomized controlled trial was able to show that administration of vitamins C and E to patients with essential hypertension improved arterial stiffness (23). Further, positive results in the pre-vention of asthma in adults (24) and children (25) and in the treatment of patients with rheumatoid arthritis (26) indicate that vitamin C has anti-inflammatory effects. In contrast to numerous observational studies on the intake of vitamin C in the diet (27–30), the majority of investigations into the prevention of coronary heart disease using vitamin C in dietary supplements have shown no clear effects. One debated cause of this is that most of the study participants were consuming adequate amounts in their diet at the start of the clinical study (31). No greater positive effect is to be expected from the additional administration of vitamin C to such participants. For this reason, in the future, care should be taken to include primarily participants with inadequate plasma vitamin C levels in studies. Several international nutrition surveys indicate that a sizeable share of the general population consumes less than the recommended amounts of vitamin C (32–34) or has inadequate blood levels (35–37). Some experts consider a daily intake of at least 200 mg (for adults) the optimal dose of vitamin C – an amount that achieves almost complete saturation of tissues and plasma and hence should ensure maximum benefit to health (38).

Additional evidence for a connection between oxidative stress, inflammation, cardiovascular disease and neurodegenerative processes was found in studies on apolipoprotein E, which is involved in the metaboliz-ation of triglyceride-rich constituents of lipoproteins. Mutations in the apoE-genotype can lead to raised blood triglyceride and cholesterol levels (39). Around 25% of the population carry a particular gene variant (and the corresponding apolipoprotein, apoE4), which was associated in studies with a lower life expectancy and an increased risk of coronary heart disease (40) and neurodegenerative diseases (e.g. Alzheimer’s) (41). When apoE4 carriers smoked, the survival rate dropped again. The oxidative status of the apoE4 carriers suggested one explanation: apolipoprotein E4 is a less effective antioxidant than other protein variants (e. g. apoE2 and apoE3) and apoE4 carriers exhibited more oxidative stress and more inflammation. It is assumed that this is the main reason for the higher rate of coronary heart disease. In one study it could be shown that the blood concentration of inflammation markers in apoE4 carriers who smoked was lowered by targeted administration of vitamin C (60 mg/day) (42) – another sign that antioxidant micronutrients can play a part in preventing the chronic inflammation that advances atherosclerosis.

Vitamin D

Current research is providing more and more evidence that vitamin D plays an important role in immune reactions and therefore also in inflammation. Specific functions of vitamin D that influence elements of the innate and acquired immune system (e.g. T and B cells and macrophages) provide possible explanations for the fact that, in some epidemiological studies, a link was observed between sufficient intake of the vitamin and a reduced incidence of many chronic inflammatory diseases (43). The vitamin D receptor is found in several blood vessel cell types and could therefore inhibit localized inflammation there via various mech-anisms and help prevent atherosclerosis and its consequences (44). Vitamin D deficiency was found signifi-cantly more frequently in patients with rheumatoid arthritis (RA), compared to the general population (45). Moreover, higher vitamin D intakes were linked with a reduced RA risk (46). In one clinical study, dietary supplementation with vitamin D3 led to a reduction in pain and a significant drop in the blood concentrations of an inflammation marker (C-reactive protein, CRP) in RA patients (47). In patients with chronic inflam-matory intestinal conditions, who are usually found to have low vitamin D levels, daily consumption of 1,200 IU of vitamin D3 led to a clearly lower rate of relapse (48). Similarly, targeted dietary supplementation with 2,000 IU of vitamin D3 a day during the first year of life could help prevent the onset of type 1 diabetes (49). Furthermore, the risk of developing multiple sclerosis (MS) increases as vitamin D status deteriorates (50), whereas targeted vitamin administration reduces the risk of developing MS and can lower the rate of relapse in MS patients (51). In addition the possible protective effect of vitamin D on chronic inflammatory skin conditions (e.g. psoriasis) and eczema as well as benefits for wound healing is under discussion (52).

Since appreciable amounts of vitamin D are found in relatively few foodstuffs (for instance fatty fish, liver and egg yolk), and the skin’s ability to synthesize it in northern latitudes and during the winter months is often inadequate, most people are prone to insufficiency. Whereas serum 25(OH)D3 levels of at least 30 ng/mL (75 nmol/L) are recommended for bone health maintenance, no clear information is available as to the levels required for optimal immunomodulatory and anti-inflammatory vitamin D activity. Studies showed that vitamin D levels of at least 20 ng/mL (50 nmol/L) are necessary for immune cells to initiate defined innate immune reactions. From a baseline value of 24 ng/mL (60 nmol/L), each 10 ng/mL increase was associated with a 25% decrease in the concentration of an inflammation marker (53), and, by increasing the vitamin D concentration by 20 ng/mL, it was possible to reduce the risk of developing MS by 41% (50).

Carotenoids

Among the nutritional components that can positively influence immune function and inflammation are plant secondary molecules found mainly in fruit and vegetables. The anti-inflammatory activity and effects on the immune system of carotenoids, especially beta-carotene, has been well studied. In several studies, high blood beta-carotene levels were associated with lower concentrations of inflammatory parameters (e.g. C-reactive protein, CRP) and leukocytes (54–57). A cellular carotenoid-binding protein appears to be involved in the anti-inflammatory activity (58). Patients with rheumatoid arthritis were found to have clearly lower blood beta-carotene levels than healthy controls two to 15 years before diagnosis (59).

In one case-control study, female participants with the highest lycopene concentrations in plasma were found to have an up to 50% lower risk of developing cardiovascular disease (60). It was also shown that the lycopene levels in asthma patients were clearly reduced (61). A clinical study showed that a high intake of carotenoid-rich vegetables and fruit significantly lowered the concentration of C-reactive protein (CRP) in the blood of participants and thus reduced inflammatory processes (62). Daily consumption of an appropriate amount of fruit and vegetables appeared to be important for such anti-inflammatory effects: study partici-pants who had eaten only two portions of fruit and vegetables or less a day revealed a clearly raised CRP concentration. In contrast, participants who had eaten eight portions of fruit and vegetables daily had sig-nificantly lower CRP values. In another randomized controlled trial an increased intake of carotenoids in carrot or tomato juice (approx. 5.7 mg of lycopene and 1 mg of beta-carotene per day) led to a significant decrease in pro-inflammatory factors (63).

Essential fatty acids

Polyunsaturated fatty acids can theoretically combat the onset of chronic inflammation via several mech-anisms: they influence intracellular signaling processes and the expression of various genes, and they form the precursor for immunomodulators. The omega-6 fatty acid arachidonic acid (AA) plays a crucial part in the latter because it provides the substrate for the synthesis of pro-inflammatory eicosanoids by specific enzymes – cyclooxygenase (COX) and lipoxygenase (LOX). Increasing intake of the omega-3 fatty acids eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) means that these (instead of AA) are incorp-orated into the membrane of inflammatory cells (64). As a consequence, fewer pro-inflammatory eicosanoids are formed. Moreover, EPA and DHA may be used for synthesis of anti-inflammatory substances (65).

Numerous epidemiological and case studies have provided indications that increased consumption of fish and omega-3 fatty acids can reduce the risk of dying of cardiovascular diseases (66–68). EPA and DHA have been shown to reduce several risk factors for cardiovascular disease. However, the extent to which their protective effect results from a beneficial influence on inflammatory processes and the prevention of atherosclerosis is not clear. The results of randomized controlled trials with fish oil indicate that in patients with rheumatoid arthritis, average intakes of 3.5 g of omega-3 fatty acids per day can reduce symptoms (pain and joint stiffness) and the use of antirheumatic painkillers (e.g. COX inhibitors) (69–71). Epidemio-logical data indicate that high intakes of omega-6 and low intakes of omega-3 fatty acids can increase the risk of developing asthma and allergies (64). While one meta-analysis of randomized controlled trials con-cluded that the effectiveness of omega-3 fatty acids in the treatment of asthmatic adults and children has not been substantiated beyond doubt (72), other studies reported successes with some patient groups or with the use of higher doses of fish oils (73). A number of clinical studies with patients suffering from chronic inflam-matory bowel diseases reported an improvement in inflammatory parameters and symptoms as well as a reduction in the medication used, such as corticosteroids (64, 69).

Obesity and its complications (e.g. impaired lipid metabolism, insulin resistance and their consequent ill-nesses, type 2 diabetes, heart attack and stroke) have become the central focus of nutrition-related debates in industrialized countries. Adipose (fatty) tissue not only stores excess energy, it also produces many immune system signaling substances and pro-inflammatory proteins (74). With chronic overeating, pro-inflammatory cytokines, oxygen radicals and saturated fatty acids reinforce local inflammation in the fatty tissue. If the cytokines leave the fatty tissue and reach the blood stream they can trigger inflammatory processes in other organs, for example in the liver or the muscles. Eventually a resistance to insulin dev-elops which can give rise to type 2 diabetes and atherosclerosis. Omega-3 fatty acids are in discussion as possible protective factors. In in vitro experiments, they demonstrated anti-inflammatory activity (20). However, losing weight appears to have the strongest anti-inflammatory effect.

Other micronutrients

Flavonoids also belong to the plant secondary molecule group and comprise around 6,500 different struct-ures. They are found mainly in the outer layers and outer leaves of plants. Results from epidemiological studies indicate that an increased intake of flavonoids could be associated with a reduced risk of developing various chronic diseases. Physiological effects of flavonoids (usually in very high doses) have been character-ized mainly from in vitro and animal experiment studies (75, 76). Both antioxidant and immunomodulatory properties are thought to be responsible for their anti-inflammatory effects. Flavonoids can function actively as antioxidants in both hydrophile and lipophile cellular systems. In vitro studies show a clear protective effect of flavonoids against membrane-damaging lipid peroxidation and therefore potentially against atheros-clerosis. Moreover, flavonoids appear to be able to inhibit the production of pro-inflammatory cytokines (tumor necrosis factor alpha and interleukin-6) and other mediators of inflammatory reactions, as well as sensations of pain, via direct inhibition of specific proteins. Human studies into the effects of flavonoids have been rare, and most of them investigated increased consumption of flavonoid-rich food rather than individual substances (77, 78).

Zinc can support the body’s antioxidative defense system in several ways. For instance, it can bind to pro-teins, making them less vulnerable to oxidative processes (79). By displacing reactive iron and copper ions from proteins and lipids, zinc can reduce the formation of oxygen radicals. Further, zinc increases the activity of the catalase enzyme and functions as co-factor in copper/zinc superoxide dismutase, both of which are important enzymes in the antioxidant defense system. Clinical studies have provided evidence that low plasma zinc concentrations in older study participants are associated with higher concentrations of markers for oxidative stress and for pro-inflammatory cytokines. This could be corrected by targeted dietary supple-mentation with zinc (80).

Selenium has an important role to play in cellular antioxidant defense, in particular as a constituent of the selenium proteins. Selenium deficiency can lead to increased oxidative stress and hence to impairment of immune cell activation, differentiation and growth. In animal models targeted administration of selenium led to increased production of selenium proteins and a decrease in inflammatory parameters in the blood (81). Selenium also appears able to inhibit the formation of pro-inflammatory molecules (tumor necrosis factor alpha and interleukin-6) via its influence on gene expression. The effectiveness of selenium administration in the prevention and treatment of chronic inflammatory conditions and immune and autoimmune diseases remains to be investigated in more depth in clinical studies (82).