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Enriched Marine Oil Supplement Increases Specific Plasma Specialized Pro-Resolving Mediators in Adults with Obesity.
Al-Shaer, AE, Regan, J, Buddenbaum, N, Tharwani, S, Drawdy, C, Behee, M, Sergin, S, Fenton, JI, Maddipati, KR, Kane, S, et al
The Journal of nutrition. 2022;152(7):1783-1791
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Plain language summary
Specialised pro-resolving mediators (SPMs) are highly potent oxylipins [metabolites] synthesized from omega-3 and omega-6 polyunsaturated fatty acids. SPMs have a critical role in resolving inflammation and returning damaged tissues to homeostasis. The main aim of this study was to determine if a marine oil supplement increased specific metabolites of the SPM biosynthetic pathway in adults with obesity. This study is a non-randomised uncontrolled clinical trial in adults with obesity. Twenty-three participants (n = 13 females, 10 males) aged between 50–65 years were enrolled. Only postmenopausal females were included in order to reduce confounding effects of oestrogen on lipid metabolism during supplementation. Results show that: - the marine oil supplement significantly increased some oxylipins of the SPM biosynthetic pathway. - there wasn’t an increase in the concentration of D-series resolvins upon intervention, although several docosahexaenoic acid-derived metabolites were increased. - the supplement decreased some HETEs [metabolites], which are synthesized from arachidonic acid. Authors conclude that their findings provide a framework for futures studies on the use of a marine oil supplement to examine the effects of how SPMs and their metabolic intermediates control varying aspects of inflammation and immunity, including antibody concentrations, in subjects with obesity.
Expert Review
Conflicts of interest:
None
Take Home Message:
- Marine oil enriched with specialised pro-resolving mediators raise levels of EPA, DPA and DHA-metabolites in adult subjects with obesity
- Larger randomised, blinded and placebo-controlled trials are required to inform healthcare practitioner clinical practice decisions relating to SPM enriched marine oil supplementation
- Future research is required to determine if increased concentrations of SPMs control the resolution of inflammation in humans with obesity.
Evidence Category:
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A: Meta-analyses, position-stands, randomized-controlled trials (RCTs)
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B: Systematic reviews including RCTs of limited number
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X
C: Non-randomized trials, observational studies, narrative reviews
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D: Case-reports, evidence-based clinical findings
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E: Opinion piece, other
Summary Review:
- Specialised pro-resolving mediators (SPMs) are oxylipins synthesised from omega-3 and -6 PUFAs which play a role in resolving inflammation.
- The authors highlight mouse studies have found that increasing the levels of SPMs and their metabolic intermediates can improve a range of obesity related complications. Thus, there is scientific interest in increasing the levels of SPMs in humans with diseases associated with chronic inflammation, such as obesity.
- This small non-randomised uncontrolled clinical trial of 23 individuals (13 female; 10 male) aged 50-65 years with obesity (BMI 30-40), aimed to determine the impacts of 1 month supplementation with marine oil particularly enriched with 14-hydroxydocosahexanenoic acid (14-HDHA), 17-HDHA and 18-hydroxydocosahenaenoic acid (HEPE) on:
- The change in levels of PUFA-derived oxylipins from baseline
- The change in abundance of circulating peripheral blood mononuclear cells (PBMCs)
- The change in antibody production
Intervention
- 2g enriched marine oil (4 capsules of SPM Active provided by Metagenics, study sponsor) once daily for 28-30 consecutive days.
Inclusion/Exclusion Criteria
- Only post-menopausal women were included to reduce confounding effects of oestrogen on lipid metabolism
- Individuals were excluded if diagnosed with Type 1 or 2 diabetes, autoimmunity, liver disease, coagulopathy, uncontrolled hypothyroid or active malignancy
- Individuals were excluded if they consumed omega-3 PUFA supplements within 3 months of intervention, regularly consumed >2 servings per week of fatty fish, had a fish/shellfish allergy or were taking a predetermined list of medications.
Findings
- Statistically significant increases were found in certain EPA, DPA and DHA-derived metabolites in response to supplementation relative to baseline. However, only 17-HDHA concentrations increased relative to baseline, with no effect on 14-HDHA or 18-HEPE, despite the supplement being enriched with all 3 metabolites
- Statistically significant decreases were found in arachidonic acid (AA)-derived oxylipins post supplementation relative to baseline
- Increases in immune cell populations in circulation did not reach significance post supplementation when measured by PBMCs.
Conclusions
An enriched marine oil supplement increased select SPMs in adults with obesity.
Clinical practice applications:
- Healthcare practitioners working with adults with obesity can use the results from this trial to understand that 1 month supplementation with 4g of enriched marine oil supplementation raises levels of certain EPA, DPA and DHA metabolites
- Practitioners may want to follow the research in this area as larger, controlled trials are conducted and comparisons made with non-enriched fatty acid supplements.
Considerations for future research:
- Future clinical studies of SPM supplementation are required that are double-blind, randomised and placebo-controlled to inform scientific findings in this area
- This study was inadequately powered to assess differences between female and male participants and therefore larger trials are needed to inform the sex differences in oxylipins within the population with obesity
- Further research is required in younger subjects with obesity to assess SPMs as a possible chronic inflammation preventative strategy, due to inflammation complications over time
- Future research should take account of the heterogeneity in the population with obesity, such as microbiome profiles, food intake and baseline metabolic status
- Further studies comparing impacts of standard marine oil with enriched marine oil on chronic inflammation would inform healthcare practitioners in their clinical practice.
Abstract
BACKGROUND Specialized pro-resolving mediators (SPMs), synthesized from PUFAs, resolve inflammation and return damaged tissue to homeostasis. Thus, increasing metabolites of the SPM biosynthetic pathway may have potential health benefits for select clinical populations, such as subjects with obesity who display dysregulation of SPM metabolism. However, the concentrations of SPMs and their metabolic intermediates in humans with obesity remains unclear. OBJECTIVES The primary objective of this study was to determine if a marine oil supplement increased specific metabolites of the SPM biosynthetic pathway in adults with obesity. The second objective was to determine if the supplement changed the relative abundance of key immune cell populations. Finally, given the critical role of antibodies in inflammation, we determined if ex vivo CD19 + B-cell antibody production was modified by marine oil intervention. METHODS Twenty-three subjects [median age: 56 y; BMI (in kg/m2): 33.1] consumed 2 g/d of a marine oil supplement for 28-30 d. The supplement was particularly enriched with 18-hydroxyeicosapentaenoic (HEPE), 14-hydroxydocosahexaenoic acid (14-HDHA), and 17-HDHA. Blood was collected pre- and postsupplementation for plasma mass spectrometry oxylipin and fatty acid analyses, flow cytometry, and B-cell isolation. Paired t-tests and Wilcoxon tests were used for statistical analyses. RESULTS Relative to preintervention, the supplement increased 6 different HEPEs and HDHAs accompanied by changes in plasma PUFAs. Resolvin E1 and docosapentaenoic acid-derived maresin 1 concentrations were increased 3.5- and 4.7-fold upon intervention, respectively. The supplement did not increase the concentration of D-series resolvins and had no effect on the abundance of immune cells. Ex vivo B-cell IgG but not IgM concentrations were lowered postsupplementation. CONCLUSIONS A marine oil supplement increased select SPMs and their metabolic intermediates in adults with obesity. Additional studies are needed to determine if increased concentrations of specific SPMs control the resolution of inflammation in humans with obesity. This trial was registered at clinicaltrials.gov as NCT04701138.
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A Low ω-6 to ω-3 PUFA Ratio (n-6:n-3 PUFA) Diet to Treat Fatty Liver Disease in Obese Youth.
Van Name, MA, Savoye, M, Chick, JM, Galuppo, BT, Feldstein, AE, Pierpont, B, Johnson, C, Shabanova, V, Ekong, U, Valentino, PL, et al
The Journal of nutrition. 2020;150(9):2314-2321
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Non-alcoholic fatty liver disease (NAFLD) is characterised by the accumulation of fat in the liver of people who drink very little or no alcohol. NAFLD is a common problem in children with obesity and diet is a contributory factor. Recent research has suggested that the Western diet and its high omega-6 and low omega-3 fat intakes may lead to the development of NAFLD. This quasi-experimental study of twenty children with obesity and NAFLD aimed to determine whether 12 weeks of low omega-6: omega-3 ratio diet affected liver fat content. The results showed that the diet did not affect weight loss but still significantly decreased liver fat content, with one third of the participants returning their liver fat content to normal. In lieu of weight loss, improvements were also observed in markers for liver function, diabetes and blood cholesterol. Interestingly those who carry a certain gene increasing their risk of developing NAFLD, showed greater improvements in liver fat percentage and liver function. It was concluded that in the absence of weight loss, a diet high in omega-3 and low in omega-6 improves fatty liver disease, risk factors for heart disease and has the potential to revert liver fat content to normal levels. This study could be used by healthcare professionals to recommend a low omega-6:omega-3 diet in children with obesity and NAFLD.
Abstract
BACKGROUND Recent literature suggests that the Western diet's imbalance between high ω-6 (n-6) and low ω-3 (n-3) PUFA intake contributes to fatty liver disease in obese youth. OBJECTIVES We tested whether 12 wk of a low n-6:n-3 PUFA ratio (4:1) normocaloric diet mitigates fatty liver and whether the patatin-like containing domain phospholipase 3 (PNPLA3) rs738409 variant affects the response. METHODS In a single-arm unblinded study, obese youth 9-19 y of age with nonalcoholic fatty liver disease were treated with a normocaloric low n-6:n-3 PUFA ratio diet for 12 wk. The primary outcome was change in hepatic fat fraction (HFF%), measured by abdominal MRI. Metabolic parameters included alanine aminotransferase (ALT), lipids, measures of insulin sensitivity, and plasma oxidized linoleic acid metabolites (OXLAMs). Outcomes were also analyzed by PNPLA3 rs738409 genotype. Wilcoxon's signed rank test, the Mann-Whitney U test, and covariance pattern modeling were used. RESULTS Twenty obese adolescents (median age: 13.3 y; IQR: 10.5-16.4 y) were enrolled and 17 completed the study. After 12 wk of dietary intervention, HFF% decreased by 25.8% (P = 0.009) despite stable weight. We observed a 34.4% reduction in ALT (P = 0.001), 21.9% reduction in triglycerides (P = 0.046), 3.28% reduction in LDL cholesterol (P = 0.071), and a 26.3% improvement in whole body insulin sensitivity (P = 0.032). The OXLAMs 9-hydroxy-octadecandienoic acid (9-HODE) (P = 0.011), 13-HODE (P = 0.007), and 9-oxo-octadecadienoic acid (9-oxoODE) (P = 0.024) decreased after 12 wk. HFF% declined in both the not-at-risk (CC/CG) and at-risk (GG) PNPLA3 rs738409 genotype groups, with significant (P = 0.016) HFF% reduction in the GG group. Changes in 9-HODE (P = 0.023), 9-oxoODE (P = 0.009), and 13-oxoODE (P = 0.003) differed between the 2 genotype groups over time. CONCLUSIONS These data suggest that, independently of weight loss, a low n-6:n-3 PUFA diet ameliorates the metabolic phenotype of adolescents with fatty liver disease and that response to this diet is modulated by the PNPLA3 rs738409 genotype.This trial was registered at clinicaltrials.gov as NCT01556113.
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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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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.
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Lack of effect of foods enriched with plant- or marine-derived n-3 fatty acids on human immune function.
Kew, S, Banerjee, T, Minihane, AM, Finnegan, YE, Muggli, R, Albers, R, Williams, CM, Calder, PC
The American journal of clinical nutrition. 2003;77(5):1287-95
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Plain language summary
There is continued interest in the effects of polyunsaturated fatty acids (PUFAs) on the human immune system. While many studies have investigated the effects of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) on human immune function, few have investigated the immunologic effects of alpha-linolenic acid (ALA). The aim of this trial was to determine the effects of enriching the diet with ALA or EPA+DHA on immune outcomes by randomly assigning 150 healthy participants to 1 of 5 intervention groups: placebo, high or low ALA and high or low EPA+DHA for six months. This study showed that an increased intake of ALA or EPA+DHA did not alter the function of immune cells, however did change the fatty acid composition of lymphocytes and monocytes. Based on these findings, the authors conclude that consumption of PUFAs could be increased without adverse effects on the immune response.
Abstract
BACKGROUND Greatly increasing dietary flaxseed oil [rich in the n-3 polyunsaturated fatty acid (PUFA) alpha-linolenic acid (ALA)] or fish oil [rich in the long-chain n-3 PUFAs eicosapentaenoic (EPA) and docosahexaenoic (DHA) acids] can reduce markers of immune cell function. The effects of more modest doses are unclear, and it is not known whether ALA has the same effects as its long-chain derivatives.
OBJECTIVE The objective was to determine the effects of enriching the diet with ALA or EPA+DHA on immune outcomes representing key functions of human neutrophils, monocytes, and lymphocytes.
DESIGN In a placebo-controlled, double-blind, parallel study, 150 healthy men and women aged 25-72 y were randomly assigned to 1 of 5 interventions: placebo (no additional n-3 PUFAs), 4.5 or 9.5 g ALA/d, and 0.77 or 1.7 g EPA+DHA/d for 6 mo. The n-3 PUFAs were provided in 25 g fat spread plus 3 oil capsules. Blood samples were taken at 0, 3, and 6 mo.
RESULTS The fatty acid composition of peripheral blood mononuclear cell phospholipids was significantly different in the groups with higher intakes of ALA or EPA+DHA. The interventions did not alter the percentages of neutrophils or monocytes engaged in phagocytosis of Escherichia coli or in phagocytic activity, the percentages of neutrophils or monocytes undergoing oxidative burst in response to E. coli or phorbol ester, the proliferation of lymphocytes in response to a T cell mitogen, the production of numerous cytokines by monocytes and lymphocytes, or the in vivo delayed-type hypersensitivity response.
CONCLUSION An intake of