ICHNFM Courses, Books, Membership, Newsletter

Essay/Excerpt: Nutrigenomics

Nutrigenomics: Pro-Inflammatory and Anti-Inflammatory Effects of Foods and Nutrients
We must look beyond the nutritional properties of foods to appreciate that dietary patterns and the consumption of specific foods can influence genetic expression and either promote or retard the development of inflammation and related clinical disorders. The purpose of this section is to help clinicians attain a more profound understanding of the value of nutrition and its critical role as a foundational component in the treatment plan of patients with inflammatory disorders. The “correct” diet for the vast majority of patients with inflammatory disorders is the “supplemented Paleo-Mediterranean diet” which I have described in several other publications. The diet is modified for the specific exclusion of allergenic foods; it is implemented on a rotation basis, and it allows for periodic fasting and vegetarianism/veganism. The implementation of health-promoting dietary modifications is an absolutely mandatory component of the treatment plan, upon which other treatments depend for their success. The study of how dietary components and nutritional supplements influence genetic expression is referred to as nutrigenomics or nutritional genomics and has been described as “the next frontier in the postgenomic era.”[1] Various nutrients have been shown to modulate genetic expression and thus alter phenotypic manifestations of disease by upregulating or downregulating specific genes, interacting with nuclear receptors, altering hormone receptors, and modifying the influence of transcription factors, such as pro-inflammatory NFkB (NFkB) and the anti-inflammatory peroxisome-proliferator activated receptors (PPARs).[2],[3],[4],[5] The previous view that nutrients only interact with human physiology at the metabolic/post-transcriptional level must be updated in light of current research showing that nutrients can, in fact, modify human physiology and phenotype at the genetic/pre-transcriptional level.       Fatty acids and their eicosanoid, leukotriene, and isoprostane intermediates and end-products modulate genetic expression in several ways. In general, n-3 fatty acids decrease inflammation and promote health while n-6 fatty acids (except for GLA, which is generally health-promoting) increase inflammation, oxidative stress, and the manifestation of disease. Corn oil, probably as a result of its high n-6 LA (linoleic acid) content, rapidly activates NFkB and thus promotes tumor development, atherosclerosis, and elaboration of proinflammatory mediators such as TNFa.[6],[7],[8] Similarly n-6 arachidonic acid increases production of the free radical superoxide approximately 4-fold when added to isolated Kupffer cells in vitro. Prostaglandin-E2 is produced from arachidonic acid by cyclooxygenase and increases genetic expression of cyclooxygenase and IL-6; thus, an increase in PG-E2 leads to additive expression of cyclooxygenase, which further increases inflammation and elevates C-reactive protein.[9] Some of the unique health-promoting effects of GLA are nutrigenomically mediated via activation of PPAR-gamma, resultant inhibition of NFkB, and impairment of estrogen receptor function.[10],[11] Supplementation with ALA leads to a dramatic reduction of prostaglandin formation in humans[12], and this effect is probably mediated by downregulation of proinflammatory gene transcription, as evidenced by reductions in CRP, IL-6, and serum amyloid A.[13] EPA appears to exert much of its anti-inflammatory benefit by suppressing NFkB activation and thus reducing elaboration of proinflammatory mediators.[14],[15] EPA also indirectly modifies gene expression and cell growth by reducing intracellular calcium levels and thus activating protein kinase R which impairs eukaryotic initiation factor-2alpha and inhibits protein synthesis at the level of translation initiation, thereby mediating an anti-cancer benefit.[16] DHA is the precursor to docosatrienes and resolvins which downregulate gene expression for IL-1, inhibit TNFa, and reduce neutrophil entry to sites of inflammation.[17] Oxidized EPA activates PPAR-alpha and thereby suppresses NFkB.[18],[19] Other nutrients that inhibit the activation of NFkB include vitamin D[20],[21], lipoic acid[22], green tea[23], rosemary[24], grape seed extract[25], resveratrol[26],[27], caffeic acid phenethyl ester (CAPE) from bee propolis[28], indole-3-carbinol[29], N-acetyl-L-cysteine[30], selenium[31], and zinc.[32] Therefore, we see that fatty acids and nutrients directly affect gene expression by complex and multiple mechanisms, as graphically illustrated in the accompanying diagram, and the synergism and potency of these anti-inflammatory nutraceuticals supports the rationale for the use of nutrition and select botanicals for the safe and effective treatment of inflammatory disorders.

 

[1] Kaput J, Rodriguez RL. Nutritional genomics: the next frontier in the postgenomic era. Physiol Genomics. 2004 Jan 15;16(2):166-77.  Very important article.

[2] Vamecq J, Latruffe N. Medical significance of peroxisome proliferator-activated receptors. Lancet. 1999;354:141-8

[3] Ehrmann et al. Peroxisome proliferator-activated receptors (PPARs) in health and disease. Biomed Pap Med Fac Univ Palacky Olomouc Czech Repub. 2002 Dec;146(2):11-4

[4] Kliewer SA, Xu HE, Lambert MH, Willson TM. Peroxisome proliferator-activated receptors: from genes to physiology. Recent Prog Horm Res. 2001;56:239-63

[5] Delerive P, Fruchart JC, Staels B. Peroxisome proliferator-activated receptors in inflammation control. J Endocrinol. 2001;169(3):453-9

[6] Rusyn I, et al. Corn oil rapidly activates nuclear factor-kappaB in hepatic Kupffer cells by oxidant-dependent mechanisms. Carcinogenesis. 1999 Nov;20(11):2095-100

[7] Rose DP, et al. Effect of diets containing different levels of linoleic acid on human breast cancer growth and lung metastasis in nude mice. Cancer Res 1993;53:4686-90

[8] Dichtl et al. Linoleic acid-stimulated vascular adhesion molecule-1 expression in endothelial cells depends on nuclear factor-kappaB. Metabolism 2002;51:327-33

[9] Bagga et al. Differential effects of prostaglandin from n-6 and n-3 polyunsaturated fatty acids on COX-2 expression and IL-6 secretion. Proc Natl Acad Sci. 2003 Feb:1751-6.

[10] Menendez JA, Colomer R, Lupu R. Omega-6 polyunsaturated fatty acid gamma-linolenic acid (18:3n-6) is a selective estrogen-response modulator in human breast cancer cells: gamma-linolenic acid antagonizes estrogen receptor-dependent transcriptional activity, transcriptionally represses estrogen receptor expression and synergistically enhances tamoxifen and ICI 182,780 (Faslodex) efficacy in human breast cancer cells. Int J Cancer. 2004 May 10;109(6):949-54

[11] Jiang WG, Redfern A, Bryce RP, Mansel RE. Peroxisome proliferator activated receptor-gamma (PPAR-gamma) mediates the action of gamma linolenic acid in breast cancer cells. Prostaglandins Leukot Essent Fatty Acids. 2000 Feb;62(2):119-27

[12] Adam O, et al. Effect of alpha-linolenic acid in the human diet on linoleic acid metabolism and prostaglandin biosynthesis. J Lipid Res. 1986 Apr;27(4):421-6

[13] Rallidis et al. Dietary alpha-linolenic acid decreases C-reactive protein, serum amyloid A and interleukin-6 in dyslipidaemic patients. Atherosclerosis. 2003;167:237-42

[14] Zhao et al. Eicosapentaenoic acid prevents LPS-induced TNF-alpha expression by preventing NFkB activation. J Am Coll Nutr. 2004 Feb;23(1):71-8

[15] Mishra et al. Oxidized omega-3 fatty acids inhibit NFkB activation via a PPARalpha-dependent pathway. Arterioscler Thromb Vasc Biol. 2004 Sep;24:1621-7

[16] Palakurthi et al. Inhibition of translation initiation mediates the anti-cancer effect of the n-3 polyunsaturated fatty acid EPA. Cancer Res. 2000 Jun 1;60(11):2919-25

[17] “These results indicate that DHA is the precursor to potent protective mediators generated via enzymatic oxygenations to novel docosatrienes and 17S series resolvins that each regulate events of interest in inflammation and resolution.” Hong S, Gronert K, Devchand PR, Moussignac RL, Serhan CN. Novel docosatrienes and 17S-resolvins generated from docosahexaenoic acid in murine brain, human blood, and glial cells. Autacoids in anti-inflammation. J Biol Chem. 2003 Apr 25;278(17):14677-87

[18] Mishra et al. Oxidized omega-3 fatty acids inhibit NFkB activation via a PPARalpha-dependent pathway. Arterioscler Thromb Vasc Biol. 2004 Sep;24:1621-7

[19] Delerive P, Fruchart JC, Staels B. Peroxisome proliferator-activated receptors in inflammation control. J Endocrinol. 2001;169(3):453-9

[20] “1Alpha,25-dihydroxyvitamin D3 (1,25-(OH)2-D3), the active metabolite of vitamin D, can inhibit NFkB activity in human MRC-5 fibroblasts, targeting DNA binding of NFkB ...” Harant et al. 1Alpha,25-dihydroxyvitamin D3 decreases DNA binding of nuclear factor-kappaB in human fibroblasts. FEBS Lett. 1998 Oct 9;436(3):329-34

[21] “Thus, 1,25(OH)2D3 may negatively regulate IL-12 production by downregulation of NF-kB activation and binding to the p40-kB sequence.” D'Ambrosio D, et al. Inhibition of IL-12 production by 1,25-dihydroxyvitamin D3. Involvement of NFkB downregulation. J Clin Invest. 1998 Jan 1;101(1):252-62

[22] “ALA reduced TNF-alpha-stimulated ICAM-1 expression in a dose-dependent manner, to levels observed in unstimulated cells. Alpha-lipoic acid also reduced NFkB activity in a dose-dependent manner.” Lee et al. Alpha-lipoic acid modulates NFkB activity in human monocytic cells by direct interaction with DNA. Exp Gerontol. 2002 Jan:401-10

[23] “In conclusion, EGCG is an effective inhibitor of IKK activity. This may explain, at least in part, some of the reported anti-inflammatory and anti-cancer effects of green tea.” Yang et al. The green tea polyphenol (-)-epigallocatechin-3-gallate blocks nuclear factor-kappa B activation by inhibiting I kappa B kinase activity in the intestinal epithelial cell line IEC-6. Mol Pharmacol. 2001 Sep;60(3):528-33

[24] “These results suggest that carnosol suppresses the NO production and iNOS gene expression by inhibiting NFkB activation, and provide possible mechanisms for its anti-inflammatory and chemopreventive action.” Lo AH, Liang YC, Lin-Shiau SY, Ho CT, Lin JK. Carnosol, an antioxidant in rosemary, suppresses inducible nitric oxide synthase through down-regulating nuclear factor-kappaB in mouse macrophages. Carcinogenesis. 2002 Jun;23(6):983-91

[25] “Constitutive and TNFalpha-induced NFkB DNA binding activity was inhibited by GSE at doses > or =50 microg/ml and treatments for > or =12 h.” Dhanalakshmi et al. Inhibition of NFkB pathway in grape seed extract-induced apoptotic death of human prostate carcinoma DU145 cells. Int J Oncol. 2003 Sep;23(3):721-7

[26] “Resveratrol's anticarcinogenic, anti-inflammatory, and growth-modulatory effects may thus be partially ascribed to the inhibition of activation of NFkB and AP-1 and the associated kinases.” Manna SK, Mukhopadhyay A, Aggarwal BB. Resveratrol suppresses TNF-induced activation of nuclear transcription factors NF-kappa B, activator protein-1, and apoptosis: potential role of reactive oxygen intermediates and lipid peroxidation. J Immunol. 2000 Jun 15;164(12):6509-19

[27] “Both resveratrol and quercetin inhibited NFkB-, AP-1- and CREB-dependent transcription to a greater extent than the glucocorticosteroid, dexamethasone.” Donnelly LE, et al. Anti-inflammatory Effects of Resveratrol in Lung Epithelial Cells. Am J Physiol Lung Cell Mol Physiol. 2004 Oct;287(4):L774-83

[28] “Caffeic acid phenethyl ester (CAPE) is an anti-inflammatory component of propolis (honeybee resin). CAPE is reportedly a specific inhibitor of nuclear factor-kappaB (NFkB).” Fitzpatrick LR, Wang J, Le T. Caffeic acid phenethyl ester, an inhibitor of nuclear factor-kappaB, attenuates bacterial peptidoglycan polysaccharide-induced colitis in rats. J Pharmacol Exp Ther. 2001 Dec;299(3):915-20

[29] Takada Y, Andreeff M, Aggarwal BB. Indole-3-carbinol suppresses NF-{kappa}B and I{kappa}B{alpha} kinase activation causing inhibition of expression of NF-{kappa}B-regulated antiapoptotic and metastatic gene products and enhancement of apoptosis in myeloid and leukemia cells. Blood. 2005 Apr 5; [Epub ahead of print]

[30] Paterson RL, Galley HF, Webster NR. The effect of N-acetylcysteine on nuclear factor-kappa B activation, interleukin-6, interleukin-8, and intercellular adhesion molecule-1 expression in patients with sepsis. Crit Care Med. 2003 Nov;31(11):2574-8

[31] Faure et al. Selenium supplementation decreases nuclear factor-kappa B activity in blood mononuclear cells from type 2 diabetic patients. Eur J Clin Invest. 2004;34(7):475-81

[32] Uzzo et al. Zinc inhibits nuclear factor-kappa B activation and sensitizes prostate cancer cells to cytotoxic agents. Clin Cancer Res. 2002;8(11):3579-83