Topic of the Month

Micronutrients and inflammatory diseases

April 1, 2012

Chronic, low-grade, tissue inflammation is a significant risk factor in the development of a variety of chronic diseases, such as cardiovascular disease, cancer, diabetesosteoporosis, arthritis, Alzheimer’s disease, and auto-immune diseases. Moreover, many discomforts, such as chronic pain, memory problems, mood swings, and general muscle fatigue, can be connected in some way to an underlying inflammatory condition. An important development in nutritional science in recent years has been the discovery of anti-inflammatory properties of certain micronutrients and their potential to prevent or treat certain diseases or conditions.

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Although inflammatory diseases and health conditions are of particular concern in older adults, who more likely suffer from chronic disease and/or disability, a strong scientific case can be made that chronic inflammation should be a concern through-out all of life. There is increasing evidence that the conditions for chronic disease are actually in many ways set in early development (“metabolic programming”). Inflammation in the pregnant mother, for example, can have adverse effects on pregnancy outcome. Likewise, childhood obesity is marked by an important underlying component of low-grade, chronic inflammation that could set the stage for the development of more adverse health outcomes in later life, such as the increased risk of developing heart disease and type 2 diabetes.   

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General remarks

There is extensive literature available on the general anti-inflammatory properties of various micronutrients. Moreover, some of these micronutrients have been tested with regard to the treatment of specific inflammation-based diseases. Much of the available scientific research on the subject is limited to pre-clinical studies in cell culture or animal models. Increasingly, however, the anti-inflammatory properties of some of these nutrients are being identified by examining dietary patterns in epidemiologic studies; some of these properties have also been explored more directly in clinical studies.

For example, the typical Mediterranean diet – richer in monounsaturated fatty acids than saturated fatty acids, with a high ratio of omega-3-to-omega-6 polyunsaturated fatty acids, and an abundance of fruits, vegetables, legumes, and grains – has a greater anti-inflammatory effect when compared to a typical Western-style diet (1). It is more difficult, however, to fully elucidate which specific components of the Mediterranean diet are responsible for these findings (2). Moreover, there will likely be a strong interaction between a person’s genetic makeup and his or her response to specific dietary components. The emerging area of nutritional genetics (“nutrigenomics”) and “personalized nutrition” tries to unravel the complex interplay of various individual genetic alterations and environmental exposures, including the diet and specific health risks. One example is the finding that the apolipoprotein E4 (apoE4) genotype, which is a significant genetic risk marker of cardiovascular and Alzheimer’s disease, is associated with a more pro-inflammatory state. This may be related to the apparent effect of the apoE4 genotype on the metabolism and retention of vitamin E, an important antioxidant vitamin (3). Furthermore, it is important to consider that the most beneficial aspects of certain dietary components may only be evident within the context of other dietary constituents or conditions. Future clinical studies will need to carefully parse the individual effects of micronutrients on inflammation, as well as the potential combinatorial benefits of various dietary changes on this condition. The following sections provide an overview of some clinical intervention trials that have studied the anti-inflammatory properties of various micronutrients under a variety of conditions and in healthy and diseased populations.

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Antioxidants

Antioxidant micronutrients are essential for protecting against oxidative damage. Research indicates that some antioxidants may also have anti-inflammatory properties: in addition to scavenging free radicals, they are also thought to lower the activation of inflammatory signals. Thus, they may provide important health benefits to people whose oxidative stress loads are high, such as those who have inflammatory conditions. Due to its powerful antioxidant properties, vitamin E has significant potential as an anti-inflammatory agent. In a recent study, the effects of vitamin E (800 IU alpha-tocopherol per day for 96 weeks) on non-alcoholic fatty liver inflammation (a common liver disease) were studied in adults without diabetes. The study found that the vitamin E treatment was associated with a significantly higher rate of improvement in the liver in comparison to the placebo, and that there was a reduction in the markers of liver inflammation (4). In a study of men with consistently elevated fasting blood glucose levels (pre- diabetes), researchers found that treatment with 1,000 IU of vitamin E and 1,000 mg of vitamin C for four weeks reduced blood levels of tumor necrosis factor-alpha (TNF- alpha), an important cytokine that can trigger the inflammatory response (5). In another study, subjects with metabolic syndrome, which is associated with an increased risk of diabetes and cardiovascular disease, were randomized to take either 800 IU of alpha-tocopherol, 800 IU of gamma-tocopherol, a combined vitamin E treatment, or a placebo every day for six weeks. The concentrations of C-reactive protein, a marker of inflammation, and serum TNF-alpha were significantly reduced by the combined treatment (6). TNF-alpha was also reduced by alpha-tocopherol treatment alone.

Mixtures of antioxidant nutrients have also been investigated for their effects on inflammation in different population groups. An observational study showed that regular exercise can decrease blood concentrations of inflammatory markers (7). Participants who took antioxidant supplements with beta carotene, vitamin C, and/or vitamin E had reduced C-reactive protein levels similar to those participants who reported higher levels of exercise (180 minutes/week or more) but did not take supplements. As revealed in previous studies, higher body mass index was related to increased levels of several inflammatory markers, such as
C-reactive protein, interleukin-6, and TNF-alpha. A study in patients with a history of sporadic colorectal adenoma found that a combination of alpha-tocopherol (800 mg), beta-carotene (24 mg), vitamin C (1000 mg), vitamin B2 (7.2 mg), vitamin B3 (80 mg), zinc (60 mg), selenomethionine (0.2 mg), and manganese (5 mg) consumed daily for four months had a beneficial effect on markers of inflammation and oxidative stress (8). Asthma is another inflammatory disease where nutrition may be able to play an ameliorating role. One study randomly assigned either a placebo or a nutrient supplement containing omega-3 fatty acids, vitamin C, and zinc to children with asthma and found a significant improvement in pulmonary function tests and inflammatory markers associated with the supplement (9). A clinical trial of healthy adults showed that consuming encapsulated fruit and vegetable juice powder concentrate for 60 days had a positive effect on various inflammatory biomarkers (10). Researchers found that consumption of tomato juice containing 21 mg lycopene for two weeks resulted in a significant reduction in C-reactive protein (11).

A study of zinc supplementation in healthy elderly subjects found that 45 mg zinc per day for six months decreased the concentration of serum C-reactive protein and various other inflammatory biomarkers (12). A study in obese prepubescent children found that supplementation with 20 mg zinc per day for eight weeks was associated with a significant decrease in markers of insulin resistance, oxidative stress, and inflammation (13).

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Vitamin D

The relationship between vitamin D and inflammatory processes and diseases is not yet clear. Vitamin D has been shown to inhibit the production of several pro-inflammatory molecules that modulate tissue-specific immune responses and restrict inflammation (14). The cardiovascular protection offered by vitamin D is thought to be mediated by the modulation of signaling molecules, e.g. cytokines, in the immune system  (15). Vitamin D receptors can be found on cells responding to inflammation signals (16). Deficiency of both vitamin D and its receptors may lead to the development of certain autoimmune diseases (17). In various cell cultures, vitamin D3 supplementation has been shown to decrease the production of inflammatory mediators (18, 19). However, observational studies have revealed variable results for the association between vitamin D and inflammation (20-22). In addition, randomized controlled trials of vitamin D supplementation have shown inconsistent results: some trials suggest a decrease of inflammatory biomarkers and others conclude that there is no effect on them (23-25). One of the several factors that can explain these conflicting findings is the possibility that the beneficial effect of vitamin D supplementation is present only in those with lower vitamin D levels and not in those with adequate or higher serum vitamin D levels. An observational study (26) supporting the hypo-thesis that, among healthy adults, the favorable association of vitamin D and the inflammatory biomarker C-reactive protein (CRP) exists only at relatively low serum levels of vitamin D and not at higher ones has been criticized by experts for being confusing. Since the study did not include risk factors other than CRP in the analysis, it would be difficult to draw any conclusions.

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Omega-3 fatty acids

The omega-6 polyunsaturated fatty acid arachidonic acid is usually the dominant substrate for the synthesis of eicosanoids acting as mediators (prostaglandins, thromboxanes, leukotrienes, and related metabolites), which have their own inflammatory actions and regulate the production of other mediators, including inflammatory cytokines (27). Consumption of long chain omega-3 polyunsaturated fatty acids decreases the potential amount of arachidonic acid in cell membranes available for eicosanoid production. Thus, omega-3 fatty acids decrease production of arachidonic acid-derived eicosanoids and their inflammatory actions. Omega-3 fatty acids also decrease the production of the classic inflammatory cytokines tumour necrosis factors, interleukin-1 and interleukin-6, and the expression of adhesion molecules involved in inflammatory interactions between leukocytes and endothelial cells. These latter effects may occur by eicosanoid-independent mechanisms, including an altering of the expression of inflammatory genes. Consequently, the anti-inflammatory actions of long chain omega-3 fatty acid-induced effects may be of therapeutic use in conditions with an acute or chronic inflammatory component.

Omega-3 fatty acids, such as eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), have shown significant anti-inflammatory effects in pre-clinical studies in cell culture, in animal studies, and in observational studies in human populations (28). However, clinical studies confirming the direct beneficial effects of omega-3 fatty acid supplementation on inflammatory diseases, such as asthma (29), ulcerative colitis (30), Crohn’s disease (31), rheumatoid arthritis (32), and joint pain (33), are generally lacking. However, a recent study of obese adolescents has provided information that omega-3 fatty acid supplementation (1.2 g per day for three months) was associated with lower serum biomarkers of inflammation (34). The anti-inflammatory effect of omega-3 fatty acids is as controversial as inflammatory disorders are complex. Preventative measures and treatment are difficult to define because of the diverse interactions between environmental and genetic factors.

References

  1. Galland L. Diet and inflammation. Nutrition in Clinical Practice. 2010; 25 (6):634–640.
  2. Calder P. C. et al. Inflammatory disease processes and interactions with nutrition. British Journal of Nutrition. 2009; 101(1):1–45.
  3. Huebbe P. et al. Implications of apolipoprotein E genotype on inflammation and vitamin E status. Molecular Nutrition & Food Research. 2010; 54(5):623–630.
  4. Sanyal A. J. et al. Pioglitazone, vitamin E, or placebo for non-alcoholic steatohepatitis. The New England Journal of Medicine. 362:1675–1685.
  5. Rizzo M. R. Et al. Evidence for anti-inflammatory effects of combined administration of vitamin E and C in older persons with impaired fasting glucose: impact on insulin action. Journal of the American College of Nutrition. 2008; 27:505–511.
  6. Devaraj S. et al. Gamma-tocopherol supplementation alone and in combination with alpha-tocopherol alters biomarkers of oxidative stress and inflammation in subjects with metabolic syndrome. Free Radical Biology & Medicine. 2008; 44:1203–1208.
  7. Colbert L. H. et al. Physical activity, exercise, and inflammatory markers in older adults: findings from The Health, Aging and Body Composition Study. Journal of the American Geriatrics Society. 2004; 52(7):1098–1104.
  8. Hopkins M. H. et al. Antioxidant micronutrients and biomarkers of oxidative stress and inflammation in colorectal adenoma patients: results from a randomized, controlled clinical trial. Cancer Epidemiology, Biomarkers & Prevention. 2010; 19(3):850–858.
  9. Biltagi M. A. et al. Omega-3 fatty acids, vitamin C and Zn supplementation in asthmatic children: a randomized self-controlled study. Acta Paediatrica. 2009; 98:737–742.
  10. Jin Y. et al. Systemic inflammatory load in humans is suppressed by consumption of two formulations of dried, encapsulated juice concentrate. Molecular Nutrition & Food Research. 2010; 54(10):1506–1514.
  11. Jacob K. et al. Influence of lycopene and vitamin C from tomato juice on biomarkers of oxidative stress and inflammation. British Journal of Nutrition. 2008; 99:137–146.
  12. Bao B. et al. Zinc decreases C-reactive protein, lipid peroxidation, and inflammatory cytokines in elderly subjects: a potential implication of zinc as an atheroprotective agent. The American Journal of Clinical Nutrition. 2010; 91(6):1634–1641.
  13. Kelishadi R. et al. Effect of zinc supplementation on markers of Insulin resistance, oxidative stress, and inflammation among prepubescent children with metabolic syndrome. Metabolic Syndrome and Related Disorders. 2010; 8(6):505–510.
  14. Lips P. Vitamin D physiology. Prog Biophys Mol Biol. 2006; 92:4–8.
  15. Andress D. L. Vitamin D in chronic kidney disease: a systemic role for selective vitamin D receptor activation. Kidney Int. 2006; 69:33–43.
  16. Artaza J. N. and Norris K. C. Vitamin D reduces the expression of collagen and key profibrotic factors by inducing an antifibrotic phenotype in mesenchymal multipotent cells. J Endocrinol. 2009; 200:207–221.
  17. Cantorna M. T. et al. Vitamin D status, 1,25-dihydroxyvitamin D3, and the immune system. Am J Clin Nutr. 2004; 80(6):1717–1720.
  18. Almerighi C. et al. 1Alpha,25-ihydroxyvitamin D3 inhibits CD40L-induced pro-inflammatory and immunomodulatory activity in human monocytes. Cytokine. 2009; 45:190–197.
  19. Gruber H. E. et al. 1,25(OH)2-vitamin D3 inhibits proliferation and decreases production of monocyte chemoattractant protein-1, thrombopoietin, VEGF, and angiogenin by human annulus cells in vitro. Spine. 2008; 1976:755–765.
  20. Peterson C. A. and Heffernan M. E. Serum tumor necrosis factor-alpha concentrations are negatively correlated with serum 25(OH)D concentrations in healthy women. J Inflamm. 2008; 5:10.
  21. Miller R. R. et al. Association of serum vitamin D levels with inflammatory response following hip fracture: the Baltimore Hip studies. J Gerontol A Biol Sci Med Sci. 2007; 62(12):1402–1406.
  22. Michos E. D. et al. Serum 25-hydroxyvitamin D levels are not associated with subclinical vascular disease or C-reactive protein in the old order Amish. Calcif Tissue Int. 2009; 84:195–202.
  23. Schleithoff S. S. et al. Vitamin D supplementation improves cytokine profiles in patients with congestive heart failure: a double-blind, randomized, placebo- controlled trial. Am J Clin Nutr. 2006; 83:754–759.
  24. Pittas A. G. et al. The effects of calcium and vitamin D supplementation on blood glucose and markers of inflammation in nondiabetic adults. Diabetes Care. 2007; 30(4):980–986.
  25. Jorde R. et al. No effect of supplementation with cholecalciferol on cytokines and markers of inflammation in overweight and obese subjects. Cytokines. 2010; 50:175–180.
  26. Amer M. and Qayyum R. Relation between serum 25-Hydroxyvitamin D and C-Reactive Protein in asymptomatic adults (from the Continuous National Health and Nutrition Examination Survey 2001 to 2006). The American Journal of Cardiology. Published online October 2011.
  27. Calder P. C. Polyunsaturated fatty acids and inflammation. Prostaglandins, Leukotrienes and Essential Fatty Acids. 2006; 75(3):197–202.
  28. Calder P. C. Dietary modification of inflammation with lipids. Proceedings of the Nutrition Society. 2002; 61:345–358.
  29. Reisman J. et al. Treating asthma with omega-3 fatty acids: where is the evidence? A systematic review. 2006; 6:26.
  30. De Ley M. et al. Fish oil for induction of remission in ulcerative colitis. Cochrane Database Syst Rev. 2007; 4.
  31. Romano C. et al. Usefulness of omega-3 fatty acid supplementation in addition to mesalazine in maintaining remission in pediatric Crohn's disease: a double-blind, randomized, placebo-controlled study. World J Gastroenterol. 2005; 11(45):7118–7121.
  32. Fortin P. R. et al. Validation of a meta-analysis: the effects of fish oil in rheumatoid arthritis. J Clin Epidemiol. 1995; 48(11):1379–1390. 
  33. Goldberg R. J. et al. A meta-analysis of the analgesic effects of omega-3 polyunsaturated fatty acid supplementation for inflammatory joint pain. Pain. 2007; 129(1-2):210–223.
  34. Dangardt F. et al. Omega-3 fatty acid supplementation improves vascular function and reduces inflammation in obese adolescents. Atherosclerosis. 2010; 212(2):580–585.