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A combined DHA-rich fish oil and cocoa flavanols intervention does not improve cognition or brain structure in older adults with memory complaints: results from the CANN randomized, controlled parallel-design study.
Vauzour, D, Scholey, A, White, DJ, Cohen, NJ, Cassidy, A, Gillings, R, Irvine, MA, Kay, CD, Kim, M, King, R, et al
The American journal of clinical nutrition. 2023;118(2):369-381
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At a population level, interventions that delay the onset of dementia by 2 years are predicted to reduce the number of dementia patients by 20%. Prospective cohort studies have consistently reported cognitive and neurophysiological benefits of the fish-derived omega-3 long-chain polyunsaturated fatty acids (PUFAs), EPA, and DHA and plant-derived flavanols (FLAVs). This study hypothesised that 12-month administration of a combination of 500 mg cocoa FLAVs with 1.5g omega-3 long-chain PUFAs would improve cognitive function in a mixed subjective cognitive impairment and mild cognitive impairment cohort. This study is based on the results of the CANN randomised controlled trial. A total of 258 participants were recruited and randomised to control or test intervention. Following baseline measurements, 125 participants were randomised into the active OM3FLAV intervention group and 121 into the control group. Results showed that the 1-year intervention with EPA and DHA and cocoa FLAVs did not improve cognition or protect the brain against atrophy in older adults with evidence of memory deficits. Authors concluded that given the complexity of neuropathological processes underpinning cognitive decline and dementia risk, multidomain, multinutrient, or whole diet approaches may be needed to positively impact the cognitive trajectory in the medium term (months to 3 years).
Abstract
BACKGROUND There is evidence that both omega-3 long-chain polyunsaturated fatty acids (PUFAs) (eicosapentaenoic acid [EPA] and docosahexaenoic acid [DHA]) and cocoa flavanols can improve cognitive performance in both healthy individuals and in those with memory complaints. However, their combined effect is unknown. OBJECTIVES To investigate the combined effect of EPA/DHA and cocoa flavanols (OM3FLAV) on cognitive performance and brain structures in older adults with memory complaints. METHODS A randomized placebo-controlled trial of DHA-rich fish oil (providing 1.1 g/d DHA and 0.4 g/d EPA) and a flavanol-rich dark chocolate (providing 500 mg/d flavan-3-ols) was conducted in 259 older adults with either subjective cognitive impairment or mild cognitive impairment. Participants underwent assessment at baseline, 3 mo, and 12 mo. The primary outcome was the number of false-positives on a picture recognition task from the Cognitive Drug Research computerized assessment battery. Secondary outcomes included other cognition and mood outcomes, plasma lipids, brain-derived neurotrophic factor (BDNF), and glucose levels. A subset of 110 participants underwent structural neuroimaging at baseline and at 12 mo. RESULTS 197 participants completed the study. The combined intervention had no significant effect on any cognitive outcomes, with the exception of reaction time variability (P = 0.007), alertness (P < 0.001), and executive function (P < 0.001), with a decline in function observed in the OM3FLAV group (118.6 [SD 25.3] at baseline versus 113.3 [SD 25.4] at 12 mo for executive function) relative to the control, and an associated decrease in cortical volume (P = 0.039). Compared with the control group, OM3FLAV increased plasma HDL, total cholesterol ratio (P < 0.001), and glucose (P = 0.008) and reduced TG concentrations (P < 0.001) by 3 mo, which were sustained to 12 mo, with no effect on BDNF. Changes in plasma EPA and DHA and urinary flavonoid metabolite concentrations confirmed compliance to the intervention. CONCLUSIONS These results suggest that cosupplementation with ω-3 PUFAs and cocoa flavanols for 12 mo does not improve cognitive outcomes in those with cognitive impairment. This trial was registered at clinicaltrials.gov as NCT02525198.
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Low omega-3 polyunsaturated fatty acids predict reduced response to standard antidepressants in patients with major depressive disorder.
Cussotto, S, Delgado, I, Oriolo, G, Kemper, J, Begarie, D, Dexpert, S, Sauvant, J, Leboyer, M, Aouizerate, B, Martin-Santos, R, et al
Depression and anxiety. 2022
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Major depressive disorder (MDD) is a leading cause of disability, and antidepressant drug treatment is only effective in over half of patients with a high prevalence of treatment resistance. The importance of nutrition in mental health is gaining recognition. Omega-3 is an essential polyunsaturated fatty acid (PUFA) vital for anti-inflammatory processes and brain integrity. In the absence of the body's ability to make Omega-3, it or its precursors must be acquired from the diet. Yet altered metabolic pathways can hamper the process and the adequate balance with PUFA Omega‐6 is also crucial, as elevated levels of Omega-6 are linked to several diseases. An extensive amount of research suggests that higher Omega-3 levels reduce the occurrence of depression. Yet results using just Omega-3s for depression have been varied. This European-wide study sought to investigate how the PUFA status could affect the clinical response to treatment with antidepressants. 60-adults with an average age of 41 with major depressive disorders received antidepressive treatment. Their red blood cell fatty acids content was determined, and at the end of the 8-week trial treatment responders and non-responders were identified. Findings affirmed the existing knowledge that depressive symptoms are strongly associated with PUFA status. Patients who did not respond to treatment showed low levels of Omega-3 and an unfavourable ratio of Omega-3 to Omega-6 at the start of treatment. Higher levels of Omega-3 fatty acid of DHA seemed to produce a better clinical response to treatments than the Omega-3 of EPA. The authors discussed some potential mechanisms and suggested that PUFA intake and metabolism could be a potential tool for the management of treatment-unresponsive patients with depression. This review highlights the clinical importance of considering PUFA status and metabolism in the support of major depressive disorders.
Expert Review
Conflicts of interest:
None
Take Home Message:
- Healthy eating such as that with low omega-6 diets has more than a physiological result on the human body and carries significant biochemical consequences when the omega-6 to omega-3 ratio is deemed to be ‘high’.
- The result of this research has pharmaceutical implications - if the findings could be imparted to the general public in layman’s terms, practitioners could empower individuals to take greater control of their mental health through more naturalistic means, i.e., optimised nutrition.
- There are wider cognitive considerations of healthy eating beyond that of treating Major Depressive Disorder due to implicated blood-brain-barrier effects, as concluded in this study.
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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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:
Sixty adults suffering from major depressive disorder (MDD) were recruited into a multicenter study assessing the impact of baseline polyunsaturated (PUFA) levels on responsiveness to antidepressants. Neuropsychiatric evaluations producing MADRS (Montgomery Åsberg Depression Rating Scale) scores at baseline, four weeks and again at eight weeks, were performed. The pre-recorded baseline PUFA levels were then used as an associative and predictive indicator when viewing the end point scoring of participants, thus categorising into responsive and nonresponsive strata.
Of those with low omega-3 and high omega-6 to omega-3 ratio at baseline, there was increased association with ‘non-responsive’ classification at end point (week 8). Participants were deemed ‘non-responsive’ to anti-depressant treatment when scores at week 8 failed to demonstrate ≥50% reduction in MADRS scoring.
Clinical practice applications:
- Clinicians could monitor MDD within at-risk-groups, such as those who are overweight (mean BMI of ALL study participants was 24.20 kg/m2 with a standard deviation of 4.21) or those experiencing an inflammatory state with blood-brain-barrier involvement, as part of a mental ill-health prevention programme.
- When presenting with symptoms of major depressive disorder and prescribing antidepressants, clinicians could recommend increasing consumption of foods high in omega-3 and/or querying the patient about their dietary habits.
- Article supports recommendations for an increase in the consumption of omega-3 rich foods amongst the general population to prevent or intervene in cases of major depressive disorder.
- Wider cognitive implications beyond major depressive disorder in the presence of low omega-3, such as cognitive decline as seen with dementia, theorised due to altered blood-brain-barrier (Cussotto et al., 2022; Gustafson et al., 2020).
Considerations for future research:
- Repeated studies, with normalised distribution of antidepressant and sample size by country, with greater geographic inclusion, along with age categorisation. The broader geographic inclusion is necessary to rule out cultural diets as a confounding variable. An example of how different cultural diets could influence the results, which has potentially been highlighted in this study, is the more predominant consumption of a Mediterranean diet which may have been the case for the participants from Spain or, as could also be the case, an underlying vitamin D deficiency of the participants from Germany.
- Novel studies for assessing diet against mood could be beneficial to fully apply the findings of this study to clinical practice applications and that of the practice of nutritional therapists. The thinking here is the potential for anti-inflammatory foods inducing better mood results through gut-brain axis links and resultant influence on microbiome.
Abstract
BACKGROUND Major depressive disorder (MDD) is characterized by a high rate of treatment resistance. Omega (ω)-3 polyunsaturated fatty acids (PUFAs) were shown to correlate with depressive phenotype both in rodents and in humans. However, few studies to date have investigated the role of PUFAs in antidepressant response. The primary aim of this study was to assess the link between baseline PUFA composition and changes in depressive symptoms as well as antidepressant response in a multicenter study of depressed patients. METHODS Sixty depressed adults who met criteria for MDD according to DSM-IV-TR were recruited. Neuropsychiatric evaluations occurred at baseline and after 4 and 8 weeks of treatment with standard antidepressants, including escitalopram (N = 45), sertraline (N = 13) and venlafaxine (N = 2). At study endpoint, patients were stratified into responders (R) or non-responders (NR) based on their MADRS (Montgomery-Åsberg Depression Rating Scale) score. Baseline PUFA levels were assessed and their association with clinical response was determined. RESULTS Lower ω-3 PUFA levels were associated to worse baseline symptomatology. Baseline levels of PUFAs were significantly different between R and NR, with R exhibiting lower docosahexaenoic acid (DHA), eicosapentaenoic acid (EPA) and ω-3 index; and higher ω-6/ω-3 ratio than NR before the start of antidepressant treatment. DHA levels as well as the ω-3 index and ω-6/ω-3 ratio significantly predicted response to antidepressants at study endpoint. CONCLUSIONS These results show that baseline levels of PUFAs predict later response to standard antidepressants in depressed subjects. They suggest that PUFA intake and/or metabolism represent a novel modifiable tool for the management of unresponsive depressed patients.
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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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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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Effect of Docosahexaenoic Acid and Eicosapentaenoic Acid Supplementation on Sleep Quality in Healthy Subjects: A Randomized, Double-Blinded, Placebo-Controlled Trial.
Yokoi-Shimizu, K, Yanagimoto, K, Hayamizu, K
Nutrients. 2022;14(19)
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Docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA) are unsaturated Omega-3 fatty acids, primarily found in fish and seafood. The fatty acids fulfil many vital roles in the body, such as creating cell membranes, supporting brain functions and being associated with many disease-protective benefits. These fatty acids also influence sleep in children and young adults, but less is known about their effect in older people. Hence, this Japanese study investigated the impact of EPA and DHA on sleep quality in people above the age of ≥ 45. 66 males and females with poor sleep participated in this randomized, placebo-controlled, double-blinded, parallel-grouped study. They either received 860 mg of combined DHA/EPA per day (576 mg DHA/284 mg EPA) or a placebo of corn oil for 12 weeks. The outcome was assessed subjectively via sleep quality and mood questionnaires, as well as objectively with a sleep scanner and blood samples. Blood samples and blood pressure where also monitored as a safety measure. Upon completion of the study there was a subjective improvement, which was backed-up by the results of the sleep scanner. This study confirmed that DHA/EPA improves sleep quality in the middle aged and older population and does so at doses lower than those administered in previous studies. The authors had set the daily minimum intake of DHA/EPA at 860 mg/day for this trial, as previous research showed no effects at lower doses. They also noted that poor responders tended to be people with pre-existing conditions or those who were pregnant. This population may require higher dosages of DHA/EPA than healthy patients. Overall, the intervention was well tolerated. Ensuring adequate DHA and EPA levels and intake could be part of nutritional strategies for sleep support.
Abstract
Docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA)-omega-3 fatty acids with various functions-influence sleep in children and young adults. However, only limited studies on their effects on sleep in middle- and old-aged adults have been reported. Therefore, we investigated the effects of DHA and EPA on sleep quality in subjects aged ≥ 45 years. We performed a randomized, placebo-controlled, double-blinded, parallel-grouped study, in which we randomly assigned 66 healthy Japanese males and females. Each individual received six 480 mg capsules containing 576 mg DHA and 284 mg EPA per day (DHA/EPA group, n = 33), or corn oil (placebo group, n = 33), for 12 weeks. Before and after the intervention, the Oguri-Shirakawa-Azumi sleep inventory MA version (OSA-MA) and the sleep state test were conducted. In the DHA/EPA group, factor III (frequent dreaming) scores among the OSA-MA scores were significantly improved compared to the placebo group. Additionally, sleep state tests revealed that sleep efficiency improved in the DHA/EPA group. To our knowledge, this study is the first to report that DHA/EPA improves sleep quality in middle- and old-aged individuals, even at doses lower than those administered in previous studies.
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Type 2 diabetes preventive effects with a 12-months sardine-enriched diet in elderly population with prediabetes: An interventional, randomized and controlled trial.
Díaz-Rizzolo, DA, Serra, A, Colungo, C, Sala-Vila, A, Sisó-Almirall, A, Gomis, R
Clinical nutrition (Edinburgh, Scotland). 2021;40(5):2587-2598
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Older people have a higher risk of developing Type 2 diabetes (T2D) due to the possibility of β-cell dysfunction due to ageing. Sardines are believed to be protective against the development of T2D. Therefore, this randomised controlled trial evaluated the preventative effects of a sardine-rich diet in elderly prediabetic patients. For one year, both the sardine group (SG) and control group (CG) followed a T2D prevention diet, with the SG consuming 200 g of sardines each week. Both groups improved body weight, BMI, waist and hip circumference, and body composition. Taurine, EPA, DHA, omega-3 fatty acid, calcium, iodine, zinc, phosphorous and fluoride, vitamin B12 and D, and lycopene and tocopherols were found to be higher in the SG than the CG, indicating the sardines were protective against T2D. In SG, HDL cholesterol and adiponectin levels were significantly increased, and blood pressure and triglycerides were decreased, signalling a reduced risk of T2D and cardiovascular disease. In addition, SG showed a reduction in HOMA-IR and an Omega-3 fatty acid was substituted for Omega-6 fatty acids in the erythrocyte membrane, suggesting a reduced risk of T2D. Further robust research is required to confirm the protective effect of a sardine-enriched diet against T2D. It may be useful to healthcare providers to comprehend how a sardine-enriched diet could improve obesity, T2D and CVD markers in pre-diabetic elderly patients.
Abstract
BACKGROUND Fish could play a role in preventing type 2 diabetes (T2D) but there has been little specification about the type of fish and the preventive mechanism involved in its health claim. The sardine is a source of omega-3 and taurine that, in isolation or in synergy, would produce T2D-delaying through different molecular mechanism. HYPOTHESIS The consumption of twice a week of sardine, during one year would reduce T2D-developing risk in a population with prediabetes (preDM) and old age. DESIGN 152 subjects with fasting glucose between 100-124 mg/dL aged ≥65 yo were recruited from three primary care centers in Barcelona and were randomly distributed among two interventional groups: control group (CG) and sardine group (SG). Both groups received same T2D-prevention nutritional during a year but only SG had to add 200 g of sardine per week. All variables were collected before to start and at the end of the diet. (ClinicalTrials.gov: NCT03557541). RESULTS 152 people were randomized into CG (n=77) and SG (n=75) with 18 and 12 drop outs respectively. Subjects in SG, significantly compared to CG, decreased percentage classified-individuals in a very high risk group to develop T2D according to FINDRISC (p=0.035). In addition to increasing HDL-cholesterol and adiponectin and decreasing triglycerides (p<0.05) and blood pressure (<0.05), SG showed a lower HOMA-IR (p=0.032). The consumption of sardine characteristics nutrients as omega-3, EPA and DHA, vitamin D, fluorine and taurine were higher for SG (p<0.05). These results agreed with the increased of taurine, fatty acid (FA) omega-3 and bile acids circulating metabolites (p<0.05). Changes erythrocyte membrane FA were detected only in SG with a decrease of 5 omega-6 FA (p<0.001) and an increase of 3 omega-3 FA types (p<0.001). CONCLUSION We conclude that a year T2D-prevention diet with sardine supplementation has a greater protective effect against developing T2D and CV events.
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Dietary alteration of n-3 and n-6 fatty acids for headache reduction in adults with migraine: randomized controlled trial.
Ramsden, CE, Zamora, D, Faurot, KR, MacIntosh, B, Horowitz, M, Keyes, GS, Yuan, ZX, Miller, V, Lynch, C, Honvoh, G, et al
BMJ (Clinical research ed.). 2021;374:n1448
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Plain language summary
This study could be of interest to practitioners who are interested in dietary interventions that may decrease the incidence or severity of headaches in women. Omega 3 fatty acids such as eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) are believed to be precursors for molecules that may have pain reducing properties. Whereas omega 6 fatty acids such as linoleic acid are believed to be precursors for molecules that may have pain promoting effects. The objective of this 3 armed randomised, double blinded controlled trial was to determine whether increasing dietary intake of omega 3 EPA and DHA, whilst either maintaining or decreasing omega 6 linoleic acid, may lead to a decrease in headache frequency and severity. 182 participants were assigned into one of 3 treatment groups, the first, H3 diet, increasing EPA and DHA to 1.5g/day and maintaining linoleic acid, the second, H3-L6 diet, increasing EPA and DHA to 1.5g/day whilst decreasing linoleic acid and the control group maintaining EPA, DHA and linoleic acid. Both the H3 and H3-L6 diets increased the levels of the molecule believed to be involved in reducing pain to a statistically significant level. This was found to be consistent with the results reported by the patients both in headache hours per day and days with headache in the month. The authors conclude that increasing levels of omega 3 fatty acids in the diet whilst decreasing levels of omega 6 fatty acids in the diet may decrease the frequency and severity of headaches. This study was for 16 weeks and predominantly women with a mean age of 38, further studies for longer and on other populations such as men, children and older populations, would be required to see if the same results could be obtained.
Expert Review
Conflicts of interest:
None
Take Home Message:
- Important from a public health perspective
- Increasing n-3 levels and decreasing n-6 levels could be modified by dietary change and appear to reduce the frequency and duration of headaches in migraine sufferers
Evidence Category:
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X
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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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:
Background
Circulating lipid mediators have been implicated in headache pathogenesis.
Objective
To determine whether dietary interventions that increase n-3 fatty acids with and without reduction in n-6 linoleic acid can alter circulating lipid mediators implicated in headache pathogenesis, and decrease headache in adults with migraine.
Study Design
Three arm, parallel group, randomized, modified double blind, controlled trial.
Participants
182 participants (88% women, mean age 38 years) with migraines on 5-20 days per month (67% met criteria for chronic migraine).
Interventions
Three diets designed with eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA), and linoleic acid altered as controlled variables:
- H3 diet (n=61)—increase EPA+DHA to 1.5 g/day and maintain linoleic acid at around 7% of total energy intake
- H3-L6 diet (n=61)—increase n-3 EPA+DHA to 1.5 g/day and decrease linoleic acid to ≤1.8% of total energy intake
- Control diet (n=60)—maintain EPA+DHA at <150 mg/day and linoleic acid at around 7% of total energy intake
All participants received foods accounting for two thirds of daily food energy and 1/3rd from foods not provided by the Research Kitchen. For these foods participants rely on their training by the dietitian and website diet guides for shopping and choosing foods in restaurants. Participants were encouraged to continue seeing their headache physician and continue usual care.
Results
In intention-to-treat analyses (n=182) at 16 weeks
- The H3-L6 and H3 diets increased circulating 17-HDHA compared with the control diet (baseline-adjusted mean difference 0.6, 95% confidence interval 0.2 to 0.9; 0.7, 0.4 to 1.1, respectively).
- The observed improvement in HIT-6 scores (quality of life) in the H3-L6 and H3 groups was not statistically significant (−1.6, −4.2 to 1.0, and −1.5, −4.2 to 1.2, respectively).
- Compared with the control diet, the H3-L6 and H3 diets decreased total headache hours per day (−1.7, −2.5 to −0.9, and −1.3, −2.1 to −0.5, respectively), moderate to severe headache hours per day, (−0.8, −1.2 to −0.4, and −0.7, −1.1 to −0.3, respectively) and headache days per month (−4.0, −5.2 to −2.7, and −2.0, −3.3 to −0.7, respectively).
- The H3-L6 diet decreased headache days per month more than the H3 diet, suggesting additional benefit from lowering dietary linoleic acid (−2.0, −3.2 to −0.8).
- The H3-L6 and H3 diets altered n-3 and n-6 fatty acids and several of their nociceptive oxylipin derivatives in plasma, serum, erythrocytes or immune cells, but did not alter classic headache mediators calcitonin gene related peptide and prostaglandin E2.
Conclusions
The H3-L6 and H3 interventions altered bioactive mediators implicated in headache pathogenesis and decreased frequency and severity of headaches, but did not significantly improve quality of life.
Clinical practice applications:
These findings might be useful for Nutritional Therapists and Clinical Practitioners:
- To inform practitioners of the benefits of assessing n-3 and n-6 fatty acids in migraine patients.
- Inform practitioners of the potential benefits to reducing n-6 as well as increasing n-3 levels in migraine patients
- Inform practitioners of the potential lack of correlation between headache duration and frequency and quality of life measures
Considerations for future research:
- Trialing larger doses of n-3
- Longer term follow up whilst maintaining these diets
- Attempting to validate an optimal serum level of 17-HDHA for these patients that could be used in clinical practice
Abstract
OBJECTIVE To determine whether dietary interventions that increase n-3 fatty acids with and without reduction in n-6 linoleic acid can alter circulating lipid mediators implicated in headache pathogenesis, and decrease headache in adults with migraine. DESIGN Three arm, parallel group, randomized, modified double blind, controlled trial. SETTING Ambulatory, academic medical center in the United States over 16 weeks. PARTICIPANTS 182 participants (88% women, mean age 38 years) with migraines on 5-20 days per month (67% met criteria for chronic migraine). INTERVENTIONS Three diets designed with eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA), and linoleic acid altered as controlled variables: H3 diet (n=61)-increase EPA+DHA to 1.5 g/day and maintain linoleic acid at around 7% of energy; H3-L6 diet (n=61)-increase n-3 EPA+DHA to 1.5 g/day and decrease linoleic acid to ≤1.8% of energy; control diet (n=60)-maintain EPA+DHA at <150 mg/day and linoleic acid at around 7% of energy. All participants received foods accounting for two thirds of daily food energy and continued usual care. MAIN OUTCOME MEASURES The primary endpoints (week 16) were the antinociceptive mediator 17-hydroxydocosahexaenoic acid (17-HDHA) in blood and the headache impact test (HIT-6), a six item questionnaire assessing headache impact on quality of life. Headache frequency was assessed daily with an electronic diary. RESULTS In intention-to-treat analyses (n=182), the H3-L6 and H3 diets increased circulating 17-HDHA (log ng/mL) compared with the control diet (baseline-adjusted mean difference 0.6, 95% confidence interval 0.2 to 0.9; 0.7, 0.4 to 1.1, respectively). The observed improvement in HIT-6 scores in the H3-L6 and H3 groups was not statistically significant (-1.6, -4.2 to 1.0, and -1.5, -4.2 to 1.2, respectively). Compared with the control diet, the H3-L6 and H3 diets decreased total headache hours per day (-1.7, -2.5 to -0.9, and -1.3, -2.1 to -0.5, respectively), moderate to severe headache hours per day (-0.8, -1.2 to -0.4, and -0.7, -1.1 to -0.3, respectively), and headache days per month (-4.0, -5.2 to -2.7, and -2.0, -3.3 to -0.7, respectively). The H3-L6 diet decreased headache days per month more than the H3 diet (-2.0, -3.2 to -0.8), suggesting additional benefit from lowering dietary linoleic acid. The H3-L6 and H3 diets altered n-3 and n-6 fatty acids and several of their nociceptive oxylipin derivatives in plasma, serum, erythrocytes or immune cells, but did not alter classic headache mediators calcitonin gene related peptide and prostaglandin E2. CONCLUSIONS The H3-L6 and H3 interventions altered bioactive mediators implicated in headache pathogenesis and decreased frequency and severity of headaches, but did not significantly improve quality of life. TRIAL REGISTRATION ClinicalTrials.gov NCT02012790.
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Vegan diet in young children remodels metabolism and challenges the statuses of essential nutrients.
Hovinen, T, Korkalo, L, Freese, R, Skaffari, E, Isohanni, P, Niemi, M, Nevalainen, J, Gylling, H, Zamboni, N, Erkkola, M, et al
EMBO molecular medicine. 2021;13(2):e13492
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As vegan diets gain popularity amongst families, there is little known about the impact of strict plant-based diets on metabolism and micronutrient status in children, apart from reduced average growth within the norm. This small study looked at 40 Finnish children from one day centre, and compared children following an omnivore or vegetarian diet to those raised on a vegan diet. The diets were analysed, and biomarkers and metabolites were measured. The metabolic profile and nutrient status of children who followed a vegan diet from birth were distinctively different to other diet patterns, including vegetarians. The authors suggest that little animal source foods are enough to shift the metabolism of children. Dietary analysis showed that vegan children had higher folate consumption and lower protein and saturated fats intake. Despite intake appearing adequate, serum markers for fat-soluble vitamins A and D were low. While the fatty acid ALA was higher compared to omnivores, DHA and overall cholesterol were decreased. The authors concluded that the bodies own cholesterol production does not seem to compensate for a lack of dietary cholesterol in this case and it remains to be established whether lower cholesterol in vegan children are negative to health. Furthermore, the circulating amino acids pool was decreased in vegan children, particularly branch chained amino acids. The most distinct difference, however, was seen in the variance of bile acid patterns. The physiological functions of bile acids go beyond digestion, yet the consequences of diverging bile acid profiles in children’s health are unknown. In conclusion, the data shows that a strict vegan diet affects the metabolism of healthy children, but much of the long-term impact on health is currently still unclear. This article highlights some of the differences, risks and uncertainties that come with raising young children on a strictly vegan diet.
Abstract
Vegan diets are gaining popularity, also in families with young children. However, the effects of strict plant-based diets on metabolism and micronutrient status of children are unknown. We recruited 40 Finnish children with a median age 3.5 years-vegans, vegetarians, or omnivores from same daycare centers-for a cross-sectional study. They enjoyed nutritionist-planned vegan or omnivore meals in daycare, and the full diets were analyzed with questionnaires and food records. Detailed analysis of serum metabolomics and biomarkers indicated vitamin A insufficiency and border-line sufficient vitamin D in all vegan participants. Their serum total, HDL and LDL cholesterol, essential amino acid, and docosahexaenoic n-3 fatty acid (DHA) levels were markedly low and primary bile acid biosynthesis, and phospholipid balance was distinct from omnivores. Possible combination of low vitamin A and DHA status raise concern for their visual health. Our evidence indicates that (i) vitamin A and D status of vegan children requires special attention; (ii) dietary recommendations for children cannot be extrapolated from adult vegan studies; and (iii) longitudinal studies on infant-onset vegan diets are warranted.
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8.
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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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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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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10.
Role of phosphatidylcholine-DHA in preventing APOE4-associated Alzheimer's disease.
Patrick, RP
FASEB journal : official publication of the Federation of American Societies for Experimental Biology. 2019;33(2):1554-1564
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Alzheimer’s disease (AD) is a neurodegenerative disorder characterised by progressive memory loss, spatial disorientation, cognitive impairment and behavioural changes. Ageing is the main risk factor for AD, with approximately one-third of Americans over the age of 85 being affected by the condition. The APOE gene provides instructions for making the apolipoprotein E family of proteins that are involved in fat metabolism and cholesterol transport. There are three different variants of this gene, one inherited from each parent. The variant called APOE4 is thought to increase AD risk from 2-3-fold (one inherited copy) to as much as 15-fold (two inherited copies), compared to individuals who do not carry this variant. The omega-3 oil docosahexaenoic acid (DHA) is an essential fatty acid, which comprises approximately 30% of the fats found in the human brain. Low levels of DHA in the brain increase the risk of developing AD, while normal and high levels may prevent the condition and ameliorate symptoms. This review paper brings together several lines of evidence on why individuals with the APOE4 gene variant don’t respond well to DHA supplementation but experience positive effects from dietary intake of DHA. The author suggests that this is due to the different forms of DHA found in dietary and supplemental sources. Some of the DHA present in fish and seafood is in phospholipid form, which is metabolised into lysophosphatidylcholine DHA (DHA-lysoPC) in the body. In contrast, fish oil supplements contain no DHA in phospholipid form, but in other forms that are mostly metabolised to free DHA. This paper puts forward an argument that, due to the breakdown of the integrity of the blood-brain barrier, APOE4 carriers have impaired brain transport of free DHA but not DHA-lysoPC. The author concludes that dietary sources that contain high amounts of DHA in phospholipid form, such as fish and fish roe may help increase plasma levels of DHA-lysoPC, which may be better transported to the brains of APOE4 carriers. She also highlights the pressing need for future clinical trials to evaluate the effects of omega-3 oils in phospholipid form on the cognitive function of APOE4 carriers with AD.
Abstract
Dietary and supplemental intake of the ω-3 fatty acid docosahexaenoic acid (DHA) reduces risk of Alzheimer's disease (AD) and ameliorates symptoms. The apolipoprotein E ( APOE) 4 allele is the strongest risk factor for sporadic AD, exclusive of age. APOE4 carriers respond well to the DHA present in fish but do not respond as well to dietary supplements. The mechanisms behind this varied response remain unknown. I posit that the difference is that fish contain DHA in phospholipid form, whereas fish oil supplements do not. This influences whether DHA is metabolized to nonesterified DHA (free DHA) or a phospholipid form called lysophosphatidylcholine DHA (DHA-lysoPC). Free DHA is transported across the outer membrane leaflet of the blood-brain barrier (BBB) via passive diffusion, and DHA-lysoPC is transported across the inner membrane leaflet of the BBB via the major facilitator superfamily domain-containing protein 2A. I propose that APOE4 carriers have impaired brain transport of free DHA but not of DHA-lysoPC, as a consequence of a breakdown in the outer membrane leaflet of the BBB, putting them at increased risk for AD. Dietary sources of DHA in phospholipid form may provide a means to increase plasma levels of DHA-lysoPC, thereby decreasing the risk of AD.-Patrick, R. P. Role of phosphatidylcholine-DHA in preventing APOE4-associated Alzheimer's disease.