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1.
Omega-3 (n-3) Fatty Acid-Statin Interaction: Evidence for a Novel Therapeutic Strategy for Atherosclerotic Cardiovascular Disease.
Djuricic, I, Calder, PC
Nutrients. 2024;(7)
Abstract
Managing atherosclerotic cardiovascular disease (ASCVD) often involves a combination of lifestyle modifications and medications aiming to decrease the risk of cardiovascular outcomes, such as myocardial infarction and stroke. The aim of this article is to discuss possible omega-3 (n-3) fatty acid-statin interactions in the prevention and treatment of ASCVD and to provide evidence to consider for clinical practice, highlighting novel insights in this field. Statins and n-3 fatty acids (eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA)) are commonly used to control cardiovascular risk factors in order to treat ASCVD. Statins are an important lipid-lowering therapy, primarily targeting low-density lipoprotein cholesterol (LDL-C) levels, while n-3 fatty acids address triglyceride (TG) concentrations. Both statins and n-3 fatty acids have pleiotropic actions which overlap, including improving endothelial function, modulation of inflammation, and stabilizing atherosclerotic plaques. Thus, both statins and n-3 fatty acids potentially mitigate the residual cardiovascular risk that remains beyond lipid lowering, such as persistent inflammation. EPA and DHA are both substrates for the synthesis of so-called specialized pro-resolving mediators (SPMs), a relatively recently recognized feature of their ability to combat inflammation. Interestingly, statins seem to have the ability to promote the production of some SPMs, suggesting a largely unrecognized interaction between statins and n-3 fatty acids with relevance to the control of inflammation. Although n-3 fatty acids are the major substrates for the production of SPMs, these signaling molecules may have additional therapeutic benefits beyond those provided by the precursor n-3 fatty acids themselves. In this article, we discuss the accumulating evidence that supports SPMs as a novel therapeutic tool and the possible statin-n-3 fatty acid interactions relevant to the prevention and treatment of ASCVD.
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Risk assessment of nutrients: There must be a threshold for their effects.
Löwik, MR, Astrup, A, Boobis, AR, Calder, PC, Daniel, H, Rietjens, IM, Sievenpiper, JL, Verhagen, H
Regulatory toxicology and pharmacology : RTP. 2024;:105539
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Abstract
Nutrients serve physiological functions in a dose-dependent manner and that needs to be recognized in risk assessment. An example of the consequences of not properly considering this can be seen in a recent assessment by the European Food Safety Authority (EFSA). EFSA concluded in 2022 that the intake of added and free sugars should be "as low as possible in the context of a nutritionally adequate diet". That conclusion of EFSA is based on the effects on two surrogate endpoints for an adverse effect found in randomized controlled trials with high sugars intake levels: fasting glucose and fasting triglycerides. The lowest intake levels in these trials were around 10 energy% and at this intake level there were no adverse effects on the two outcomes. This indicates that the adverse effects of sugars have an observable threshold value for these two endpoints. The most appropriate interpretation from the vast amount of data is that currently no definitive conclusion can be drawn on the tolerable upper intake level for dietary sugars. Therefore, EFSA's own guidance would lead to the conclusion that the available data do not allow the setting of an upper limit for added sugars and hence, that more robust data are required to identify the threshold value for intake of sugars.
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Omega-3 fatty acid supplementation affects tryptophan metabolism during a 12-week endurance training in amateur runners: a randomized controlled trial.
Tomczyk, M, Bidzan-Wiącek, M, Kortas, JA, Kochanowicz, M, Jost, Z, Fisk, HL, Calder, PC, Antosiewicz, J
Scientific reports. 2024;(1):4102
Abstract
The effects of long-term omega-3 polyunsaturated fatty acid (n-3 PUFA) supplementation during endurance training on tryptophan (Trp) metabolism and mental state of healthy individuals have not been evaluated so far. Concentrations of plasma Trp, its metabolites and IL-6 were assessed in 26 male runners before and after a 12-week training program combined with supplementation of n-3 PUFAs (O-3 + TRAIN group) or medium chain triglycerides (MCTs; TRAIN group). After the 12-week program participants' mood before and after stress induction was also assessed. The effects of the same supplementation protocol were evaluated also in 14 inactive subjects (O-3 + SEDEN group). Concentrations of 3-hydroxykynurenine (3-HK) and picolinic acid (PA) significantly increased only in the O-3 + TRAIN group (p = 0.01; [Formula: see text] = 0.22 and p = 0.01; [Formula: see text]= 0.26). Favorable, but not statistically significant changes in the concentrations of kynurenic acid (KYNA) (p = 0.06; [Formula: see text]= 0.14), xanthurenic acid (XA) (p = 0.07; [Formula: see text]= 0.13) and 3-hydroxyanthranilic acid (3-HAA) (p = 0.06; [Formula: see text]= 0.15) and in the ratio of neurotoxic to neuroprotective metabolites were seen also only in the O-3 + TRAIN group. No changes in mood and IL-6 concentrations were observed in either group. Supplementation with n-3 PUFAs during endurance training has beneficial effects on Trp's neuroprotective metabolites.Trial registry: This study was registered at ClinicalTrials.gov with identifier NCT05520437 (14/07/2021 first trial registration and 2018/31/N/NZ7/02962 second trial registration).
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Combining proteins with n-3 PUFAs (EPA + DHA) and their inflammation pro-resolution mediators for preservation of skeletal muscle mass.
Blaauw, R, Calder, PC, Martindale, RG, Berger, MM
Critical care (London, England). 2024;(1):38
Abstract
The optimal feeding strategy for critically ill patients is still debated, but feeding must be adapted to individual patient needs. Critically ill patients are at risk of muscle catabolism, leading to loss of muscle mass and its consequent clinical impacts. Timing of introduction of feeding and protein targets have been explored in recent trials. These suggest that "moderate" protein provision (maximum 1.2 g/kg/day) is best during the initial stages of illness. Unresolved inflammation may be a key factor in driving muscle catabolism. The omega-3 (n-3) fatty acids eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) are substrates for synthesis of mediators termed specialized pro-resolving mediators or SPMs that actively resolve inflammation. There is evidence from other settings that high-dose oral EPA + DHA increases muscle protein synthesis, decreases muscle protein breakdown, and maintains muscle mass. SPMs may be responsible for some of these effects, especially upon muscle protein breakdown. Given these findings, provision of EPA and DHA as part of medical nutritional therapy in critically ill patients at risk of loss of muscle mass seems to be a strategy to prevent the persistence of inflammation and the related anabolic resistance and muscle loss.
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Influence of Dietary n-3 Long Chain Polyunsaturated Fatty Acid Intake on Oxylipins in Erythrocytes of Women with Rheumatoid Arthritis.
Lindqvist, HM, Winkvist, A, Gjertsson, I, Calder, PC, Armando, AM, Quehenberger, O, Coras, R, Guma, M
Molecules (Basel, Switzerland). 2023;(2)
Abstract
Oxylipins derived from n-3 fatty acids are suggested as the link between these fatty acids and reduced inflammation. The aim of the present study was to explore the effect of a randomized controlled cross-over intervention on oxylipin patterns in erythrocytes. Twenty-three women with rheumatoid arthritis completed 2 × 11-weeks exchanging one cooked meal per day, 5 days a week, for a meal including 75 g blue mussels (source for n-3 fatty acids) or 75 g meat. Erythrocyte oxylipins were quantified by liquid chromatography-tandem mass spectrometry (LC-MS/MS). The results were analyzed with multivariate data analysis. Orthogonal projections to latent structures (OPLS) with effect projections and with discriminant analysis were performed to compare the two diets' effects on oxylipins. Wilcoxon signed rank test was used to test pre and post values for each dietary period as well as post blue-mussel vs. post meat. The blue-mussel diet led to significant changes in a few oxylipins from the precursor fatty acids arachidonic acid and dihomo-ɣ-linolenic acid. Despite significant changes in eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) and free EPA in erythrocytes in the mussel group, no concurrent changes in their oxylipins were seen. Further research is needed to study the link between n-3 fatty-acid intake, blood oxylipins, and inflammation.
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Association of Intima-Media Thickness Measured at the Common Carotid Artery With Incident Carotid Plaque: Individual Participant Data Meta-Analysis of 20 Prospective Studies.
Tschiderer, L, Seekircher, L, Izzo, R, Mancusi, C, Manzi, MV, Baldassarre, D, Amato, M, Tremoli, E, Veglia, F, Tuomainen, TP, et al
Journal of the American Heart Association. 2023;(12):e027657
Abstract
Background The association between common carotid artery intima-media thickness (CCA-IMT) and incident carotid plaque has not been characterized fully. We therefore aimed to precisely quantify the relationship between CCA-IMT and carotid plaque development. Methods and Results We undertook an individual participant data meta-analysis of 20 prospective studies from the Proof-ATHERO (Prospective Studies of Atherosclerosis) consortium that recorded baseline CCA-IMT and incident carotid plaque involving 21 494 individuals without a history of cardiovascular disease and without preexisting carotid plaque at baseline. Mean baseline age was 56 years (SD, 9 years), 55% were women, and mean baseline CCA-IMT was 0.71 mm (SD, 0.17 mm). Over a median follow-up of 5.9 years (5th-95th percentile, 1.9-19.0 years), 8278 individuals developed first-ever carotid plaque. We combined study-specific odds ratios (ORs) for incident carotid plaque using random-effects meta-analysis. Baseline CCA-IMT was approximately log-linearly associated with the odds of developing carotid plaque. The age-, sex-, and trial arm-adjusted OR for carotid plaque per SD higher baseline CCA-IMT was 1.40 (95% CI, 1.31-1.50; I2=63.9%). The corresponding OR that was further adjusted for ethnicity, smoking, diabetes, body mass index, systolic blood pressure, low- and high-density lipoprotein cholesterol, and lipid-lowering and antihypertensive medication was 1.34 (95% CI, 1.24-1.45; I2=59.4%; 14 studies; 16 297 participants; 6381 incident plaques). We observed no significant effect modification across clinically relevant subgroups. Sensitivity analysis restricted to studies defining plaque as focal thickening yielded a comparable OR (1.38 [95% CI, 1.29-1.47]; I2=57.1%; 14 studies; 17 352 participants; 6991 incident plaques). Conclusions Our large-scale individual participant data meta-analysis demonstrated that CCA-IMT is associated with the long-term risk of developing first-ever carotid plaque, independent of traditional cardiovascular risk factors.
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Nutrition and immunity: perspectives on key issues and next steps.
Dunbar, CL, Aukema, HM, Calder, PC, Gibson, DL, Henrickson, SE, Khan, S, Mailhot, G, Panahi, S, Tabung, FK, Tom, M, et al
Applied physiology, nutrition, and metabolism = Physiologie appliquee, nutrition et metabolisme. 2023;(7):484-497
Abstract
In January 2022, a group of experts came together to discuss current perspectives and future directions in nutritional immunology as part of a symposium organized by the Canadian Nutrition Society. Objectives included (1) creating an understanding of the complex interplay between diet and the immune system from infants through to older adults, (2) illustrating the role of micronutrients that are vital to the immune system, (3) learning about current research comparing the impact of various dietary patterns and novel approaches to reduce inflammation, autoimmune conditions, allergies, and infections, and (4) discussing select dietary recommendations aimed at improving disease-specific immune function. The aims of this review are to summarize the symposium and to identify key areas of research that require additional exploration to better understand the dynamic relationship between nutrition and immune function.
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Nutrition and immunity: lessons from coronavirus disease-2019.
Calder, PC
The Proceedings of the Nutrition Society. 2023;:1-16
Abstract
This review will provide an overview of the immune system and then describe the effects of frailty, obesity, specific micronutrients and the gut microbiota on immunity and susceptibility to infection including data from the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic where relevant. A key role for the immune system is providing host defence against pathogens. Impaired immunity predisposes to infections and to more severe infections and weakens the response to vaccination. A range of nutrients, including many micronutrients, play important roles in supporting the immune system to function. The immune system can decline in later life and this is exaggerated by frailty. The immune system is also weakened with obesity, generalised undernutrition and micronutrient deficiencies, which all result in increased susceptibility to infection. Findings obtained during the SARS-CoV-2 pandemic support what was already known about the effects of ageing, frailty and obesity on immunity and susceptibility to infection. Observational studies conducted during the pandemic also support previous findings that multiple micronutrients including vitamins C, D and E, zinc and selenium and long-chain n-3 fatty acids are important for immune health, but whether these nutrients can be used to treat those already with coronavirus disease discovered in 2019 (COVID-19), particularly if already hospitalised, is uncertain from current inconsistent or scant evidence. There is gut dysbiosis in patients with COVID-19 and studies with probiotics report clinical improvements in such patients. There is an inverse association between adherence to a healthy diet and risk of SARS-CoV-2 infection and hospitalisation with COVID-19 which is consistent with the effects of individual nutrients and other dietary components. Addressing frailty, obesity and micronutrient insufficiency will be important to reduce the burden of future pandemics and nutritional considerations need to be a central part of the approach to preventing infections, optimising vaccine responses and promoting recovery from infection.
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The role of omega-3 polyunsaturated fatty acids in the intensive care unit.
Singer, P, Calder, PC
Current opinion in clinical nutrition and metabolic care. 2023;(2):129-137
Abstract
PURPOSE OF REVIEW This review provides an update on the actions of omega-3 polyunsaturated fatty acids (PUFAs) and presents the most recent findings from trials in patients in the intensive care unit (ICU) setting including relevant meta-analyses. Many specialized pro-resolving mediators (SPMs) are produced from bioactive omega-3 PUFAs and may explain many of the beneficial effects of omega-3 PUFAs, although other mechanisms of action of omega-3 PUFAs are being uncovered. RECENT FINDINGS SPMs resolve inflammation, promote healing and support antiinfection activities of the immune system. Since publication of the ESPEN guidelines, numerous studies further support the use of omega-3 PUFAs. Recent meta-analyses favor the inclusion of omega-3 PUFAs in nutrition support of patients with acute respiratory distress syndrome or sepsis. Recent trials indicate that omega-3 PUFAs may protect against delirium and liver dysfunction in patients in the ICU, although effects on muscle loss are unclear and require further investigation. Critical illness may alter omega-3 PUFA turnover. There has been significant discussion about the potential for omega-3 PUFAs and SPMs in treatment of coronavirus disease 2019. SUMMARY Evidence for benefits of omega-3 PUFAs in the ICU setting has strengthened through new trials and meta-analyses. Nevertheless, better quality trials are still needed. SPMs may explain many of the benefits of omega-3 PUFAs.
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10.
Vital role for primary healthcare providers: urgent need to educate the community about daily nutritional self-care to support immune function and maintain health.
Calder, PC, Bach-Faig, A, Bevacqua, T, Caballero Lopez, CG, Chen, ZY, Connolly, D, Koay, WL, Meydani, SN, Pinar, AS, Ribas-Filho, D, et al
BMJ nutrition, prevention & health. 2023;(2):392-401
Abstract
The importance of self-care to improve health and social well-being is well recognised. Nevertheless, there remains a need to encourage people to better understand how their body works, and how to keep it healthy. Because of its important role, part of this understanding should be based on why the immune system must be supported. This highly complex system is essential for defending against pathogens, but also for maintaining health throughout the body by preserving homeostasis and integrity. Accordingly, the immune system requires active management for optimal functioning and to reduce the risk of chronic diseases. In addition to regular exercise, healthy sleeping patterns, cultivating mental resilience, adequate nutrition through healthy and diverse dietary habits is key to the daily support of immune function. Diet and the immune system are closely intertwined, and a poor diet will impair immunity and increase the risk of acute and chronic diseases. To help elucidate the roles of primary healthcare providers in supporting individuals to engage in self-care, an international group of experts reviewed the evidence for the roles of the immune system in maintaining health and for nutrition in daily immune support, and discussed implications for population health and clinical practice.