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Enriched Marine Oil Supplements Increase Peripheral Blood Specialized Pro-Resolving Mediators Concentrations and Reprogram Host Immune Responses: A Randomized Double-Blind Placebo-Controlled Study.
Souza, PR, Marques, RM, Gomez, EA, Colas, RA, De Matteis, R, Zak, A, Patel, M, Collier, DJ, Dalli, J
Circulation research. 2020;126(1):75-90
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Plain language summary
Specialized pro-resolving mediators (SPM) are derived from essential fatty acids and promote resolution of inflammation. The main aim of this study was to establish the relationship(s) between supplement dose, peripheral blood SPM concentrations, and cellular responses using a novel enriched marine oil preparation. This study is a double-blind, randomized, crossover, dose escalation placebo-controlled study in healthy volunteers. Participants (n=22) were randomised to one of eight groups. Results show supplementation with refined marine oils lead to a rapid upregulation of peripheral blood SPM concentrations and reprograming of peripheral blood cell responses to sterile and infectious stimuli, changes that were found to persist after SPM concentrations returned to baseline. Authors conclude that enriched marine oil supplementation leads to a dose-and time-dependent increase of plasma SPM concentrations.
Abstract
RATIONALE Specialized pro-resolving mediators (SPM-lipoxins, resolvins, protectins, and maresins) are produced via the enzymatic conversion of essential fatty acids, including the omega-3 fatty acids docosahexaenoic acid and n-3 docosapentaenoic acid. These mediators exert potent leukocyte directed actions and control vascular inflammation. Supplementation of animals and humans with essential fatty acids, in particular omega-3 fatty acids, exerts protective actions reducing vascular and systemic inflammation. Of note, the mechanism(s) activated by these supplements in exerting their protective actions remain poorly understood. OBJECTIVE Given that essential fatty acids are precursors in the biosynthesises of SPM, the aim of the present study was to establish the relationship between supplementation and peripheral SPM concentrations. We also investigated the relationship between changes in plasma SPM concentrations and peripheral blood platelet and leukocyte responses. METHODS AND RESULTS Healthy volunteers were enrolled in a double-blinded, placebo-controlled, crossover study, and peripheral blood was collected at baseline, 2, 4, 6, and 24 hours post administration of placebo or one of 3 doses of an enriched marine oil supplement. Assessment of plasma SPM concentrations using lipid mediator profiling demonstrated a time- and dose-dependent increase in peripheral blood SPM concentration. Supplementation also led to a regulation of peripheral blood cell responses. Here we found a dose-dependent increase in neutrophil and monocyte phagocytosis of bacteria and a decrease in the diurnal activation of leukocytes and platelets, as measured by a reduction in adhesion molecule expression. In addition, transcriptomic analysis of peripheral blood cells demonstrated a marked change in transcript levels of immune and metabolic genes 24 hours post supplementation when compared with placebo. CONCLUSIONS Together, these findings demonstrate that supplementation with an enriched marine oil leads to an increase in peripheral blood SPM concentrations and reprograms peripheral blood cells, indicating a role for SPM in mediating the immune-directed actions of this supplement. CLINICAL TRIAL REGISTRATION URL: http://www.clinicaltrials.gov. Unique identifier: NCT03347006.
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Treatment With a Marine Oil Supplement Alters Lipid Mediators and Leukocyte Phenotype in Healthy Patients and Those With Peripheral Artery Disease.
Schaller, MS, Chen, M, Colas, RA, Sorrentino, TA, Lazar, AA, Grenon, SM, Dalli, J, Conte, MS
Journal of the American Heart Association. 2020;9(15):e016113
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Plain language summary
Peripheral artery disease (PAD) is one of the most advanced forms of atherosclerosis. This disease state begins from an inflammatory lesion. The aim of this study was to investigate the impact of a short-course, oral, enriched marine oil supplement on circulating leukocytes and biochemical mediators in patients with symptomatic PAD and healthy controls. This study is a prospective, open-label, nonblinded study. Twenty participants completed the study: ten with PAD and 10 healthy individuals. Results show: - a shift in the leukocyte profiling towards a less inflammatory and more pro-resolving phenotype, most notably within the PAD cohort. - that supplementation led to an increase in phagocytic [a type of immune cell] activity of peripheral blood monocytes and neutrophils. - that circulating monocyte phenotyping demonstrated reduced expression of multiple proinflammatory markers. - that gene expression patterns in mono-derived macrophage from patients with PAD displayed a less inflammatory (type 1 macrophage) and greater reparative (type 2 macrophage) phenotype after supplementation. Authors conclude that their findings provide a foundation for characterising biochemical and cellular biomarkers of inflammation and resolution in PAD.
Abstract
Background Peripheral artery disease (PAD) is an advanced form of atherosclerosis characterized by chronic inflammation. Resolution of inflammation is a highly coordinated process driven by specialized pro-resolving lipid mediators endogenously derived from omega-3 fatty acids. We investigated the impact of a short-course, oral, enriched marine oil supplement on leukocyte phenotype and biochemical mediators in patients with symptomatic PAD and healthy volunteers. Methods and Results This was a prospective, open-label study of 5-day oral administration of an enriched marine oil supplement, assessing 3 escalating doses in 10 healthy volunteers and 10 patients with PAD. Over the course of the study, there was a significant increase in the plasma level of several lipid mediator families, total specialized pro-resolving lipid mediators, and specialized pro-resolving lipid mediator:prostaglandin ratio. Supplementation was associated with an increase in phagocytic activity of peripheral blood monocytes and neutrophils. Circulating monocyte phenotyping demonstrated reduced expression of multiple proinflammatory markers (cluster of differentiation 18, 163, 54, and 36, and chemokine receptor 2). Similarly, transcriptional profiling of monocyte-derived macrophages displayed polarization toward a reparative phenotype postsupplementation. The most notable cellular and biochemical changes over the study occurred in patients with PAD. There were strong correlations between integrated biochemical measures of lipid mediators (specialized pro-resolving lipid mediators:prostaglandin ratio) and phenotypic changes in circulating leukocytes in both healthy individuals and patients with PAD. Conclusions These data suggest that short-term enriched marine oil supplementation dramatically remodels downstream lipid mediator pathways and induces a less inflammatory and more pro-resolution phenotype in circulating leukocytes and monocyte-derived macrophages. Further studies are required to determine the potential clinical relevance of these findings in patients with PAD. Registration URL: https://www.clinicaltrials.gov; Unique identifier: NCT02719665.