Showing papers by "Philip C. Calder published in 2017"

Omega-3 fatty acids and inflammatory processes: from molecules to man.

Abstract: Inappropriate, excessive or uncontrolled inflammation contributes to a range of human diseases. Inflammation involves a multitude of cell types, chemical mediators and interactions. The present article will describe nutritional and metabolic aspects of omega-6 (n-6) and omega-3 (n-3) fatty acids and explain the roles of bioactive members of those fatty acid families in inflammatory processes. Eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) are n-3 fatty acids found in oily fish and fish oil supplements. These fatty acids are capable of partly inhibiting many aspects of inflammation including leucocyte chemotaxis, adhesion molecule expression and leucocyte–endothelial adhesive interactions, production of eicosanoids like prostaglandins and leukotrienes from the n-6 fatty acid arachidonic acid and production of pro-inflammatory cytokines. In addition, EPA gives rise to eicosanoids that often have lower biological potency than those produced from arachidonic acid, and EPA and DHA give rise to anti-inflammatory and inflammation resolving mediators called resolvins, protectins and maresins. Mechanisms underlying the anti-inflammatory actions of EPA and DHA include altered cell membrane phospholipid fatty acid composition, disruption of lipid rafts, inhibition of activation of the pro-inflammatory transcription factor nuclear factor κB so reducing expression of inflammatory genes and activation of the anti-inflammatory transcription factor peroxisome proliferator-activated receptor γ. Animal experiments demonstrate benefit from EPA and DHA in a range of models of inflammatory conditions. Human trials demonstrate benefit of oral n-3 fatty acids in rheumatoid arthritis and in stabilizing advanced atherosclerotic plaques. Intravenous n-3 fatty acids may have benefits in critically ill patients through reduced inflammation. The anti-inflammatory and inflammation resolving actions of EPA, DHA and their derivatives are of clinical relevance.

Very long-chain n-3 fatty acids and human health: fact, fiction and the future.

Abstract: EPA and DHA appear to be the most important n-3 fatty acids, but roles for n-3 docosapentaenoic acid are now also emerging. Intakes of EPA and DHA are usually low, typically below those recommended. Increased intakes result in higher concentrations of EPA and DHA in blood lipids, cells and tissues. Increased content of EPA and DHA modifies the structure of cell membranes and the function of membrane proteins. EPA and DHA modulate the production of lipid mediators and through effects on cell signalling can alter the patterns of gene expression. Through these mechanisms, EPA and DHA alter cell and tissue responsiveness in a way that often results in more optimal conditions for growth, development and maintenance of health. DHA has vital roles in brain and eye development and function. EPA and DHA have a wide range of physiological roles, which are linked to certain health or clinical benefits, particularly related to CVD, cancer, inflammation and neurocognitive function. The benefits of EPA and DHA are evident throughout the life course. Future research will include better identification of the determinants of variation of responses to increased intake of EPA and DHA; more in-depth dose-response studies of the effects of EPA and DHA; clearer identification of the specific roles of EPA, docosapentaenoic acid and DHA; testing strategies to enhance delivery of n-3 fatty acids to the bloodstream; and exploration of sustainable alternatives to fish-derived very long-chain n-3 fatty acids.

Consensus Statement Immunonutrition and Exercise

Abstract: In this consensus statement on immunonutrition and exercise, a panel of knowledgeable contributors from across the globe provides a consensus of updated science, including the background, the aspects for which a consensus actually exists, the controversies and, when possible, suggested directions for future research.

Can Early Omega-3 Fatty Acid Exposure Reduce Risk of Childhood Allergic Disease?

Abstract: A causal link between increased intake of omega-6 (n-6) polyunsaturated fatty acids (PUFAs) and increased incidence of allergic disease has been suggested. This is supported by biologically plausible mechanisms, related to the roles of eicosanoid mediators produced from the n-6 PUFA arachidonic acid. Fish and fish oils are sources of long chain omega-3 (n-3) PUFAs. These fatty acids act to oppose the actions of n-6 PUFAs particularly with regard to eicosanoid synthesis. Thus, n-3 PUFAs may protect against allergic sensitisation and allergic manifestations. Epidemiological studies investigating the association between maternal fish intake during pregnancy and allergic outcomes in infants/children of those pregnancies suggest protective associations, but the findings are inconsistent. Fish oil provision to pregnant women is associated with immunologic changes in cord blood. Studies performed to date indicate that provision of fish oil during pregnancy may reduce sensitisation to common food allergens and reduce prevalence and severity of atopic eczema in the first year of life, with a possible persistence until adolescence. A recent study reported that fish oil consumption in pregnancy reduces persistent wheeze and asthma in the offspring at ages 3 to 5 years. Eating oily fish or fish oil supplementation in pregnancy may be a strategy to prevent infant and childhood allergic disease.

Systematic Review on N-3 and N-6 Polyunsaturated Fatty Acid Intake in European Countries in Light of the Current Recommendations - Focus on Specific Population Groups

Abstract: Background: Earlier reviews indicated that in many countries adults, children and adolescents consume on an average less polyunsaturated fatty acids (PUFAs) than

Palmitoleic acid reduces the inflammation in LPS‐stimulated macrophages by inhibition of NFκB, independently of PPARs

Abstract: Summary Palmitoleic acid (PM, 16:1n-7) has anti-inflammatory properties that could be linked to higher expression of PPARα, an inhibitor of NFκB. Macrophages play a major role in the pathogenesis of chronic inflammation, however, the effects of PM on macrophages are underexplored. Thus, we aimed to investigate the effects of PM in activated macrophages as well the role of PPARα. Primary macrophages were isolated from C57BL/6 wild type (WT) and PPARα knockout (KO) mice, cultured under standard conditions and exposed to lipopolysaccharides LPS (2.5 μg/ml) and PM 600 μmol/L conjugated with albumin for 24 hours. The stimulation with LPS increased the production of interleukin (IL)-6 and IL-1β while PM decreased the production of IL-6 in WT macrophages. In KO macrophages, LPS increased the production of tumour necrosis factor (TNF)-α and IL-6 and PM decreased the production of TNFα. The expression of inflammatory markers such NFκB and IL1β were increased by LPS and decreased by PM in both WT and KO macrophages. PM reduced the expression of MyD88 and caspase-1 in KO macrophages, and the expression of TLR4 and HIF-1α in both WT and KO macrophages, although LPS had no effect. CD86, an inflammatory macrophage marker, was reduced by PM independently of genotype. PM increased PPARγ and reduced PPARβ gene expression in macrophages of both genotypes, and increased ACOX-1 expression in KO macrophages. In conclusion, PM promotes anti-inflammatory effects in macrophages exposed to LPS through inhibition of inflammasome pathway, which was independent of PPARα, PPARϒ and AMPK, thus the molecular mechanisms of anti-inflammatory response caused by PM is still unclear.

Docosahexaenoic acid enrichment in NAFLD is associated with improvements in hepatic metabolism and hepatic insulin sensitivity: a pilot study

Abstract: Treatment of subjects with non-alcoholic fatty liver disease (NAFLD) with omega-3 polyunsaturated fatty acids (FAs) suggests high levels of docosahexaenoic acid (DHA) tissue enrichment decrease liver fat content. We assessed whether changes in erythrocyte DHA enrichment (as a surrogate marker of changes in tissue enrichment) were associated with alterations in hepatic de novo lipogenesis (DNL), postprandial FA partitioning and hepatic and peripheral insulin sensitivity in a sub-study of the WELCOME trial (Wessex Evaluation of fatty Liver and Cardiovascular markers in NAFLD (non-alcoholic fatty liver disease) with OMacor thErapy). Sixteen participants were randomised to 4 g/day EPA+DHA (n=8) or placebo (n=8) for 15–18 months and underwent pre- and post-intervention measurements. Fasting and postprandial hepatic FA metabolism was assessed using metabolic substrates labelled with stable-isotope tracers (2H2O and [U13C]palmitate). Insulin sensitivity was measured by a stepped hyperinsulinaemic-euglycaemic clamp using deuterated glucose. Participants were stratified according to change in DHA erythrocyte enrichment (< or ⩾2% post intervention). Nine participants were stratified to DHA⩾2% (eight randomised to EPA+DHA and one to placebo) and seven to the DHA<2% group (all placebo). Compared with individuals with erythrocyte <2% change in DHA abundance, those with ⩾2% enrichment had significant improvements in hepatic insulin sensitivity, reduced fasting and postprandial plasma triglyceride concentrations, decreased fasting hepatic DNL, as well as greater appearance of 13C from dietary fat into plasma 3-hydroxybutyrate (all P<0.05). The findings from our pilot study indicate that individuals who achieved a change in erythrocyte DHA enrichment ⩾2% show favourable changes in hepatic FA metabolism and insulin sensitivity, which may contribute to decreasing hepatic fat content.

Oral fish oil positively influences nutritional-inflammatory risk in patients with haematological malignancies during chemotherapy with an impact on long-term survival: a randomised clinical trial.

Abstract: Background Studies suggest that the ingestion of fish oil (FO), a source of the omega-3 polyunsaturated fatty acids docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA), can reduce the deleterious side-effects of chemotherapy. The aim of this randomised clinical trial was to evaluate the effect of supplementation with oral FO for 9 weeks on nutritional parameters and inflammatory nutritional risk in patients with haematological malignancies during the beginning of chemotherapy. Methods Twenty-two patients with leukaemia or lymphoma were randomised to the unsupplemented group (UG) (n = 13) or supplemented group (SG) (n = 9). SG received 2 g/day of fish oil for 9 weeks. Nutritional status, serum acute-phase proteins and plasma fatty acids were evaluated before (T0) and after (T1) the intervention period. Data were analysed using two models; model 1, comprising data from all patients included in the study, and model 2, comprising data from UG patients with no increase in the proportions of EPA and DHA in plasma and data from SG patients showing an at least 100% increase in plasma EPA and DHA. Results SG showed an increased plasma proportion of EPA and DHA in both models. In model 2, C-reactive protein (CRP) and CRP/albumin ratio showed larger reductions in the SG. Overall long-term survival in both models (465 days after the start of the chemotherapy) was higher in the group ingesting fish oil (P < 0.05). Conclusions These findings indicate an improved nutritional-inflammatory risk and potential effects on long-term survival in patients with haematological malignancies supplemented with FO during the beginning of chemotherapy.

Omega-3: The good oil

Abstract: Omega-3 (n-3) fatty acids are a family of polyunsaturated fatty acids. They are characterised by the position of the double bond closest to the methyl terminus of the hydrocarbon (acyl) chain being on carbon number three, when counting the methyl carbon as number one. Functionally, the most important omega-3 fatty acids are eicosapentaenoic acid (EPA; 20:5n-3) and docosahexaenoic acid (DHA; 22:6n-3) (Calder 2014, 2016), although roles for docosapentaenoic acid (DPA; 22:5n-3) are now also emerging (Kaur et al. 2011). EPA and DHA (and also DPA) are found in fairly high amounts in seafood, especially fatty fish (sometimes called ‘oily fish’); in the blubber and tissues of sea mammals such as whales and seals; in supplements such as fish oils, cod liver oil and krill oil; in some algal oils; and in a limited number of pharmaceutical-grade preparations. Table 1 shows typical values for the EPA, DPA and DHA content of selected fish, while Table 2 shows typical values for the EPA and DHA content of different types of omega-3 supplements. EPA, DPA and DHA are related metabolically to one another, and there is a pathway by which EPA can be synthesised from simpler, plant-derived omega-3 fatty acids (Fig. 1). The initial substrate for this pathway is the essential fatty acid a-linolenic acid (ALA; 18:3n-3). The pathway for conversion of ALA to EPA involves three steps, catalysed in turn by delta-6-desaturase, elongase 5 and delta-5-desaturase (Fig. 1). Further conversion of EPA to DHA, via DPA, occurs by a complex pathway (Fig. 1) involving chain elongation catalysed by elongase 5, a second chain elongation catalysed by elongase 2 or 5, desaturation by delta-6desaturase and then removal of two carbon atoms by limited b-oxidation in peroxisomes. The enzymes of omega-3 fatty acid interconversion are shared with the analogous omega-6 (n-6) fatty acid biosynthetic pathway of conversion of linoleic acid (18:2n-6) to arachidonic acid (20:4n-6). The high intake of linoleic acid relative to ALA in many Western diets (Blasbalg et al. 2011) favours linoleic acid conversion over that of ALA. This may be one explanation for the frequently reported low rate of conversion of ALA along this pathway (Arterburn et al. 2006; Baker et al. 2016), although this rate can be influenced by several factors including stage of the life course, age, sex, hormones, genetics and disease (Baker et al. 2016). Because fatty fish are the richest dietary source of EPA and DHA, intake of those fatty acids is influenced strongly by fish consumption. In most Western populations, the distribution of fatty fish consumption is bimodal, with a smaller proportion of the population being regular fatty fish consumers. For example, in the UK it is estimated that only 25% of the adult population regularly consume fatty fish (SACN/COT 2004). The other 75% of the population consume fatty fish rarely or never. Mean intakes of EPA + DHA among adults in many Western populations are considered to be around 0.1– 0.2 g/day. However, it is difficult to be precise about this figure for several reasons, as discussed elsewhere (Calder 2014). Australian data suggest mean intake of EPA + DPA + DHA in adults to be around 0.2 g/day but with a skewed distribution such that the median intake is around 0.1 g/day or even less (Meyer et al. 2003; Howe et al. 2006). Australian children and adolescents aged 2–16 years consumed a mean of about 0.08 g/day of EPA + DPA + DHA, with a median intake of about 0.03 g/day (Rahmawaty et al. 2013). The intakes described for omega-3 fatty acids may be compared with current recommendations. In the UK, the Scientific Advisory Committee on Nutrition (SACN) based its recommendation for all adults on the consumption of a minimum of one lean and one Correspondence: Professor Philip C. Calder, Faculty of Medicine, University of Southampton, IDS Building, MP887 Southampton General Hospital, Tremona Road, Southampton SO16 6YD, UK. E-mail: pcc@soton.ac.uk

Abdominal aortic aneurysm and omega-3 polyunsaturated fatty acids: Mechanisms, animal models, and potential treatment

Abstract: Abdominal aortic aneurysm (AAA) is an inflammatory disease associated with macrophage accumulation in the adventitia, oxidative stress, medial elastin degradation and aortic dilation. Progression of AAA is linked to increased risk of rupture, which carries a high mortality rate. Drug therapies trialled to date lack efficacy and although aneurysm repair is available for patients with large aneurysm, peri-surgical morbidity and mortality have been widely reported. Recent studies using rodent models of AAA suggest that long chain omega-3 polyunsaturated fatty acids (LC n-3 PUFAs) and their metabolites can moderate inflammation and oxidative stress perpetuated by infiltrating macrophages and intervene in the destruction of medial elastin. This review examines evidence from these animal studies and related reports of inhibition of inflammation and arrest of aneurysm development following prophylactic supplementation with LC n-3 PUFAs. The efficacy of LC n-3 PUFAs for management of existing aneurysm is unclear and further investigations involving human clinical trials are warranted.

Restored in vivo-like membrane lipidomics positively influence in vitro features of cultured mesenchymal stromal/stem cells derived from human placenta

Abstract: The study of lipid metabolism in stem cell physiology has recently raised great interest. The role of lipids goes beyond the mere structural involvement in assembling extra- and intra-cellular compartments. Nevertheless, we are still far from understanding the impact of membrane lipidomics in stemness maintenance and differentiation patterns. In the last years, it has been reported how in vitro cell culturing can modify membrane lipidomics. The aim of the present work was to study the membrane fatty acid profile of mesenchymal stromal cells (MSCs) derived from human fetal membranes (hFM-MSCs) and to correlate this to specific biological properties by using chemically defined tailored lipid supplements (Refeed®). Freshly isolated hFM-MSCs were characterized for their membrane fatty acid composition. hFM-MSCs were cultivated in vitro following a classical protocol and their membrane fatty acid profile at different passages was compared to the profile in vivo. A tailored Refeed® lipid supplement was developed with the aim of reducing the differences created by the in vitro cultivation and was tested on cultured hFM-MSCs. Cell morphology, viability, proliferation, angiogenic differentiation, and immunomodulatory properties after in vitro exposure to the tailored Refeed® lipid supplement were investigated. A significant modification of hFM-MSC membrane fatty acid composition occurred during in vitro culture. Using a tailored lipid supplement, the fatty acid composition of cultured cells remained more similar to their in vivo counterparts, being characterized by a higher polyunsaturated and omega-6 fatty acid content. These changes in membrane composition had no effect on cell morphology and viability, but were linked with increased cell proliferation rate, angiogenic differentiation, and immunomodulatory properties. In particular, Refeed®-supplemented hFM-MSCs showed greater ability to express fully functional cell membrane molecules. Culturing hFM-MSCs alters their fatty acid composition. A tailored lipid supplement is able to improve in vitro hFM-MSC functional properties by recreating a membrane environment more similar to the physiological counterpart. This approach should be considered in cell therapy applications in order to maintain a higher cell quality during in vitro passaging and to influence the outcome of cell-based therapeutic approaches when cells are administered to patients.

Plasma Levels of Eicosapentaenoic Acid Are Associated with Anti-TNF Responsiveness in Rheumatoid Arthritis and Inhibit the Etanercept-driven Rise in Th17 Cell Differentiation in Vitro.

Abstract: Objective. To determine whether levels of plasma n-3 polyunsaturated fatty acids are associated with response to antitumor necrosis factor (anti-TNF) agents in rheumatoid arthritis (RA), and whether this putative effect may have its basis in altering anti-TNF–driven Th17 cell differentiation. Methods. Plasma was collected at baseline and after 3 months of anti-TNF treatment in 22 patients with established RA, and fatty acid composition of the phosphatidylcholine (PC) component was measured. CD4+CD25− T cells and monocytes were purified from the blood of healthy donors and cocultured in the presence of anti-CD3, with or without etanercept (ETN), eicosapentaenoic acid (EPA), or the control fatty acid, linoleic acid (LA). Expression of interleukin 17 and interferon-γ was measured by intracellular staining and flow cytometry. Results. Plasma PC EPA levels and the EPA/arachidonic acid ratio correlated inversely with change in the Disease Activity Score at 28 joints (DAS28) at 3 months (−0.51, p = 0.007 and −0.48, p = 0.01, respectively), indicating that higher plasma EPA was associated with a greater reduction in DAS28. Plasma PC EPA was positively associated with European League Against Rheumatism response (p = 0.02). An increase in Th17 cells post-therapy has been associated with nonresponse to anti-TNF. ETN increased Th17 frequencies in vitro . Physiological concentrations of EPA, but not LA, prevented this. Conclusion. EPA status was associated with clinical improvements to anti-TNF therapy in vivo and prevented the effect of ETN on Th17 cells in vitro . EPA supplementation might be a simple way to improve anti-TNF outcomes in patients with RA by suppressing Th17 frequencies.

Maternal plasma phosphatidylcholine polyunsaturated fatty acids during pregnancy and offspring growth and adiposity

Abstract: Background Polyunsaturated fatty acids (PUFA) are essential for offspring development, but it is less clear whether pregnancy PUFA status affects growth and adiposity. Methods In 985 mother-offspring pairs from the ongoing Singaporean GUSTO cohort, we analyzed the associations between offspring growth and adiposity outcomes until age 5 years and five PUFAs of interest, measured in maternal plasma at 26–28 weeks' gestation: linoleic acid (LA), arachidonic acid, α-linolenic acid, eicosapentaenoic acid, and docosahexaenoic acid (DHA). We measured fetal growth by ultrasound (n=924), neonatal body composition (air displacement plethysmography (n=252 at birth, and n=317 at age 10 days), and abdominal magnetic resonance imaging (n=317)), postnatal growth (n=979) and skinfold thicknesses (n=981). Results were presented as regression coefficients for a 5% increase in PUFA levels. Results LA levels were positively associated with birthweight (β (95% CI): 0.04 (0.01, 0.08) kg), body mass index (0.13 (0.02, 0.25) kg/m 2 ), head circumference (0.11 (0.03, 0.19) cm), and neonatal abdominal adipose tissue volume (4.6 (1.3, 7.8) mL for superficial subcutanous tissue, and 1.2 (0.1, 2.4) mL for internal tissue), but not with later outcomes. DHA levels, although not associated with birth outcomes, were related to higher postnatal length/height: 0.63 (0.09, 1.16) cm at 12 months and 1.29 (0.34, 2.24) cm at 5 years. Conclusions LA was positively associated with neonatal body size, and DHA with child height. Maternal PUFA status during pregnancy may influence fetal and child growth and adiposity.

New evidence that omega-3 fatty acids have a role in primary prevention of coronary heart disease

Abstract: A recently published study (1) provides new evidence that omega-3 fatty acids have a role in the primary prevention of coronary heart disease (CHD). This new publication included pooled data from 19 cohort studies conducted in 16 countries and including over 45,000 individuals with a median follow-up time of 10 years. Importantly, omega-3 fatty acid concentrations in blood or tissue compartments at study entry were used as the measure of exposure. It was found that each of the four omega-3 fatty acids reported α-linolenic acid (ALA), eicosapentaenoic acid (EPA), docosapentaenoic acid (DPA) and docosahexaenoic acid (DHA) was associated with reduced risk of fatal CHD, with about a 10% reduction in relative risk (RR) for each one standard deviation increase in concentration of the omega-3 fatty acid. These findings make a very valuable contribution to the ongoing discussion about the role of omega-3 fatty acids in cardiovascular disease (CVD) and provide further evidence to support recommendations for the population to consume these fatty acids as part of a healthy diet.

Lipidomics Profiling of Human Adipose Tissue Identifies a Pattern of Lipids Associated with Fish Oil Supplementation

Abstract: To understand the interaction between diet and health, biomarkers that accurately reflect consumption of foods of perceived health relevance are needed. The aim of this investigation was to use direct infusion–mass spectrometry (DI–MS) lipidomics to determine the effects of fish oil supplementation on lipid profiles of human adipose tissue. Adipose tissue samples from an n-3 polyunsaturated fatty acid (PUFA) supplementation study (n = 66) were analyzed to compare the pattern following supplementation equivalent to zero or four portions of oily fish per week. Eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) were incorporated into highly unsaturated (≥5 double bonds) triglycerides (TGs), phosphocholines, and phosphoethanolamines as well as being detected directly as the nonesterified fatty acid forms. Multivariate statistics demonstrated that phospholipids were the most accurate and sensitive lipids for the assessing EPA and DHA incorporation into adipose tissue. Potential confounding factors (adi...