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Probiotic improves symptomatic and viral clearance in Covid19 outpatients: a randomized, quadruple-blinded, placebo-controlled trial.
Gutiérrez-Castrellón, P, Gandara-Martí, T, Abreu Y Abreu, AT, Nieto-Rufino, CD, López-Orduña, E, Jiménez-Escobar, I, Jiménez-Gutiérrez, C, López-Velazquez, G, Espadaler-Mazo, J
Gut microbes. 2022;14(1):2018899
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Expert Review
Conflicts of interest:
None
Take Home Message:
- It is advisable for those over 60 years old with a metabolic risk factor (BMI>30, diabetes and/or hypertension) to consult with their clinical practitioners if tested positive for Covid-19.
- Specific probiotic strains are reported to show positive results in reducing the duration and severity of Covid-19 symptoms in adults under 60 years old.
- These probiotics (Lactiplantibacillus plantarum KABP022, KABP023, and KAPB033, plus strain Pediococcus acidilactici KABP021) have also shown a positive effect on reducing inflammation and supporting remission of Covid-19.
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:
A quadruple-blinded, randomized trial was conducted in adults with symptomatic Coronavirus Disease 2019(Covid19) outpatients.
Three hundred subjects between the ages of 18 and 60 years, with a peripheral oxygen saturation (SpO2) ≥ 90% and in whom 42% had known metabolic risk factors for severe Covid19, were randomized to a oral probiotic containing Lactiplantibacillus plantarum KABP022, KABP023, and KAPB033, with Pediococcus acidilactici strain KABP021, totaling 2 x 109 colony-forming units (n=150), or placebo (n=150), for 30 days. At endpoint, 293/300 subjects finished the study.
Primary clinical outcomes were:
- Complete remission was achieved by 78 of 147 (53.1%) in probiotic group compared to 41 of 146 (28.1%) in placebo (P< .001).
- Adverse events were lower in the probiotic group (p=0.008), though not statistically significant in those taking ≥2 medications daily (risk ratio 0.66 (95%CI 0.29-1.48)
- No hospitalizations or deaths occurred during the study.
Secondary clinical outcomes were:
- The probiotic treatment was well-tolerated and reduce the duration of both digestive and non-digestive symptoms, compared to placebo.
- The probiotic treatment was associated with reduce nasopharyngeal viral load compared to placebo (P < .001) and reduce lung infiltrates (P < .001).
Furthermore, the probiotic treatment
- significantly increased specific IgM and IgG against Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV2) and
- lower serum levels of high-sensitivity C-reactive protein (hsCRP) (P<00.1) and D-Dimer levels (P,00.1) compared to placebo.
- shortened median recovery time by 5 days (p<0.001).
Clinical practice applications:
- General practitioners, pharmacists, and clinic nurses are generally the first point of contact for patients who are not feeling well. Especially, during a pandemic when hospitals are inundated with patients who need urgent care. It is therefore essential for clinicians to have outpatient treatment protocols available to support the community.
- The microbiome is reported to be the first line of defense and interacts with the human host’s immune system. Therefore, probiotics may be useful as a preventative and supportive measure during a pandemic.
- Based on this study, practitioners could therefore consider a probiotic containing Lactiplantibacillus plantarum and Pediococcus acidilactici strains alone or in combination with other probiotic strains as a supportive measure.
Considerations for future research:
- Future studies are needed to replicate these findings and elucidate its mechanism of action, particularly as fecal microbiome analysis in a subset of n=100 subjects did not detect a difference in fecal microbiome composition between groups at baseline or endpoint.
- Additionally, further studies are needed to identify specific probiotic strains that display immune effects and their required dosage.
- Elevated D-Dimer levels are associated with a higher risk of thrombotic events such as pulmonary embolism and have been associated with Covid19 severity and mortality. Therefore, further investigation of this probiotic formula in helping prevent thrombotic complications in Covid19 is warranted.
- All the subjects in the study were of Hispanic ethnicity, therefore further studies of other ethnicities are required.
- This study was capped at 60-year-olds, thus studies in older subjects are warranted.
- Conflict of interest statement: This study was fully funded by the manufacturer of the provided probiotic, and authors received either speaker fees or institutional support from the manufacturer.
Abstract
Intestinal bacteria may influence lung homeostasis via the gut-lung axis. We conducted a single-center, quadruple-blinded, randomized trial in adult symptomatic Coronavirus Disease 2019 (Covid19) outpatients. Subjects were allocated 1:1 to probiotic formula (strains Lactiplantibacillus plantarum KABP022, KABP023, and KAPB033, plus strain Pediococcus acidilactici KABP021, totaling 2 × 109 colony-forming units (CFU)) or placebo, for 30 days. Co-primary endpoints included: i) proportion of patients in complete symptomatic and viral remission; ii) proportion progressing to moderate or severe disease with hospitalization, or death; and iii) days on Intensive Care Unit (ICU). Three hundred subjects were randomized (median age 37.0 years [range 18 to 60], 161 [53.7%] women, 126 [42.0%] having known metabolic risk factors), and 293 completed the study (97.7%). Complete remission was achieved by 78 of 147 (53.1%) in probiotic group compared to 41 of 146 (28.1%) in placebo (RR: 1.89 [95 CI 1.40-2.55]; P < .001), significant after multiplicity correction. No hospitalizations or deaths occurred during the study, precluding the assessment of remaining co-primary outcomes. Probiotic supplementation was well-tolerated and reduced nasopharyngeal viral load, lung infiltrates and duration of both digestive and non-digestive symptoms, compared to placebo. No significant compositional changes were detected in fecal microbiota between probiotic and placebo, but probiotic supplementation significantly increased specific IgM and IgG against Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV2) compared to placebo. It is thus hypothesized this probiotic primarily acts by interacting with the host's immune system rather than changing colonic microbiota composition. Future studies should replicate these findings and elucidate its mechanism of action (Registration: NCT04517422).Abbreviations: AE: Adverse Event; BMI: Body Mass Index; CONSORT CONsolidated Standards of Reporting Trials; CFU: Colony-Forming Units; eDRF: Electronic Daily Report Form; GLA: Gut-Lung Axis; GSRS Gastrointestinal Symptoms Rating Scale; hsCRP: High-sensitivity C-Reactive Protein; HR: Hazard Ratio; ICU: Intensive Care Unit; OR: Odds Ratio; PCoA: Principal Coordinate Analysis; RR: Relative Risk; RT-qPCR: Real-Time Quantitative Polymerase Chain Reaction; SARS-CoV2: Severe acute respiratory syndrome coronavirus 2; SpO2: Peripheral Oxygen Saturation; WHO: World Health Organization.
2.
Effects of Lactococcus lactis subsp. cremoris YRC3780 daily intake on the HPA axis response to acute psychological stress in healthy Japanese men.
Matsuura, N, Motoshima, H, Uchida, K, Yamanaka, Y
European journal of clinical nutrition. 2022;76(4):574-580
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The hypothalamic-pituitary-adrenal (HPA) axis is involved in the stress response and is linked to the microbiome through a number of possible mechanisms, including immune-related ones. Lactococcus lactis subsp. cremoris YRC3780 (YRC3780), a probiotic isolated from kefir, has been shown to have beneficial immune-modulatory properties. The aim of this double-blind, placebo-controlled trial, which included 27 healthy young men, was to assess sleep quality, mental health, HPA axis activity (salivary cortisol) and response to an acute stress test during/after 8 weeks of supplementation with YRC3780. At 8 weeks, salivary morning cortisol levels were significantly reduced in the probiotic compared to the placebo group. The effect on the stress test depended on whether or not participants were considered “cortisol-responders” or not. Improvements in sleep quality were seen at 6 weeks (but not at any other time points) in 1 out of 2 sleep questionnaires in the YRC3780 group, whilst no significant differences were observed in actigraphy-measured sleep efficiency. There were no differences in mood between groups, but significant improvements in general health in the probiotic group. Interestingly, no changes in the microbiome of the probiotic group were seen, suggesting that the observed effects may be mediated via the immune system.
Expert Review
Conflicts of interest:
None
Take Home Message:
- Research indicates a bidirectional interaction between the gut microbiome and the central nervous system, affecting the functions of the brain and spinal cord.
- This clinical trial suggests that daily intake of Lactococcus lactis subsp. cremoris (YRC3780) may enhance the HPA axis response to acute psychological stress, potentially linked to a reduction in morning cortisol levels.
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:
Introduction
A randomized, placebo-controlled, double-blind clinical trial was conducted to investigate the influence of Lactococcus lactis subsp. cremoris (YRC3780), isolated from kefir, on stress response, sleep quality, and mental health.
Method
Twenty-seven healthy young men, with an average age of 23.5 years, and mean body mass index of 21.5 kg/m2 , were randomly assigned to either the YRC3780 group or the placebo group. Participants were administered YRC3780 or a placebo daily for 8 weeks.
Throughout the study, participants completed assessments, including the Athens Insomnia Scale (AIS), the Pittsburgh Sleep Quality Index (PSQI), the General Health Questionnaire (GHQ-28), and the Profile of Mood States 2nd Edition-Adult Short, Total Mood Disturbance subscale (POMS 2 TMD), every 2 weeks. Additionally, diurnal rhythms of HPA axis activity were assessed every 2 weeks through saliva samples collected at 2-hour intervals during the day. At the end of the 8-week supplementation period, participants underwent the Trier Social Stress Test (TSST) to evaluate the effects of daily YRC3780 intake on the HPA axis stress response. In addition, three fecal samples were collected to analyse the gut microbiome (on the last day of baseline, and at 4 and 8 weeks).
A total of 27 out of 33 subjects (81%) completed the study, with six participants withdrawing without providing explanations.
Results
The primary findings of this study were as follows:
- At week 6 of YRC3780 supplementation, salivary cortisol levels at 2 hours and 6 hours after waking were significantly lower in the YRC3780 group compared to the placebo group (p=0.05).
- Salivary cortisol concentrations at 40 minutes after the TSST were significantly lower in the YRC3780 group (4.2 ± 4.4 nmol/L, mean ± SD) than in the placebo group (7.6 ± 4.7 nmol/L) (p=0.043).
- AIS scores at 6 weeks and GHQ-28 scores at 8 weeks were significantly lower in the YRC3780 group compared to the placebo group (AIS, p=0.031; GHQ-28, p=0.038) indicating better sleep quality and a better mental state.
Conclusion:
Oral supplementation with YRC3780 may have beneficial effects on the HPA axis response to acute psychological stress, potentially associated with a decrease in morning cortisol levels. Additionally, the study suggests that the lower basal activity and stress reactivity of the HPA axis may lead to improvements in subjective sleep quality and mental health.
Clinical practice applications:
- The precise mechanisms underlying the correlation between the gut microbiota and the gut-brain axis remain incompletely understood, emphasising the need for further research.
- This clinical trial demonstrated that daily intake of YRC3780 decreased morning salivary cortisol levels at 6 and 8 weeks and reduced the salivary cortisol response to acute psychological stress.
Considerations for future research:
- Larger, adequately powered clinical trials are required to provide deeper insights into the mechanisms responsible for the stress-reducing and sleep-improving effects of Lactococcus lactis subsp. cremoris.
- Furthermore, investigations into optimal dosage and duration of probiotic supplementation are warranted for a more comprehensive understanding, particularly in diverse demographic groups.
- Comparative research is needed to explore the effects of various probiotic strains on objective stress responses.
Abstract
BACKGROUND Lactococcus lactis subsp. cremoris (YRC3780), which is isolated from kefir, has been associated with anti-allergic effects in humans. However, it remains unknown whether daily intake of YRC3780 attenuates the response to psychological stress in humans in parallel with changes to the gut microbiome. We examined the fundamental role of YRC3780 in the gut microbiome, stress response, sleep, and mental health in humans. METHODS Effects of daily intake of YRC3780 on the hypothalamic-pituitary-adrenal (HPA) axis response to acute psychological stress were investigated in a double-blind, placebo-controlled clinical trial involving 27 healthy young men (mean age and body mass index: 23.5 years and 21.5 kg/m2) who were randomly assigned to placebo (n = 13) or YRC3780 (n = 14) groups. The HPA axis response to acute psychological stress, the diurnal rhythm of HPA axis activity, and gut microbiome were assessed and compared between the two groups. RESULTS The results showed that daily intake of YRC3780 significantly lowered morning salivary cortisol levels compared with placebo. In addition, salivary cortisol levels following a social stress test significantly decreased +40 min after beginning the TSST in the YRC3780-treated group compared to placebo. There were no significant differences between the two groups in terms of actigraphy-based sleep quality, but the subjective sleep quality and mental health were significantly improved in the YRC3780-treated group compared to placebo. CONCLUSIONS Our study suggests that daily intake of YRC3780 improves the HPA axis response to acute psychological stress, which might be associated with a decrease in morning cortisol levels.
3.
Effect of selenium on thyroid autoimmunity and regulatory T cells in patients with Hashimoto's thyroiditis: A prospective randomized-controlled trial.
Hu, Y, Feng, W, Chen, H, Shi, H, Jiang, L, Zheng, X, Liu, X, Zhang, W, Ge, Y, Liu, Y, et al
Clinical and translational science. 2021;14(4):1390-1402
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Hashimoto thyroiditis (HT) is the most common thyroid autoimmune disease. Multiple factors contribute to the development of the disease leading to immune system-mediated destruction of the thyroid gland. In the absence of specific therapeutic approaches that address the immunological activity, thyroid hormone replacement is the primary treatment. Selenium (Se) is an essential trace element for humans and the thyroid gland utilises high amounts of selenium for the production of enzymes and antioxidants. Supplementing Se has shown positive effects in HT, as demonstrated in some studies. Yet, there have been inconsistencies in the results and the understanding of the mechanisms involved are limited. The authors of this prospective, randomized controlled study tried to shed some light on the efficacy of Se supplementation and its mechanisms. 43 HT-patients on no thyroid medication, received 200mcg Se per day for 6 months. Various markers were assessed including antibodies, thyroid stimulating hormone (TSH), antioxidant enzymes and T-helper immune cells that regulate immunological activity, which were compared to the HT-control group (n=47) and healthy individuals (n=36). The outcome of the intervention showed that Se supplementation can reduce thyroid antibodies, and TSH and can increase antioxidant enzymes in patients with HT and along with the findings the authors discussed some potential mechanisms at play. This study suggests that supplementary Se can benefit HT, particularly subclinical HT.
Expert Review
Conflicts of interest:
None
Take Home Message:
- Selenium supplementation is reported to reduce TPOAb, TGAb, and TSH levels, as well as increase Se, GPx3, and SePP1 concentrations in patients with HT without the use of levothyroxine replacement.
- Practitioners could consider selenium supplementation in patients with HT who have serum selenium levels less than 120ug/L.
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:
A prospective randomised controlled trial was conducted to investigate the effect of selenium (Se) supplementation in patients with Hashimoto’s thyroiditis (HT). The study also explored the potential mechanisms of action of Selenium in thyroid autoimmunity.
One hundred and twenty-six subjects (90 with HT and 36 healthy individuals) were included in the study. The patients with HT were randomly assigned into two groups. The Se-treated group (n=43) received 200ug of selenium in a selenious yeast tablet (SYT) per day for 6 months. No treatment was given to the control group (n=47). At the endpoint, 126/126 subjects completed the study.
Primary clinical outcomes were:
- Antithyroid peroxidase antibodies (TPOAb) levels were significantly lower compared with the control group at 6 months (ΔTPOAb [IU/ml] = −28.4 [−103.9,0] vs. 0 [−18.1, 20.5], p = 0.001).
- There was a significant difference in antithyroglobulin antibodies TGAb titers between the Se-treated group and the control group at 6 months (ΔTGAb [IU/ml] = −48.8 [−139.7, −2.0] vs. 18.3 [−23.5, 77.4], p = 0.001.
- Compared with baseline, thyroid stimulating hormone (TSH) presented slightly lower levels in the Se-treated group, whereas there was a statistical increase in the control group at 6 months (ΔTSH [mIU/L] = −0.16 [−2.1, 0.28] vs. 0.48 [−0.15, 1.47], p = 0.001).
Secondary clinical outcomes were:
- aTreg cells in the Se-treated group were significantly higher than the control group at 6 months (13.19 ± 3.5 vs. 11.49 ± 2.79, p = 0.012)
- There was a pronounced increase in glutathione peroxidase (GPx3) at 6 months of treatment in the Se-treated group compared with the control group (p=0.028).
- Furthermore, Selenoprotein P1 (SePP1) levels increased in the Se-treated group compared with the control group at 6 months (17.2 [9.8, 22.1] vs. 10.7 [8.9, 14.6], p = 0.007).
Clinical practice applications:
- There is no specific approach to suppress autoimmunity, thus thyroxine replacement has become the generally accepted therapy for patients with Hashimoto’s thyroiditis (HT) with hypothyroidism.
- The thyroid gland contains the highest concentration of selenium, which is incorporated into selenoproteins, such as glutathione peroxidase (GPx), selenoprotein P (SePP), thioredoxin reductase, and iodothyronine deiodinases. These selenoenzymes play important roles in thyroid hormone metabolism by acting as antioxidants and immunomodulators.
- Based on this study, practitioners could therefore consider using 200ug of selenium for six months as a supportive measure specifically in patients with serum selenium levels less than 120ug/L.
Considerations for future research:
- Although about 20 studies have investigated the treatment of selenium in HT further research is warranted to help explore the appropriate use of selenium.
- Furthermore, investigations are needed to establish if certain HT patients could benefit more from Se supplementation.
- Additionally, investigations are needed to understand the relationship between selenium and Treg cells and their impact on thyroid antibodies.
- This study was completed over six months, longer studies are required to investigate the effect of selenium supplementation over the clinical course of HT.
Abstract
Selenium (Se) is an essential trace element in human. Recent studies of Se supplementation on the effect of Hashimoto's thyroiditis (HT) have been reported, but the exact benefit is unclear as well as the underlying immunologic mechanism. We aimed to evaluate the clinical effect of Se supplement in patients with HT, and explore the potential mechanism against thyroid autoimmunity. A prospective, randomized-controlled study was performed in patients with HT assigned to two groups. Se-treated group (n = 43) received selenious yeast tablet (SYT) for 6 months, whereas no treatment in control group (n = 47). The primary outcome is the change of thyroid peroxidase antibody (TPOAb) or thyroglobulin antibody (TGAb). Second, thyroid function, urinary iodine, Se, Glutathione peroxidase3 (GPx3), and Selenoprotein P1 (SePP1) levels were measured during the SYT treatment. Meanwhile, regulatory T cells (Tregs) and their subsets activated Tregs (aTregs), resting Tregs, and secreting Tregs, as well as Helios and PD-1 expression on these cells were also detected. The results showed that SYT treatment significantly decreased TPOAb, TGAb, and thyroid stimulating hormone (TSH) levels, accompanied with the increased Se, GPx3, and SePP1, compared with the control group. Subgroup analysis revealed that subclinical HT may benefit more from this treatment in the decrease of TSH levels by interaction test. Moreover, the percentage of aTregs, Helios/Tregs, and Helios/aTregs were significantly higher in the Se-treated group than control. In conclusion, Se supplementation may have a beneficial effect on thyroid autoantibodies and thyroid function by increasing the antioxidant activity and upregulating the activated Treg cells.
4.
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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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.