Showing papers by "Philip C. Calder published in 2006"

Polyunsaturated fatty acids and inflammation

Abstract: The n-6 polyunsaturated fatty acid arachidonic acid gives rise to the eicosanoid family of mediators (prostaglandins, thromboxanes, leukotrienes and related metabolites). These have inflammatory actions in their own right and also regulate the production of other mediators including inflammatory cytokines. Consumption of long chain n-3 polyunsaturated fatty acids decreases the amount of arachidonic acid in cell membranes and so available for eicosanoid production. Thus, n-3 polyunsaturated fatty acids decrease production of arachidonic acid-derived eicosanoids. These fatty acids also decrease the production of the classic inflammatory cytokines tumour necrosis factor, 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 modulation of the activation of transcription factors involved in inflammatory processes. The anti-inflammatory actions of long chain n-3 fatty acid-induced effects may be of therapeutic use in conditions with an acute or chronic inflammatory component.

Dietary α-linolenic acid and health-related outcomes: a metabolic perspective

Abstract: alpha-Linolenic acid (alphaLNA; 18: 3n-3) is essential in the human diet, probably because it is the substrate for the synthesis of longer-chain, more unsaturated n-3 fatty acids, principally EPA (20: 5n-3) and DHA (22: 6n-3), which confer important biophysical properties on cell membranes and so are required for tissue function. The extent to which this molecular transformation occurs in man is controversial. The present paper reviews the recent literature on the metabolism of alphaLNA in man, including the use of dietary alphaLNA in beta-oxidation, recycling of carbon by fatty acid synthesis de novo and conversion to longer-chain PUFA. Sex differences in alphaLNA metabolism and the possible biological consequences are discussed. Increased consumption of EPA and DHA in fish oil has a number of well-characterised beneficial effects on health. The present paper also reviews the efficacy of increased alphaLNA consumption in increasing the concentrations of EPA and DHA in blood and cell lipid pools, and the extent to which such dietary interventions might be protective against CVD and inflammation. Although the effects on CVD risk factors and inflammatory markers are variable, where beneficial effects have been reported these are weaker than have been achieved from increasing consumption of EPA+DHA or linoleic acid. Overall, the limited capacity for conversion to longer-chain n-3 fatty acids, and the lack of efficacy in ameliorating CVD risk factors and inflammatory markers in man suggests that increased consumption of alphaLNA may be of little benefit in altering EPA+DHA status or in improving health outcomes compared with other dietary interventions.

Early nutrition and immunity – progress and perspectives

Abstract: The immune system exists to protect the host against pathogenic organisms and highly complex pathways of recognition, response, elimination and memory have evolved in order to fulfil this role. The immune system also acts to ensure tolerance to 'self', to food and other environmental components, and to commensal bacteria. A breakdown in the tolerogenic pathways can also lead to inflammatory diseases. The prevalence of inflammatory diseases, including atopic disorders, has increased over the last 60 years. The development of tolerance is the result of active immune mechanisms and both development and maintenance of tolerance are lifelong processes which start very early in life, even prenatally. Profound immunologic changes occur during pregnancy, involving a polarization of T helper (Th) cells towards a dominance of Th2 and regulatory T cell effector responses in both mother and fetus. This situation is important to maintain pregnancy through avoidance of the rejection of the immunologically incompatible fetus. During the third trimester of human pregnancy, fetal T cells are able to mount antigen-specific responses to environmental and food-derived antigens and antigen-specific T cells are detectable in cord blood in virtually all newborns indicating in utero sensitization. If the neonatal immune system is not able to down-regulate the pre-existing Th2 dominance effectively then an allergic phenotype may develop. Changes occur at, and soon after, birth in order that the immune system of the neonate becomes competent and functional and that the gut becomes colonized with bacteria. Exposure to bacteria during birth and from the mother's skin and the provision of immunologic factors in breast milk are amongst the key events that promote maturation of the infant's gut and gut-associated and systemic immune systems. The introduction of formula and of solid foods exposes the infant to novel food antigens and also affects the gut flora. Nutrition may be the source of antigens to which the immune system must become tolerant, provide factors, including nutrients, that themselves might modulate immune maturation and responses, and provide factors that influence intestinal flora, which in turn will affect antigen exposure, immune maturation and immune responses. Through these mechanisms it is possible that nutrition early in life might affect later immune competence, the ability to mount an appropriate immune response upon infection, the ability to develop a tolerogenic response to 'self' and to benign environmental antigens, and the development of immunologic disorders. A Workshop held in February 2006 considered recent findings in the areas of oral tolerance, routes of sensitization to allergens and factors affecting the development of atopic disease; factors influencing the maturation of dendritic cells and the development of regulatory T cells; the influence of gut microflora on immunity, allergic sensitization and infectious disease; the role of nutrition in preventing necrotizing enterocolitis in an animal model of preterm birth; and the role of PUFA of different classes in influencing immune responses and in shaping the development of atopic disease. This report summarizes the content of the lectures and the subsequent discussions.

Polyunsaturated fatty acid concentrations in young men and women consuming their habitual diets.

Abstract: Young women of reproductive age appear to have a greater capacity than men to convert the essential fatty acid alpha-linolenic acid to DHA. The purpose of this study was to test the hypothesis that gender-related differences in n-3 PUFA metabolism are reflected in the concentrations of n-3 PUFA in plasma lipids. The subjects were healthy men (n 13) and women (n 23) aged 18-35 years consuming their habitual diet. Dietary habits were assessed by food-frequency questionnaire. Venous blood samples were collected following an overnight fast. For the women, blood collection took place on the tenth day of their menstrual cycle. The fatty acid concentrations of plasma phosphatidylcholine, triacylglycerol, NEFA and cholesteryl esters were determined by gas chromatography. There were no significant differences between men and women in their consumption of protein, carbohydrate, total fat, alcohol, individual fatty acids and selected micronutrients. DHA concentration alone was significantly higher in plasma phosphatidylcholine (31 %, P = 0.02), triacylglycerol (71 %, P = 0.02) and NEFA (33 %, P = 0.01), but not cholesteryl esters, in women compared with men. There were no significant differences between men and women in the concentrations of any other fatty acids measured. Overall, the present data support the suggestion that greater DHA synthesis in women than men results in a higher DHA concentration in plasma lipids.

Lack of effect of meal fatty acid composition on postprandial lipid, glucose and insulin responses in men and women aged 50–65 years consuming their habitual diets

Abstract: The aim of the study was to determine the effect of consuming meals with different fatty acid compositions on the postprandial changes over 6 h in plasma triacylglycerol, NEFA, total cholesterol, glucose and insulin concentrations in middle-aged men and women. Men (n 11; 58 (5) years) and women (n 11; 56 (4) years) consumed four test meals with a similar macronutrient energy content in random order: a reference meal based on the habitual pattern of fatty acid intake in the UK, a meal with an increased (155 %) linoleic acid (LA) to alpha-linolenic acid (alphaLNA) ratio (high LA:alphaLNA), a meal with increased (23 %) MUFA content (high MUFA) and a meal with increased (583 %) EPA and DHA content (high EPA+DHA). The high-LA:alphaLNA and high-EPA+DHA meals selectively increased the ratio of LA to alphaLNA (men 341 %; women 310 %) and the EPA+DHA (men 414 %; women 438 %) concentration in plasma triacylglycerol. The high-MUFA meal did not alter the change in MUFA content of the plasma. Plasma triacylglycerol, NEFA, glucose and insulin, but not total cholesterol, concentrations changed significantly after each meal. There was no significant effect of meal fatty acid composition or gender on maximum change in concentration, time to maximum concentration or area under the curve of any of the metabolites measured in the blood. These results suggest that differences in meal fatty acid composition exert little or no effect on postprandial changes in plasma lipids, glucose and insulin concentrations

Nutrition and allergic disease

Abstract: The prevalence of asthma and allergic diseases has increased dramatically over the past few decades with the highest incidence occurring in children. Most asthma and related atopic disorders have their origins in early life. Thus, it is imperative to understand the early life origins of the disease in order to identify targets for prevention and early intervention. Although atopic diseases have genetic determinants, the increased incidence of these diseases has occurred far too rapidly for genetic changes to explain the increase. This, most likely, results from changes in environmental influences acting on a pre-existent genetic susceptibility. One of the environmental changes over the last 20–40 years that could have contributed to the recent increase in atopic diseases is diet. Food allergy is often one of the earliest manifestations of atopy, and sensitization to food is a risk factor for the subsequent appearance of respiratory allergy and asthma. However, studies investigating the effects of dietary restrictions on the prevention of allergy have been disappointing. On the other hand, current data suggests that exclusive breastfeeding should be encouraged for at least 4–6 months in infants at both high and low risk of atopy. Increased risk of asthma has also been observed in low birth weight infants, suggesting that under-nutrition can detrimentally alter foetal development. Epidemiological and immunological studies also suggest that dietary modification or supplementation in the foetal and early life could reduce the development of atopic diseases. The current dietary hypotheses relate to antioxidants, lipids, electrolytes and probiotics. The aims of this report are: (i) to assess the best methods to analyse nutrient intake and nutrient status; (ii) to review the existing epidemiological evidence for an association between dietary intake (nutrients and food) and allergic diseases; and (iii) to define the windows of opportunity for nutritional supplementation to be used as a preventative strategy for asthma and allergy.

Use of fish oil in parenteral nutrition: Rationale and reality.

Abstract: Excessive or inappropriate inflammation and immunosuppression are components of the response to surgery, trauma, injury and infection in some individuals and can lead, progressively, to sepsis and septic shock. The hyperinflammation is characterised by the production of inflammatory cytokines, arachidonic acid-derived eicosanoids and other inflammatory mediators, while the immunosuppression is characterised by impairment of antigen presentation and of T-helper lymphocyte type-1 responses. Long-chain n-3 fatty acids from fish oil decrease the production of inflammatory cytokines and eicosanoids. They act both directly (by replacing arachidonic acid as an eicosanoid substrate and by inhibiting arachidonic acid metabolism) and indirectly (by altering the expression of inflammatory genes through effects on transcription factor activation). Thus, long-chain n-3 fatty acids are potentially useful anti-inflammatory agents and may be of benefit in patients at risk of hyperinflammation and sepsis. As a consequence, an emerging application for n-3 fatty acids, in which they may be added to parenteral (or enteral) formulas, is in surgical or critically-ill patients. Parenteral nutrition that includes n-3 fatty acids appears to preserve immune function better than standard formulas and appears to diminish the extent of the inflammatory response. Studies to date are suggestive of clinical benefits from these approaches, especially in patients post surgery, although evidence of clinical benefit in patients with sepsis is emerging.

Long-chain polyunsaturated fatty acids and inflammation

Abstract: Although part of the normal host response to infection or injury, inflammation is involved in many pathological conditions and disease states. Most interest in the influence of fatty acids on inflammatory processes has centred on the opposing actions of n-6 and n-3 polyunsaturated fatty acids (PUFAs). The n-6 PUFA arachidonic acid gives rise to the eicosanoid family of inflammatory mediators (prostaglandins, leukotrienes and related metabolites) and through these regulates the activities of inflammatory cells, the production of inflammatory cytokines, etc. Consumption of long-chain n-3 PUFAs [eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA)] decreases the amount of arachidonic acid in inflammatory cell membranes and so available for eicosanoid production. Thus, consumption of long-chain n-3 PUFAs results in decreased production of eicosanoids from arachidonic acid. EPA acts as an alternative substrate for eicosanoid synthesis giving rise to mediators tha t are less potent than the analogues produced from arachidonic acid. EPA and DHA give rise to newly discovered families of mediators termed E- and Dresolvins, respectively, which have anti-inflammatory and inflammation-resolving actions. In addition to this range of effects, long-chain n-3 PUFAs affect cell-signalling processes and gene expression in inflammatory cells, resulting in decreased expression of inflammatory cytokines and adhesion molecules. Such long-chain n-3 PUFA-induced effects may be of importance in protecting against the development of and lowering the severity of acute and chronic inflammatory conditions. There is good evidence for the efficacy of long-chain n-3 PUFAs in rheumatoid arthritis, with less strong evidence in other inflammatory conditions. The precursor n-3 PUFA, ?-linolenic acid, exerts some anti-inflammatory effects at very high intakes, perhaps reflecting the need for its conversion to EPA to be effective. Keywords: arachidonic acid; cytoki n e; eicosanoid; fish oil; inflammation; macrophage

Abnormal fatty acid profiles occur in atopic dermatitis but what do they mean

Abstract: There are two principal families of polyunsaturated fatty acids (PUFAs), the n-6 (or o-6) and the n-3 (or o-3) families [1]. These are distinguished by the position of the terminal double bond within the fatty acyl chain. The simplest members of each family, linoleic acid (18:2n-6) and a-linolenic acid (18:3n-3), cannot be synthesized by mammals. As their absence from the diet results in symptoms indicative of a deficiency state, these two fatty acids are considered to be essential. Linoleic acid is found in significant quantities in many vegetable oils, including corn, sunflower and soybean oils, and in products made from such oils, such as margarines. a-Linolenic acid is found in green plant tissues, in some common vegetable oils, including soybean and rapeseed oils, and in flaxseed (also known as linseed) and flaxseed oil. Between them, linoleic and a-linolenic acids contribute over 95%, and perhaps as much as 98% of dietary PUFA intake in most western diets. The intake of linoleic acid in western countries increased greatly from about 1970, following the introduction and marketing of cooking oils and margarines. a-Linolenic acid intake probably changed little over this time. However, although typical intakes of both essential fatty acids are in excess of requirements, the changed pattern of consumption of linoleic acid has resulted in a marked increase in the ratio of n-6 to n-3 PUFAs in the diet. This ratio is currently between 5 and 20 in most western populations [2]. Although linoleic and a-linolenic acids cannot be synthesized by humans they can be metabolized to other fatty acids (Fig. 1). This is achieved by the insertion of additional double bonds into the acyl chain (i.e. unsaturation) and by elongation of the acyl chain. Thus, linoleic acid can be converted via g-linolenic acid (18:3n-6) and di-homo-g-linolenic acid (20:3n-6) to arachidonic acid (20:4n-6) (Fig. 1). By an analogous set of reactions catalysed by the same enzymes a-linolenic acid can be converted to eicosapentaenoic acid (EPA; 20:5n-3). Both arachidonic acid and EPA can be further metabolized, EPA giving rise to docosapentaenoic acid (DPA; 22:5n-3) and docosahexaenoic acid (DHA; 22:6n-3) (Fig. 1). Dietary intakes of the longer chain, more unsaturated PUFAs are much, much lower than of linoleic and a-linolenic acids. Some plant oils contain g-linolenic acid, dihomo-g-linolenic acid and stearidonic acid (18:4n-3), but typical intakes of these fatty acids from the diet are likely to be o 10 mg/day. Arachidonic acid is found in meat and offal and intakes are estimated at 50–500 mg/day. EPA, DPA and DHA are found in fish, especially so-called ‘oily’ fish (tuna, salmon, mackerel, herring, sardine). One oily fish meal can provide between 1.5 and 3.5 g of these long chain n-3 PUFAs, equivalent to a daily consumption of 200–500 mg [3]. The commercial products known as fish oils also contain EPA, DPA and DHA, which typically will contribute about 30% of the fatty acids present. Thus, consumption of one typical 1 g fish oil capsule per day can provide about 300 mg of these fatty acids. In the absence of oily fish or fish oil consumption, intake of long chain n-3 PUFAs is likely to be o 100 mg/day, although foods, such as eggs, milks or breads, fortified with these fatty acids are now available in many countries. PUFAs are important constituents of cells where they play roles assuring the correct environment for membrane protein function, maintaining membrane fluidity and regulating gene expression and cellular function [1]. In addition, some PUFAs, particularly arachidonic acid, act as substrates for synthesis of eicosanoids, which are involved in regulation of many cell and tissue responses. Arachidonic acid-derived eicosanoids are intimately involved in the regulation of inflammatory processes and immune cell functional responses [4, 5]. For example, prostaglandin E2 (PGE2) inhibits the production of T-helper type 1 (Th1)-type cytokines and promotes the production of Th2-type cytokines and of IgE, while leukotriene B4 is a leucocyte chemoattractant and promotes leucocyte adhesion and degranulation. One factor limiting the synthesis of eicosanoids is the availability of the substrate, arachidonic acid, in the membranes of inflammatory cells. Because the dietary intake of linoleic E-mail: pcc@soton.ac.uk Clinical and Experimental Allergy, 36, 138–141

CD36: taste the difference?

Abstract: Fat intake in Western populations typically averages 35–40% of energy. Such consumption will frequently exceed recommendations for fat intake, which are typically a maximum of 30–35% of energy. The higher than recommended intake of fat undoubtedly increases the risk of weight gain, obesity, type 2 diabetes, hypertension and cardiovascular disease and may also increase inflammation [1] and diminish the immune response [2]. Complex psychological, behavioural and social factors as well as orosensory phenomena, such as texture and odour, influence individuals’ preferences for fat [3]. Laboratory rodents also show a preference for fat-rich diets [4], however, suggesting that there may be a physiological basis for such a preference. A recent publication reported evidence that the protein CD36 is involved in the detection of dietary fat by taste buds [5], suggesting that it may act as an oral fat sensor.

Conjugated linoleic acid and human health-related outcomes

Abstract: There has been increasing interest in health benefits of conjugated linoleic acid (CLA) based on findings with laboratory animals. Some human studies have also suggested health benefits of CLA, but because of the mixes used these could not be readily associated with a particular isomer of CLA. A recent study examined the separate effects of near-pure cis-9,trans-11 CLA (c9,t11 CLA) or trans-10,cis-12 CLA (t10,c12 CLA) on health-related outcomes in healthy young males. The CLA isomers were provided in capsules and at three doses (up to about 2.5 g/day) each for 8 weeks. Both c9,t11 and t10,c12 CLA were incorporated in a dose–response fashion into blood lipids and cells. At the doses and durations used, neither isomer of CLA affected bodyweight, body mass index or body composition, insulin sensitivity, immune function or markers of inflammation. However, at the doses and durations used, c9,t11 and t10,c12 CLA had opposing effects on blood lipid concentrations. Altered dairy cow-feeding practices were used to produce c9,t11 CLA-rich milk and, from this ultra heat-treated milk, cheese and butter were produced. The milk and the dairy products made from it had ninefold higher contents of c9,t11 CLA, higher contents of n-3 fatty acids and lower contents of total fat and of saturated fatty acids. They also contained much higher contents of trans-vaccenic acid (tVA). The modified dairy products were used in a 6-week controlled dietary intervention study in healthy middle-aged males. c9,t11 CLA and tVA were incorporated from dairy products into blood lipids and cells. Consumption of the CLA-rich (and tVA-rich) dairy products did not affect bodyweight or body mass index, insulin sensitivity or inflammatory markers. However, there were some detrimental effects on blood lipids. These effects may be due to tVA rather than to c9,t11 CLA, as they are consistent with the effects of trans fatty acids and not consistent with the effects of c9,t11 CLA identified in the earlier study with c9,t11 CLA in capsules.

Differences in maternal protein intake in pregnant rats alone alter the docosahexaenoic acid concentration in the fetal and adult offspring.

Abstract: To the Editor: We read with interest the study by Rao et al [1] in a recent issue of Metabolism. Their study showed that feeding pregnant rats a diet containing 30% less protein and 4-fold more folic acid than controls was associated with reduced docosahexaenoic acid (22:6n-3) concentration in the brain of the adult male offspring, but not in females. There was no effect on 22:6n-3 concentration in the offspring when pregnant dams were fed a diet with reduced protein content, but an amount of folic acid equivalent to the control diet, or the protein-restricted diet without folic acid. This suggests that increased folic acid intake during pregnancy might adversely affect the amount of 22:6n-3 in the brain of male rats, which is of concern because this fatty acid is required for normal development and function of the central nervous system [2]. Unfortunately, Rao et al did not report whether this effect also occurred if animals were fed a diet with the control amount of protein (18%) but supplemented with folic acid. It appears to have escaped the notice of Rao et al that we have published a series of reports on the effect of dietary protein restriction in rats on the concentration of 22:6n-3 in the pregnant dams, and in the fetal and adult offspring. In contrast to the observations of Rao et al, we found that feeding a diet containing 9% protein alone during pregnancy resulted in lower 22:6n-3 concentration in liver phospholipids, and in plasma phospholipids and triacylglycerol in the pregnant dams, and in fetal brain phosphatidylcholine and phosphatidylethanolamine [3]. The concentration of 22:6n-3 was also reduced in placental phospholipids and triacylglycerol [4]. This suggests that the protein-restricted diet constrained supply of 22:6n-3 from the dam to the placenta and developing fetal brain, possibly by limiting the pregnancy-associated physiological increase in 22:6n-3 concentration in plasma phospholipids [5]. This deficit in 22:6n-3 accumulation in brain persisted in the recently weaned offspring [6]. Interestingly, supplementation of the 9% protein diet with the methyl donor glycine did not alter

Applied nutritional investigation Limited effect of eicosapentaenoic acid on T-lymphocyte and natural killer cell numbers and functions in healthy young males

Abstract: Objective: Greatly increasing the amount of long-chain -3 polyunsaturated fatty acids in the diet has been reported in some studies to decrease T-lymphocyte and natural killer functions. However, dose-response relations have not been identified. The objective of this study was to determine the effect of supplementing the diet of young male subjects with different amounts of an oil rich in eicosapentaenoic acid (EPA) on T-lymphocyte proliferation, cytokine production by T lymphocytes, and natural killer cell activity. Methods: In a placebo-controlled, double-blind, parallel study, healthy young (18 to 42 y) males were randomized to one of four supplements. These were placebo (no additional -3 polyunsatu- rated fatty acids) or different amounts of an EPA-rich oil that provided 1.35, 2.7, or 4.05 g/d of EPA for 12 wk. Blood samples were taken at baseline and after 12 wk. Results: Eicosapentaenoic acid was incorporated in a linear dose-response fashion into mononu- clear cell phospholipids. EPA did not alter the proportions of T lymphocytes, helper T lymphocytes, cytotoxic T lymphocytes, B lymphocytes, or natural killer cells in the bloodstream. T-lymphocyte proliferation in response to concanavalin A and the production of the cytokines interleukin-2, interferon-, and interleukin-10 were not affected by the different treatments. However, interleu- kin-4 production was increased with increasing intake of EPA. Natural killer cell activity was little affected by the treatments, although there was a trend for EPA to increase activity at a low effector-to-target cell ratio. Conclusion: T-lymphocyte and natural killer cell numbers and function in healthy young males are little affected by supplemental EPA intakes up to 4 g/d. © 2006 Elsevier Inc. All rights reserved.

Basic nutritional investigation Fish oil alters T-lymphocyte proliferation and macrophage responses in Walker 256 tumor-bearing rats

Abstract: Objective: We investigated the effect of the dietary ratio of -6 to -3 polyunsaturated fatty acids (PUFAs) from postweaning until adulthood on T-lymphocyte proliferation, T-lymphocyte subpopu- lations (helper and cytotoxic), and production of cytotoxic mediators by macrophages in tumor- bearing rodents. Methods: Weanling male Wistar rats received a normal low-fat (40 g/kg of diet) chow diet or a high-fat (300 g /kg) diet that included fish or sunflower oil or blends of fish and sunflower oils to yield -6:-3 PUFA ratios of approximately 6:1, 30:1, and 60:1 ad libitum. After 8 wk, 50% of rats in each group were inoculated with 1 mL of 2 10 7 Walker 256 cells. Fourteen days after tumor inoculation, animals were killed and lymphocytes and macrophages were obtained for study. Results: The diets richest in -6 PUFA resulted in higher proliferation of thymus, spleen, and gut-associated lymphocytes compared with the chow diet irrespective of tumor burden. In contrast, the fish oil diet resulted in lower proliferation of thymus and spleen lymphocytes compared with the chow diet. Diets rich in -6 PUFA decreased the proportion of CD8 lymphocytes. In non-tumor- bearing and tumor-bearing rats, hydrogen peroxide production by macrophages was highest in rats that consumed diets high in -3 PUFAs. Superoxide and nitric oxide production were little affected by the dietary ratio of -6 to -3 PUFAs. Conclusion: Dietary -6 and -3 PUFA contents alter immune function in non-tumor-bearing and tumor-bearing rats. The -3 PUFAs decreased T-cell proliferation but increased hydrogen peroxide production compared with -6 PUFAs. Decreased tumor growth and cachexia and increased survival previously reported forfish oil in Walker 256 tumor-bearing rats may be related to improved macrophage