- Email: [email protected]
When less is adequate: Protein and calorie restriction boosts immunity and possibly, longevity—but how and why?
Nutrition 25 (2009) 892–895
Editorial
www.nutritionjrnl.com
When less is adequate: Protein and calorie restriction boosts immunity and possibly, longevity—but how and why? Energy balance is a homeostatic system. High-energy diet consumption and protein–energy undernutrition cause malfunction of this system and lead to obesity and malnutrition, respectively. By definition, malnutrition is an imbalance between the nutrients the body needs and the nutrients it gets. Thus, malnutrition includes overnutrition, i.e., consumption of too many calories or too much of any specific nutrient— protein, fat, vitamin, mineral, or other dietary supplement— and this is common in the developed world, especially excess consumption of calories from fat and protein, and in the developing countries, protein–energy undernutrition is common, especially in children. Undernutrition causes stunted growth, decreases muscle mass and strength, causes smaller internal organs (such as kidneys with a decreased number of glomeruli, relatively fewer pancreatic b-cells, etc.), and impairs immunity that renders children more susceptible to develop insulin resistance, metabolic syndrome, and type 2 diabetes mellitus in adult life [1]. It is surprising that even overnutrition produces similar consequences. For instance, overnutrition not only leads to obesity but also impairs immunity and causes low-grade systemic inflammation that is associated with progressive atherosclerosis, pancreatic b-cell dysfunction in the form of insulin resistance, type 2 diabetes mellitus, hypertension, and certain forms of cancer [2]. Conversely, protein and calorie restriction without malnutrition improves immunity by protecting against hepatitis B virus and malaria infections, delaying or preventing development of cancer and metastasis, and possibly delaying the onset of numerous age-associated diseases including atherosclerosis, diabetes mellitus and greatly increasing lifespan [3–5]. In this context, the results of Oarada et al. [6] on the beneficial effects of a low-protein (1.5% casein) diet on host resistance to fungal infection in mice are interesting. They showed that animals fed a proteinrestricted diet (1.5% casein) had higher antifungal activity in the spleen and liver and increases in spleen and liver levels of interleukin-6 (IL-6), interferon-g (IFN-g), and antimicrobial protein myeloperoxidase, and mediators of inflammation such as cytokine IL-18, nuclear factor-kB, inducible nitric oxide synthase, and granulocyte-macrophage colony stimulating factor were less profoundly increased E-mail address: [email protected] (U.N. Das). 0899-9007/09/$ – see front matter Ó 2009 Elsevier Inc. All rights reserved. doi:10.1016/j.nut.2009.03.005
compared with those seen in mice fed a 20% casein diet. The low-protein diet–fed animals (1.5% casein) showed a less dramatic gain in total body, spleen, and liver weights compared with those that were fed the ‘‘optimal protein diet’’ (20% casein). From data provided by the investigators, it is not clear whether the resistance to fungal infection observed in the low-protein diet–fed animals was due to less gain in weight. This is an important variable because inappropriate weight gain could have a dampening effect on optimal immune response [7,8], although the mice fed a 20% casein diet in the study reported by Oarada et al. were not necessarily obese by definition. These results also emphasize the fact that the composition of the diet is an important factor in the modulation of immune response(s) because the diets used were isocaloric except for the change in protein content. Why would a change in the protein content of the diet influence immune response? Why, how, and what is responsible for the beneficial effects of restricted protein intake on stress induced by infection? Is it possible that some of the lessons learned from the beneficial actions of 20% to 40% calorie restriction on lifespan extension and its protective actions against cardiovascular diseases, cancer, diabetes, and neurodegenerative diseases could be extended to the benefits observed with a low-protein diet? In a study that evaluated the combination of angiotensinconverting enzyme inhibitors and a low-protein diet (0.6 to 0.7 g $ kg 1 $ d 1 instead of 1 g $ kg 1 $ d 1), it was noted that not only did kidney disease not progress but insulin resistance improved remarkably as measured by oral glucose tolerance testing and glucose, insulin, and C-peptide determinations. Furthermore, these patients showed decreased plasma triacylglycerol very-low-density lipoprotein concentrations, decreased proteinuria, and an increased high-density lipoprotein concentration [9]. Because angiotensin-converting enzyme inhibitors do not improve insulin resistance in patients with chronic renal disease, the change noticed in insulin resistance in this study could be attributed to a lowprotein diet. In this context, it is interesting to note that even calorie restriction improves insulin resistance, possibly by enhancing the activation of sirtuins (that include SIRT1, SIRT3, SIRT4, SIRT6, and SIRT7), a group of oxidized nicotinamide adenosine dinucleotide–dependent deacetylases. Of these, SIRT1 has been well characterized and deacetylates
U. N. Das / Nutrition 25 (2009) 892–895
transcription factor p53, forkhead subgroup O proteins, and the DNA repair factor KU, thereby increasing the stress resistance of cells by inhibiting apoptosis and increasing repair [10]. SIRT1 regulates glucose and lipid homeostasis and increases mitochondrial biogenesis and metabolism. In
893
mammals, calorie restriction not only decreases blood glucose, triacylglycerols, and growth factors but also increases physical activity. The molecular mechanism for this increase in physical activity is not known, but it has been suggested that calorie restriction triggers changes in brain regions that
DIET
Calorie/protein restricted
Protein rich
Carbohydrate rich
Plasma Glucose
Plasma Insulin
6
5
No protein
Incretins
Desaturases
Dietary and endogenous EFAs
GLA, AA, EPA, DHA Lipoxins, Resolvins, Protectins, Maresins
Macrophages/Lymphocytes/PMNs
Motility/adhesion
GIT
Free radicals/MPO
Liver
Cytokines
Hypothalamus/Brain
Humoral and cell mediated Immune response Fig. 1. Scheme showing possible interaction(s) among diet, EFAs, the gut–liver–brain axis, and the immune system. A diet rich in carbohydrates produces an inappropriate increase in plasma glucose and insulin levels that could inhibit the activities of 6-6- and 6-5-desaturases leading to a decrease in the production of GLA, AA, EPA, and DHA and as a consequence the formation of lipoxins, resolvins, protectins, and maresins. High plasma glucose would also inhibit macrophage/leukocyte function, enhance their adhesion, and augment production of proinflammatory cytokines interleukin-6 and tumor necrosis factor-a. A carbohydrate-rich diet also inhibits neuropeptide Y levels in the hypothalamus that could enhance the production of interferon-g. Continued consumption of a high-carbohydrate diet may dampen the production of incretins that could, in part, lead to persistent hyperglycemia and secondary insulin resistance. A similar, if not identical, scenario may exist with a diet rich in protein. A protein-poor or protein-free diet may decrease protein synthesis, inhibit 6-6- and 6-5-desaturases and its consequences, leading to immunosuppression that is, in part, due to decreased production of interleukin-6, tumor necrosis factor-a, and interferon-g. A calorie-/protein-restricted diet that does not produce malnutrition inhibits inappropriate increases in plasma glucose and insulin levels, enhances the activities of 6-6- and 6-5-desaturases, and thus leads to the formation of need-based concentrations of lipoxins, resolvins, protectins, and maresins that protect against infections and enhance wound healing. A calorie-/protein restricted diet may also maintain physiologic levels of hypothalamic peptides and other neurotransmitters. Enhanced activities of 6-6- and 6-5-desaturases protect cells from inflammation, infections, and other cytotoxins and suppress inappropriate production of proinflammatory cytokines. AA, arachidonic acid; DHA, docosahexaenoic acid; EPA, eicosapentaenoic acid; GIT, glucose intolerance; GLA, g-linolenic acid; MPO, myeloperoxidase; PMN, polymorphonuclear leukocytes.
894
U. N. Das / Nutrition 25 (2009) 892–895
govern physical activity and that sirtuins could regulate this pathway [11]. It is also interesting to note the close relation between protein, lipid, and carbohydrate feeding and the metabolism of essential fatty acids (EFAs), the precursors of many biologically active molecules. Linoleic acid (18:2 u-6) and a-linolenic acid (18:3 u-3) are EFAs. The conversion of linoleic acid to its long-chain metabolites such as g-linolenic acid (GLA; 18:3 u-6), and arachidonic acid (AA; 20:4 u6) and that of a-linolenic acid to eicosapentaenoic acid (EPA; 20:5 u-3) and docosahexaenoic acid (DHA; 22:6 u-3) depends on the activities of 6-6- and 6-5-desaturases [12,13]. AA, EPA, and DHA form precursors to potent anti-inflammatory and immunomodulatory molecules, i.e., lipoxins, resolvins, protectins, and maresins. In addition, GLA, AA, EPA, and DHA possess antibacterial, antiviral, and antifungal actions [15–17]. Of the several factors that modulate the activities of 6-6- and 6-5-desaturases, dietary glucose, protein, and plasma insulin play a major role. A 96-h fasting produces a significant reduction, whereas calorie restriction enhances the activity of 6-6-desaturase. When protein is the only source of calories in the diet, a marked increase in 6-6desaturase is observed. In contrast, glucose administration results in a significant decrease in its activity. Insulin seems to have two principal effects in vivo: an enhancement of the activity of 6-6-desaturase, probably by enhancing protein synthesis, and a decrease in 6-6-desaturase through a stimulation of glycolysis. However, when an insulin dose that is sufficient to increase protein synthesis without producing detectable changes in the blood glucose level is employed, insulin enhances 6-6-desaturase activity [12,13,18]. Thus, the effects of various types of diets and insulin on the metabolism of EFAs appear to be complex and the final result might depend on the balance between plasma glucose and insulin levels and the major source of calories. In the study reported by Oarada et al. [6], the observation that the group that received a 1.5% casein showed higher antifungal activity compared with groups that received 20% and 0% casein diets could be attributed to lower plasma glucose and optimal insulin levels. In contrast, the group that received 0% casein obtained all their calories from sucrose that may have resulted in higher plasma glucose levels leading to suppression of 66- and 6-5-desaturases. It may be noted here that hyperglycemia is cytotoxic and suppresses immune response. These proposals could be verified by studying the plasma and tissue (especially liver and macrophage) concentrations of EFAs and their metabolites. It is important to note that GLA, AA, EPA, and DHA and their products lipoxins, resolvins, protectins, and maresins suppress excess production of IL-6, tumor necrosis factor-a (TNF-a), macrophage migration inhibitory factor, and free radicals [12,13]. Thus, it is possible that under physiologic conditions there is a delicate balance maintained between plasma/tissue glucose, protein synthesis, plasma/ tissue EFAs and their metabolites, cytokines, and free radicals that ultimately determines the local and systemic responses to
infection and injury and recovery and tissue repair. Furthermore, EFAs, lipoxins, resolvins, protectins, maresins, and insulin possess cytoprotective actions [12,13,19], whereas higher concentrations of IL-6, TNF-a, macrophage migration inhibitory factor, and free radicals are cytotoxic in nature despite the fact that optimal amounts of cytokines and free radicals are essential for normal immune response and to eliminate the invading organisms. The role of the food–gut–brain–liver axis in the regulation of food intake, energy homeostasis, and immune response also needs attention. When nutrients are delivered into the gut, homeostatic mechanisms in place there are activated so that blood glucose levels are not unduly perturbed. The reason for this effect is that ingested nutrients stimulate the release of gut peptides called incretins, which enhance the secretion of insulin. This link between nutrient sensing in the gut and insulin secretion and action in the liver involves an intestine–brain–liver circuit within the parasympathetic nervous system. Because the hypothalamus is an important regulator of appetite, satiety, and food intake by elaborating several peptides that include neuropeptide Y (NPY) and leptin, it is important to know whether these peptides have any immunomodulatory actions. NPY being an orexigenic peptide, its levels will be low after food intake and high during fasting. Studies have shown that NPY has a regulatory role in innate immunity [20] and suppresses the phagocytic and leishmanicidal capacities of macrophages [21]. Furthermore, stimulating non-adherent splenocytes and helper T-cell clones with antigens in vitro in the presence NPY greatly enhance IL-4 production and inhibit IFN-g [22,23]. Thus, reinterpreting the data provided by Oarada et al. [6], it is tempting to suggest that groups that received 0% and 20% casein diets showed enhanced hypothalamic NPY production that, in turn, altered IFN-g and IL-6 secretion. It is possible that plasma and tissue concentrations of insulin and glucose also have a modulatory effect on IFN-g and IL-6 secretion. Thus, the effects of various nutrients including their carbohydrate, protein, and lipid content on immune response is complex and no simple explanation will be sufficient to explain all the variables noted. A better and proper understanding of the relations between nutrients, the effects of individual component of various diets on immune response, and the response of the host to infection(s) needs a very comprehensive study that includes not only cytokines and free radical generation but also the behavior of macrophages and other immune cells, modulatory influence of insulin, glucose, and fatty acids, sympathetic and parasympathetic nervous systems, and the role of various hypothalamic peptides and neurotransmitters on cell and humoral immune responses, as depicted in Figure 1. Undurti N. Das, M.D., F.A.M.S UND Life Sciences, Shaker Heights, Ohio, USA; and Department of Medicine, Bharati Vidyapeeth University Medical College, Pune, India
U. N. Das / Nutrition 25 (2009) 892–895
References [1] Das UN. Perinatal and childhood nutrition and its impact on cognitive function and adult diseases. Agro Food Ind Hi-tech 2008;19:4–8. [2] Das UN. Is metabolic syndrome X a disorder of the brain? Curr Nutr Food Sci 2008;4:73–108. [3] Weindruch R, Walford RL. The retardation of aging and disease by dietary restriction. Springfield, IL: Charles C Thomas; 1988. [4] Holliday R. Food,reproduction longevity: is the extended life span of calorie-restricted animals an evolutionary adaptation? Bioessays 1989;10:125–7. [5] Yu BP, Masoro EJ, McMahan CA. Nutritional influences on ageing of Fischer-34 rats. 1. Physical, metabolic, and longevity characteristics. J Gerontol 1985;40:657–70. [6] Oarada M, Kamei K, Gonoi T, Tsuzuki T, Toyotome T, Hirasaka K, et al. Beneficial effects of a low protein diet on host resistance to Paracoccidioides brasiliensis in mice. Nutrition 2009;25:954–63. [7] Katagiri K, Arakawa S, Kurahashi R, Hatano Y. Impaired contact hypersensitivity in diet-induced obese mice. J Dermatol Sci 2007;46: 117–26. [8] Eliakim A, Schwindt C, Zaldivar F, Casali P, Cooper DM. Reduced tetanus antibody titers in overweight children. Autoimmunity 2006; 39:137–41. [9] Stefikova K, Spustova V, Gazdikova K, Krivosikova Z, Dzurik R. Dietary protein restriction in combination with angiotensin converting enzyme inhibitor improves insulin resistance in patients with chronic renal disease. Int Urol Nephrol 1997;29:497–507. [10] Guarente L. Sirtuins as potential targets for metabolic syndrome. Nature 2006;444:868–74. [11] Chen D, Steele AD, Lindquist S, Guarente L. Increase in activity during calorie restriction requires Sirt1. Science 2005;310:1641. [12] Das UN. Essential fatty acids: biochemistry, physiology and pathology. Biotechnol J 2006;1:420–39.
895
[13] Das UN. Essential fatty acids—review. Curr Pharm Biotechnol 2006; 7:467–82. [14] Das UN. Antibiotic-like action of essential fatty acids. Can Med Assoc J 1985;132:1350. [15] Leu G-Z, LinT-Y Hsu TA. Anti-HCV activities of selective polyunsaturated fatty acids. Biochem Biophys Res Commun 2004; 318:275–80. [16] Das UN. Do unsaturated fatty acids behave as endogenous anti-bacterial and anti-viral molecules? Am J Clin Nutr 2006;83:390–1. [17] Das UN. Can essential fatty acids reduce the burden of diseases(s)? Lipids Health Dis 2008;7:9. [18] Peluffo RO, De Gomez Dumm NT, De Alaniz JT, Brenner RR. Effect of protein and insulin on linoleic acid desaturation of normal and diabetic rats. J Nutr 1971;101:1075–84. [19] Li J, Zhang H, Wu F, Nan Y, Ma H, Guo W, et al. Insulin inhibits tumor necrosis factor-a induction in myocardial ischemia/reperfusion: role of Akt and endothelial nitric oxide synthase phosphorylation. Crit Care Med 2008;36:1551–8. [20] Styer KL, Singh V, Macosko E, Steele SE, Bargmann CL, Aballay A. Innate immunity in Caenorhabditis elegans is regulated by neurons expressing NPR-1/GPCR. Science 2008;322:460–4. [21] Ahmed AA, Wahbi AH, Nordlin K. Neuropeptides modulate a murine monocyte/macrophage cell line capacity for phagocytosis and killing of Leishmania major parasites. Immunopharmacol Immunotoxicol 2001; 23:397–409. [22] Kawamura N, Tamura H, Obana S, Wenner M, Ishikawa T, Nakata A, Yamamoto H. Differential effects of neuropeptides on cytokine production by mouse helper T cell subsets. Neuroimmunomodulation 1998; 5:9–15. [23] Von Horsten S, Ballof J, Hefritz F, Nave H, Meyer D, Schmidt RE, et al. Modulation of innate immune functions by intracerebroventricularly applied neuropeptide Y: dose and time dependent effects. Life Sci 1998;63:909–22.
Editorial
www.nutritionjrnl.com
When less is adequate: Protein and calorie restriction boosts immunity and possibly, longevity—but how and why? Energy balance is a homeostatic system. High-energy diet consumption and protein–energy undernutrition cause malfunction of this system and lead to obesity and malnutrition, respectively. By definition, malnutrition is an imbalance between the nutrients the body needs and the nutrients it gets. Thus, malnutrition includes overnutrition, i.e., consumption of too many calories or too much of any specific nutrient— protein, fat, vitamin, mineral, or other dietary supplement— and this is common in the developed world, especially excess consumption of calories from fat and protein, and in the developing countries, protein–energy undernutrition is common, especially in children. Undernutrition causes stunted growth, decreases muscle mass and strength, causes smaller internal organs (such as kidneys with a decreased number of glomeruli, relatively fewer pancreatic b-cells, etc.), and impairs immunity that renders children more susceptible to develop insulin resistance, metabolic syndrome, and type 2 diabetes mellitus in adult life [1]. It is surprising that even overnutrition produces similar consequences. For instance, overnutrition not only leads to obesity but also impairs immunity and causes low-grade systemic inflammation that is associated with progressive atherosclerosis, pancreatic b-cell dysfunction in the form of insulin resistance, type 2 diabetes mellitus, hypertension, and certain forms of cancer [2]. Conversely, protein and calorie restriction without malnutrition improves immunity by protecting against hepatitis B virus and malaria infections, delaying or preventing development of cancer and metastasis, and possibly delaying the onset of numerous age-associated diseases including atherosclerosis, diabetes mellitus and greatly increasing lifespan [3–5]. In this context, the results of Oarada et al. [6] on the beneficial effects of a low-protein (1.5% casein) diet on host resistance to fungal infection in mice are interesting. They showed that animals fed a proteinrestricted diet (1.5% casein) had higher antifungal activity in the spleen and liver and increases in spleen and liver levels of interleukin-6 (IL-6), interferon-g (IFN-g), and antimicrobial protein myeloperoxidase, and mediators of inflammation such as cytokine IL-18, nuclear factor-kB, inducible nitric oxide synthase, and granulocyte-macrophage colony stimulating factor were less profoundly increased E-mail address: [email protected] (U.N. Das). 0899-9007/09/$ – see front matter Ó 2009 Elsevier Inc. All rights reserved. doi:10.1016/j.nut.2009.03.005
compared with those seen in mice fed a 20% casein diet. The low-protein diet–fed animals (1.5% casein) showed a less dramatic gain in total body, spleen, and liver weights compared with those that were fed the ‘‘optimal protein diet’’ (20% casein). From data provided by the investigators, it is not clear whether the resistance to fungal infection observed in the low-protein diet–fed animals was due to less gain in weight. This is an important variable because inappropriate weight gain could have a dampening effect on optimal immune response [7,8], although the mice fed a 20% casein diet in the study reported by Oarada et al. were not necessarily obese by definition. These results also emphasize the fact that the composition of the diet is an important factor in the modulation of immune response(s) because the diets used were isocaloric except for the change in protein content. Why would a change in the protein content of the diet influence immune response? Why, how, and what is responsible for the beneficial effects of restricted protein intake on stress induced by infection? Is it possible that some of the lessons learned from the beneficial actions of 20% to 40% calorie restriction on lifespan extension and its protective actions against cardiovascular diseases, cancer, diabetes, and neurodegenerative diseases could be extended to the benefits observed with a low-protein diet? In a study that evaluated the combination of angiotensinconverting enzyme inhibitors and a low-protein diet (0.6 to 0.7 g $ kg 1 $ d 1 instead of 1 g $ kg 1 $ d 1), it was noted that not only did kidney disease not progress but insulin resistance improved remarkably as measured by oral glucose tolerance testing and glucose, insulin, and C-peptide determinations. Furthermore, these patients showed decreased plasma triacylglycerol very-low-density lipoprotein concentrations, decreased proteinuria, and an increased high-density lipoprotein concentration [9]. Because angiotensin-converting enzyme inhibitors do not improve insulin resistance in patients with chronic renal disease, the change noticed in insulin resistance in this study could be attributed to a lowprotein diet. In this context, it is interesting to note that even calorie restriction improves insulin resistance, possibly by enhancing the activation of sirtuins (that include SIRT1, SIRT3, SIRT4, SIRT6, and SIRT7), a group of oxidized nicotinamide adenosine dinucleotide–dependent deacetylases. Of these, SIRT1 has been well characterized and deacetylates
U. N. Das / Nutrition 25 (2009) 892–895
transcription factor p53, forkhead subgroup O proteins, and the DNA repair factor KU, thereby increasing the stress resistance of cells by inhibiting apoptosis and increasing repair [10]. SIRT1 regulates glucose and lipid homeostasis and increases mitochondrial biogenesis and metabolism. In
893
mammals, calorie restriction not only decreases blood glucose, triacylglycerols, and growth factors but also increases physical activity. The molecular mechanism for this increase in physical activity is not known, but it has been suggested that calorie restriction triggers changes in brain regions that
DIET
Calorie/protein restricted
Protein rich
Carbohydrate rich
Plasma Glucose
Plasma Insulin
6
5
No protein
Incretins
Desaturases
Dietary and endogenous EFAs
GLA, AA, EPA, DHA Lipoxins, Resolvins, Protectins, Maresins
Macrophages/Lymphocytes/PMNs
Motility/adhesion
GIT
Free radicals/MPO
Liver
Cytokines
Hypothalamus/Brain
Humoral and cell mediated Immune response Fig. 1. Scheme showing possible interaction(s) among diet, EFAs, the gut–liver–brain axis, and the immune system. A diet rich in carbohydrates produces an inappropriate increase in plasma glucose and insulin levels that could inhibit the activities of 6-6- and 6-5-desaturases leading to a decrease in the production of GLA, AA, EPA, and DHA and as a consequence the formation of lipoxins, resolvins, protectins, and maresins. High plasma glucose would also inhibit macrophage/leukocyte function, enhance their adhesion, and augment production of proinflammatory cytokines interleukin-6 and tumor necrosis factor-a. A carbohydrate-rich diet also inhibits neuropeptide Y levels in the hypothalamus that could enhance the production of interferon-g. Continued consumption of a high-carbohydrate diet may dampen the production of incretins that could, in part, lead to persistent hyperglycemia and secondary insulin resistance. A similar, if not identical, scenario may exist with a diet rich in protein. A protein-poor or protein-free diet may decrease protein synthesis, inhibit 6-6- and 6-5-desaturases and its consequences, leading to immunosuppression that is, in part, due to decreased production of interleukin-6, tumor necrosis factor-a, and interferon-g. A calorie-/protein-restricted diet that does not produce malnutrition inhibits inappropriate increases in plasma glucose and insulin levels, enhances the activities of 6-6- and 6-5-desaturases, and thus leads to the formation of need-based concentrations of lipoxins, resolvins, protectins, and maresins that protect against infections and enhance wound healing. A calorie-/protein restricted diet may also maintain physiologic levels of hypothalamic peptides and other neurotransmitters. Enhanced activities of 6-6- and 6-5-desaturases protect cells from inflammation, infections, and other cytotoxins and suppress inappropriate production of proinflammatory cytokines. AA, arachidonic acid; DHA, docosahexaenoic acid; EPA, eicosapentaenoic acid; GIT, glucose intolerance; GLA, g-linolenic acid; MPO, myeloperoxidase; PMN, polymorphonuclear leukocytes.
894
U. N. Das / Nutrition 25 (2009) 892–895
govern physical activity and that sirtuins could regulate this pathway [11]. It is also interesting to note the close relation between protein, lipid, and carbohydrate feeding and the metabolism of essential fatty acids (EFAs), the precursors of many biologically active molecules. Linoleic acid (18:2 u-6) and a-linolenic acid (18:3 u-3) are EFAs. The conversion of linoleic acid to its long-chain metabolites such as g-linolenic acid (GLA; 18:3 u-6), and arachidonic acid (AA; 20:4 u6) and that of a-linolenic acid to eicosapentaenoic acid (EPA; 20:5 u-3) and docosahexaenoic acid (DHA; 22:6 u-3) depends on the activities of 6-6- and 6-5-desaturases [12,13]. AA, EPA, and DHA form precursors to potent anti-inflammatory and immunomodulatory molecules, i.e., lipoxins, resolvins, protectins, and maresins. In addition, GLA, AA, EPA, and DHA possess antibacterial, antiviral, and antifungal actions [15–17]. Of the several factors that modulate the activities of 6-6- and 6-5-desaturases, dietary glucose, protein, and plasma insulin play a major role. A 96-h fasting produces a significant reduction, whereas calorie restriction enhances the activity of 6-6-desaturase. When protein is the only source of calories in the diet, a marked increase in 6-6desaturase is observed. In contrast, glucose administration results in a significant decrease in its activity. Insulin seems to have two principal effects in vivo: an enhancement of the activity of 6-6-desaturase, probably by enhancing protein synthesis, and a decrease in 6-6-desaturase through a stimulation of glycolysis. However, when an insulin dose that is sufficient to increase protein synthesis without producing detectable changes in the blood glucose level is employed, insulin enhances 6-6-desaturase activity [12,13,18]. Thus, the effects of various types of diets and insulin on the metabolism of EFAs appear to be complex and the final result might depend on the balance between plasma glucose and insulin levels and the major source of calories. In the study reported by Oarada et al. [6], the observation that the group that received a 1.5% casein showed higher antifungal activity compared with groups that received 20% and 0% casein diets could be attributed to lower plasma glucose and optimal insulin levels. In contrast, the group that received 0% casein obtained all their calories from sucrose that may have resulted in higher plasma glucose levels leading to suppression of 66- and 6-5-desaturases. It may be noted here that hyperglycemia is cytotoxic and suppresses immune response. These proposals could be verified by studying the plasma and tissue (especially liver and macrophage) concentrations of EFAs and their metabolites. It is important to note that GLA, AA, EPA, and DHA and their products lipoxins, resolvins, protectins, and maresins suppress excess production of IL-6, tumor necrosis factor-a (TNF-a), macrophage migration inhibitory factor, and free radicals [12,13]. Thus, it is possible that under physiologic conditions there is a delicate balance maintained between plasma/tissue glucose, protein synthesis, plasma/ tissue EFAs and their metabolites, cytokines, and free radicals that ultimately determines the local and systemic responses to
infection and injury and recovery and tissue repair. Furthermore, EFAs, lipoxins, resolvins, protectins, maresins, and insulin possess cytoprotective actions [12,13,19], whereas higher concentrations of IL-6, TNF-a, macrophage migration inhibitory factor, and free radicals are cytotoxic in nature despite the fact that optimal amounts of cytokines and free radicals are essential for normal immune response and to eliminate the invading organisms. The role of the food–gut–brain–liver axis in the regulation of food intake, energy homeostasis, and immune response also needs attention. When nutrients are delivered into the gut, homeostatic mechanisms in place there are activated so that blood glucose levels are not unduly perturbed. The reason for this effect is that ingested nutrients stimulate the release of gut peptides called incretins, which enhance the secretion of insulin. This link between nutrient sensing in the gut and insulin secretion and action in the liver involves an intestine–brain–liver circuit within the parasympathetic nervous system. Because the hypothalamus is an important regulator of appetite, satiety, and food intake by elaborating several peptides that include neuropeptide Y (NPY) and leptin, it is important to know whether these peptides have any immunomodulatory actions. NPY being an orexigenic peptide, its levels will be low after food intake and high during fasting. Studies have shown that NPY has a regulatory role in innate immunity [20] and suppresses the phagocytic and leishmanicidal capacities of macrophages [21]. Furthermore, stimulating non-adherent splenocytes and helper T-cell clones with antigens in vitro in the presence NPY greatly enhance IL-4 production and inhibit IFN-g [22,23]. Thus, reinterpreting the data provided by Oarada et al. [6], it is tempting to suggest that groups that received 0% and 20% casein diets showed enhanced hypothalamic NPY production that, in turn, altered IFN-g and IL-6 secretion. It is possible that plasma and tissue concentrations of insulin and glucose also have a modulatory effect on IFN-g and IL-6 secretion. Thus, the effects of various nutrients including their carbohydrate, protein, and lipid content on immune response is complex and no simple explanation will be sufficient to explain all the variables noted. A better and proper understanding of the relations between nutrients, the effects of individual component of various diets on immune response, and the response of the host to infection(s) needs a very comprehensive study that includes not only cytokines and free radical generation but also the behavior of macrophages and other immune cells, modulatory influence of insulin, glucose, and fatty acids, sympathetic and parasympathetic nervous systems, and the role of various hypothalamic peptides and neurotransmitters on cell and humoral immune responses, as depicted in Figure 1. Undurti N. Das, M.D., F.A.M.S UND Life Sciences, Shaker Heights, Ohio, USA; and Department of Medicine, Bharati Vidyapeeth University Medical College, Pune, India
U. N. Das / Nutrition 25 (2009) 892–895
References [1] Das UN. Perinatal and childhood nutrition and its impact on cognitive function and adult diseases. Agro Food Ind Hi-tech 2008;19:4–8. [2] Das UN. Is metabolic syndrome X a disorder of the brain? Curr Nutr Food Sci 2008;4:73–108. [3] Weindruch R, Walford RL. The retardation of aging and disease by dietary restriction. Springfield, IL: Charles C Thomas; 1988. [4] Holliday R. Food,reproduction longevity: is the extended life span of calorie-restricted animals an evolutionary adaptation? Bioessays 1989;10:125–7. [5] Yu BP, Masoro EJ, McMahan CA. Nutritional influences on ageing of Fischer-34 rats. 1. Physical, metabolic, and longevity characteristics. J Gerontol 1985;40:657–70. [6] Oarada M, Kamei K, Gonoi T, Tsuzuki T, Toyotome T, Hirasaka K, et al. Beneficial effects of a low protein diet on host resistance to Paracoccidioides brasiliensis in mice. Nutrition 2009;25:954–63. [7] Katagiri K, Arakawa S, Kurahashi R, Hatano Y. Impaired contact hypersensitivity in diet-induced obese mice. J Dermatol Sci 2007;46: 117–26. [8] Eliakim A, Schwindt C, Zaldivar F, Casali P, Cooper DM. Reduced tetanus antibody titers in overweight children. Autoimmunity 2006; 39:137–41. [9] Stefikova K, Spustova V, Gazdikova K, Krivosikova Z, Dzurik R. Dietary protein restriction in combination with angiotensin converting enzyme inhibitor improves insulin resistance in patients with chronic renal disease. Int Urol Nephrol 1997;29:497–507. [10] Guarente L. Sirtuins as potential targets for metabolic syndrome. Nature 2006;444:868–74. [11] Chen D, Steele AD, Lindquist S, Guarente L. Increase in activity during calorie restriction requires Sirt1. Science 2005;310:1641. [12] Das UN. Essential fatty acids: biochemistry, physiology and pathology. Biotechnol J 2006;1:420–39.
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