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Modulating the Gut Microbiome in Multiple Sclerosis Management: A Systematic Review of Current Interventions.
Tsogka, A, Kitsos, DK, Stavrogianni, K, Giannopapas, V, Chasiotis, A, Christouli, N, Tsivgoulis, G, Tzartos, JS, Giannopoulos, S
Journal of clinical medicine. 2023;12(24)
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Multiple sclerosis (MS) is an autoimmune disease caused by the altered immune system mistakenly attacking the central nervous system. While genetics play a leading causative role in the manifestation of this disease, other contributing environmental factors can also exist, such as a disruption in the intestinal microbial composition. Previous research has shown that the bidirectional communication between the brain's and gut's health, also known as the gut-brain axis, may contribute to the prognosis of MS. Modulating gut microbial composition can be a therapeutic strategy in MS patients to manage symptoms and prevent disease progression. This systematic review assessed different protocols for modulating gut microbial composition, including dietary modifications, probiotic use, intermittent fasting, and faecal microbial transplantation. The review included thirteen studies that compared the effects of the above gut microbial modulation intervention protocols in MS patients with healthy participants. While different dietary modification strategies improved MS symptoms, probiotic supplementations and intermittent fasting reduced inflammation, and faecal microbial transplantation showed promising positive effects in a few reports. Due to the methodological limitations of the included studies, further robust studies are required to evaluate the beneficial effects of gut microbial modulation strategies in reducing the symptoms of MS patients. However, healthcare professionals can use the results of this study to understand the benefits of gut microbial modulation in MS patients.
Abstract
This review attempted to explore all recent clinical studies that have investigated the clinical and autoimmune impact of gut microbiota interventions in multiple sclerosis (MS), including dietary protocols, probiotics, fecal microbiota transplantation (FMT), and intermittent fasting (IF). Methods: Thirteen studies were held between 2011 and 2023 this demonstrated interventions in gut microbiome among patients with MS and their impact the clinical parameters of the disease. These included specialized dietary interventions, the supply of probiotic mixtures, FMT, and IF. Results: Dietary interventions positively affected various aspects of MS, including relapse rates, EDSS disability scores, MS-related fatigue, and metabolic features. Probiotic mixtures showed promising results on MS-related fatigue, EDSS parameters, inflammation; meanwhile, FMT-though a limited number of studies was included-indicated some clinical improvement in similar variables. IF showed reductions in EDSS scores and significant improvement in patients' emotional statuses. Conclusions: In dietary protocols, clinical MS parameters, including relapse rate, EDSS, MFIS, FSS, and MSQoL54 scales, were significantly improved through the application of a specific diet each time. Probiotic nutritional mixtures promote a shift in inflammation towards an anti-inflammatory cytokine profile in patients with MS. The administration of such mixtures affected disability, mood levels, and quality of life among patients with MS. FMT protocols possibly demonstrate a therapeutic effect in some case reports. IF protocols were found to ameliorate EDSS and FAMS scores. All interventional means of gut microbiome modulation provided significant conclusions on several clinical aspects of MS and highlight the complexity in the relationship between MS and the gut microbiome.
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Intake of Lactiplantibacillus plantarum HEAL9 Improves Cognition in Moderately Stressed Subjects: A Randomized Controlled Study.
Önning, G, Montelius, C, Hillman, M, Larsson, N
Nutrients. 2023;15(15)
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It is thought that there is a bidirectional communication pathway between the gut microbiota and the brain, known as the gut-brain axis. Stress, anxiety and low mood and the hormones produced when experiencing these have been shown to be improved by the introduction of healthy gut microbiota through probiotic use. As such, the use of probiotics may be of benefit to mental health problems. This randomised control trial of 129 individuals with moderate stress aimed to determine the effect of one probiotic strain Lactoplantibacillus plantarum HEAL9 (LPHEAL9) on the gut-brain axis. The results showed that following supplementation for 12 weeks, cognitive function was significantly improved compared to placebo and there was an improvement in the feelings of confusion, anger, and depression. There was a trend for improved sleep for individuals given LPHEAL9, however this was not significantly better than individuals given placebo. There were no benefits to perceived stress following LPHEAL9 supplementation. It was concluded that LPHEAL9 improved cognitive function compared to placebo and this may be due to improved mood and sleep. This study could be used by healthcare professionals to specifically recommend LPHEAL9 to individuals with stress, anxiety, and low mood.
Abstract
BACKGROUND The usage of probiotics has expanded beyond the areas of gut and immune health improvement. Several studies have shown the positive impact associated between probiotics and stress, cognition, and mood; a relationship referred to as the gut-brain axis. METHOD The aim of this exploratory study was to evaluate the effect of the probiotic strain Lactiplantibacillus plantarum HEAL9 (LPHEAL9) on the gut-brain axis in subjects with moderate stress. One hundred and twenty-nine subjects aged 21-52 years completed the study, randomized to consume either LPHEAL9 (n = 65) or placebo (n = 64) for 12 weeks. RESULTS Perceived stress and awakening cortisol were significantly reduced over time in both groups. A significant improvement in four cognition tests after consumption of LPHEAL9 compared to placebo was observed (rapid information processing test, numeric working memory test, paired associated learning, and word recall, p < 0.05). There was a tendency for a significantly better improvement in the LPHEAL9 group for three mood subscales (Confusion-Bewilderment, Anger-Hostility, and Depression-Dejection) and for fewer subjects with poor sleep in the LPHEAL9 group compared to placebo (p < 0.10). CONCLUSIONS Intake of LPHEAL9 significantly improved cognitive functions compared to the placebo, potentially by ameliorating aspects of mood and sleep.
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Lactobacillus rhamnosus CNCM I-3690 decreases subjective academic stress in healthy adults: a randomized placebo-controlled trial.
Wauters, L, Van Oudenhove, L, Accarie, A, Geboers, K, Geysen, H, Toth, J, Luypaerts, A, Verbeke, K, Smokvina, T, Raes, J, et al
Gut microbes. 2022;14(1):2031695
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Previous research has shown a bidirectional relationship between the gut and psychological stress, which could be mediated by intestinal permeability followed by an immune and inflammatory response. However, the exact mechanisms of this relationship are yet to be elucidated. This randomised, double-blind, placebo-controlled trial evaluated the beneficial effects of Lactobacillus rhamnosus CNCM I-3690 on intestinal permeability and stress markers during a public speech in healthy students. Participants consumed either milk containing Lactobacillus rhamnosus CNCM I-3690 or acidified milk twice daily for four weeks to assess subjective and objective stress markers and markers of intestinal permeability. Lactobacillus rhamnosus CNCM I-3690 reduced the stress-induced hyperpermeability to mannitol and subjective stress markers (State-Trait Anxiety Inventory/ STAI). A subgroup of healthy students with stress-induced cortisol >P90 of baseline showed a reduction in perceived stress score following Lactobacillus rhamnosus CNCM I-3690 intervention. To evaluate the additional effects of Lactobacillus rhamnosus CNCM I-3690 on stress and gut health, further robust studies are needed. Healthcare professionals can use the findings of this study to understand the anxiolytic effects of Lactobacillus rhamnosus CNCM I-3690.
Abstract
Psychological stress negatively affects the intestinal barrier function in animals and humans. We aimed to study the effect of Lactobacillus rhamnosus CNCM I-3690 on intestinal permeability and stress-markers during public speech. Healthy students were randomized to L. rhamnosus-containing (test) or acidified (placebo) milk consumed twice daily for 4 weeks, with 46 subjects per treatment group. Small intestinal permeability was quantified by a 2 h urinary lactulose-mannitol ratio (LMR, primary outcome), fractional excretion of lactulose (FEL) and mannitol (FEM). Salivary cortisol, State-Trait Anxiety Inventory (STAI) and Perceived Stress scores (PSS) were collected. No between-treatment differences were found for LMR (p = .71), FEL or FEM. Within-treatment analyses showed similar LMR and FEL but a stress-induced increase of FEM with the placebo (p < .05) but not test product. Despite a similar increase in salivary cortisol, the stress-induced increase in STAI was significantly lower with the test product vs. placebo (p = .01). Moreover, a stress-preventative effect of the probiotic was found for PSS and more pronounced in subjects with high stress-induced cortisol (p = .01). While increased FEM was mediated by salivary cortisol levels, the effect of the test product on subjective stress was not mediated by changes in FEM. No serious adverse events occurred. In conclusion, we demonstrated that L. rhamnosus CNCM I-3690 prevented stress-induced hyperpermeability to mannitol. Subjective but not objective stress-markers were reduced with L. rhamnosus vs. placebo, suggesting anxiolytic effects, which were independent of barrier stabilization and attractive for the reduction of stress in both health and disease. Clinicaltrials.gov, number NCT03408691.
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Effects of Lactiplantibacillus plantarum OLL2712 on Memory Function in Older Adults with Declining Memory: A Randomized Placebo-Controlled Trial.
Sakurai, K, Toshimitsu, T, Okada, E, Anzai, S, Shiraishi, I, Inamura, N, Kobayashi, S, Sashihara, T, Hisatsune, T
Nutrients. 2022;14(20)
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On the Alzheimer’s disease spectrum, which is the most common cause of dementia, the typical symptom at onset is impaired memory. As the disease progresses, other cognitive domains, such as language, visuospatial cognition, and executive function, are impaired, gradually making it impossible to maintain independence in daily life. The aim of this study was to test the protective effects of 12 weeks of supplementation with heat-treated Lactiplantibacillus OLL2712 cells on memory function in older adults. This study was a double-blind placebo-controlled trial in which participants were randomly assigned to the active or placebo group. Results showed that OLL2712 consumption had a protective effect on memory function in older adults. However, there was no significant effect of OLL2712 intake on verbal memory in either of the analyses. Furthermore, in the gut microbiota analysis, the bacterial composition of the active group showed significantly lower abundance ratios of bacterial species linked to inflammation (Lachnoclostridium, Monoglobus, and Oscillibacter). Authors conclude that continuous intake of OLL2712 may be an effective approach to protect memory function in older adults.
Abstract
The use of probiotics is expected to be an intervention in neurodegenerative conditions that cause dementia owing to their ability to modulate neuroinflammatory responses via the microbiome-gut-brain axis. Therefore, we selected Lactiplantibacillus plantarum OLL2712 (OLL2712), the optimal anti-inflammatory lactic acid bacteria strain with high IL-10-inducing activity in immune cells, and aimed to verify its protective effects on memory function in older adults. A 12-week, randomized, double-blind, placebo-controlled trial was performed with older adults over the age of 65 years with declining memory. The participants consumed either powder containing heat-treated OLL2712 cells or placebo. Memory function was assessed using a computer-assisted cognitive test, Cognitrax. Daily dietary nutrient intake was assessed using the Brief-type Self-administered Diet History Questionnaire (BDHQ). The composition of the gut microbiota was analyzed by fecal DNA extraction and 16S rDNA sequencing. Data from 78 participants who completed the entire procedure were analyzed, and significant improvements in composite memory and visual memory scores were observed in the active group, after accounting for the effect of daily nutritional intake (p = 0.044 and p = 0.021, respectively). In addition, the active group had a lower abundance ratio of Lachnoclostridium, Monoglobus, and Oscillibacter genera, which have been reported to be involved in inflammation. The present study suggests that OLL2712 ingestion has protective effects against memory function decline in older adults.
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A randomized trial of probiotic supplementation in nurses to reduce stress and viral illness.
Slykerman, RF, Li, E
Scientific reports. 2022;12(1):14742
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Dynamic communication occurs between the gut microbiota and the central nervous system along multiple physiological pathways. Stress increases glucocorticoid production and activation of the hypothalamic–pituitary–adrenal axis, affecting immunological function and neuronal changes. The aim of this study was to investigate whether supplementation with the probiotic Lactobacillus rhamnosus HN001 could reduce symptoms of stress and anxiety and improve psychological wellbeing in nurses working during the COVID19 pandemic. This study was a large double-blind, placebo-controlled randomised trial of probiotic supplementation with two parallel arms and a ratio of allocation to probiotic or placebo of 1:1. Results showed that following the intervention, stress, anxiety, and psychological wellbeing were not significantly different between nurses supplemented with the probiotic and those who received the placebo. Furthermore, the average number of days per week that nurses reported symptoms of cold or flu-like illness did not significantly differ between the probiotic and placebo supplemented groups. Authors conclude that there weren’t significant differences in outcomes between the probiotic and placebo groups.
Abstract
Animal studies demonstrate how the gut microbiota influence psychological health and immunity to viral infections through their actions along multiple dynamic pathways in the body. Considerable interest exists in probiotics to reduce stress and illness symptoms through beneficial effects in the gut, but translating pre-clinical evidence from animal models into humans remains challenging. We conducted a large trial in nurses working during the 2020 COVID19 pandemic year to establish whether daily ingestion of the probiotic Lactobacillus rhamnosus HN001 reduced perceived stress and the number of days participants reported symptoms of a viral illness. Our results showed no significant difference in perceived stress or the average number of illness days between probiotic supplemented nurses and the placebo group. Stress and viral illness symptoms reduced during the study for all participants, a trajectory likely influenced by societal-level factors. The powerful effect of a well-managed public health response to the COVID19 pandemic and the elimination of COVID19 from the community in 2020 may have altered the trajectory of stress levels and reduced circulating viral infections making it difficult to detect any effect of probiotic supplementation. Our study highlights the challenge in controlling environmental factors in human trials.
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Partial sleep restriction-induced changes in stress, quality of life, and lipid metabolism in relation to cold hypersensitivity: A before-and-after intervention study.
Baek, Y, Jung, K, Kim, H, Lee, S
Medicine. 2022;101(46):e31933
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Inadequate sleep has been associated with an increased risk of cardiovascular disease and has an adverse impact on quality of life (QOL), metabolism and the immune system. Furthermore, sleep is associated with the body’s thermoregulation ability, which is closely associated with distal and proximal skin temperature, as well as core body temperature. The hypothesis of this study was that the physiological and psychological changes caused by insufficient sleep will differ according to cold hypersensitivity (CH). This study was an uncontrolled, before-and-after study with 3 days of 4-hour sleep restriction (SR) as intervention. A total of 130 participants completed the study. Results showed that less-than-optimal sleep duration leads to worsened stress and QOL and reduced low-density lipoprotein cholesterol levels. These changes were significant in the CH group compared to the non-CH group. Authors conclude that their findings provide additional information for evaluating the clinical risks posed by sleep disturbances and assessing the usual sleep patterns according to CH.
Abstract
Sleep disturbances are associated with cold hypersensitivity (CH) and characterized by excessive cold sensation in specific body parts and cold thermal discomfort. This study investigated the effects of short-term sleep restriction followed by a recovery phase on subjective health status, inflammation, and lipid metabolism in different types of CH. A total of 118 healthy adults aged 35 to 44 years without sleep disturbances were enrolled. Participants underwent 4-hour sleep restrictions per day for 3 days at a hospital and then returned to their daily lives for 4 days of rest. CH was assessed using a structured questionnaire with eight characteristic symptoms. A questionnaire and blood tests were administered baseline, after sleep restriction, and follow-up to assess cortisol, lipid profiles, and self-reported stress and quality of life (QOL). Participants were divided into CH (44.1%) and non-CH (55.9%) groups. The CH group showed increased stress, impaired QOL, and decreased low-density lipoprotein-cholesterol (LDL-C) levels compared to the non-CH group after sleep restriction. The variance for QOL (effect size = 0.07), subjective stress (effect size = 0.053), and LDL-C (effect size = 0.029) among time points depended on the group. Short-term sleep restriction was associated with deterioration of subjective health and reduced lipid metabolism; such changes were more evident in the CH group. Our findings suggest the need to consider an individual's CH status to assess the clinical risk associated with insufficient sleep.
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Gluten and FODMAPs Relationship with Mental Disorders: Systematic Review.
Aranburu, E, Matias, S, Simón, E, Larretxi, I, Martínez, O, Bustamante, MÁ, Fernández-Gil, MDP, Miranda, J
Nutrients. 2021;13(6)
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There is growing evidence that gluten and FODMAPs, such as fermentable oligosaccharides, disaccharides, monosaccharides and polyols, can cause gastrointestinal symptoms, inflammation, and immune responses in patients with celiac disease and irritable bowel syndrome. In addition, a high intake of gluten and FODMAPs may also be associated with neurological and psychiatric disorders. Thirteen studies were included in this systematic review to examine the relationship between gluten and FODMAP consumption and illnesses affecting the central nervous system. In addition, the studies examined the effects of potential dietary strategies that consider gluten and FODMAP intake on mental disorders, anxiety, depression, schizophrenia, Alzheimer’s disease, and autism spectrum disorders. Several possible mechanisms identified in this systematic review could contribute to neurological and psychiatric disorders, including the release of proinflammatory cytokines, immune responses, gut dysbiosis, intestinal permeability, and interactions between the gut-brain axis. In patients with fibromyalgia, celiac disease, and irritable bowel syndrome, avoiding or limiting gluten may reduce depression, anxiety, and cognitive impairment. However, the effects of a low-FODMAP diet on the central nervous system are inconclusive. There is some evidence that gluten-free diets can improve cognition in schizophrenia patients. In addition, those with autism spectrum disorders may benefit from a gluten-free diet and a low-FODMAP diet. Further robust research is required to evaluate the beneficial effects of interventions that avoid or restrict the consumption of foods high in FODMAPs and gluten. However, healthcare professionals can use the results of this systematic review to understand the potential benefits of therapeutic interventions that consider the intake of FODMAPs and gluten on illnesses affecting the central nervous system and their possible mechanisms of action.
Abstract
Nowadays, gluten and FODMAP food components (fermentable oligosaccharides, disaccharides, monosaccharides and polyols) are increasingly studied due to their possible relation with extraintestinal-associated conditions. In recent years, gluten-free diets (GFD) and low-FODMAP diets (LFD) are becoming more popular not only in order to avoid the food components that cause intolerances or allergies in some people, but also due to the direct influence of marketing movements or diet trends on feeding habits. Likewise, neurological and psychiatric diseases are currently of increasing importance in developed countries. For this reason, a bibliographic systematic review has been carried out to analyse whether there is a pathophysiological relationship between the dietary intake of gluten or FODMAPs with mental disorders. This review collects 13 clinical and randomized controlled trials, based on the PRISMA statement, which have been published in the last ten years. Based on these results, limiting or ruling out gluten or FODMAPs in the diet might be beneficial for symptoms such as depression, anxiety (7 out of 7 articles found any positive effect), or cognition deficiency (improvements in several cognition test measurements in one trial), and to a lesser extent for schizophrenia and the autism spectrum. Nevertheless, further studies are needed to obtain completely reliable conclusions.
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Ramadan Fasting in Germany (17-18 h/Day): Effect on Cortisol and Brain-Derived Neurotrophic Factor in Association With Mood and Body Composition Parameters.
Riat, A, Suwandi, A, Ghashang, SK, Buettner, M, Eljurnazi, L, Grassl, GA, Gutenbrunner, C, Nugraha, B
Frontiers in nutrition. 2021;8:697920
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Ramadan fasting (RF) is a type of intermittent fasting and has been reported to have benefits on body composition, fatigue, mood and health related to quality of life (QOL) in healthy people. The aim of this study of 34 healthy men and women was to elucidate the mechanisms, in particular links between mood and QOL and the stress hormone cortisol and brain-derived neurotrophic factor (BDNF) which is important for mental and cognitive function. The study compared a number of biochemical parameters before, in the middle and towards the end of the fast as well as 1 week and 1 months after RF. Patterns differed between men and women. Whilst women showed a significant increase in interleukin 8, an important mediator of the innate immune system, at the start of RF, it decreased toward the end of RF in men. Cortisol levels decreased after RF in both men and women, but more so in women, whilst BDNF decreased significantly in men but stayed the same in women. The authors conclude that the benefits of RF for mood are mediated by different biological mediators, particularly cortisol and BDNF.
Abstract
Ramadan fasting (RF) is a type of diurnal intermittent fasting. Previous studies reported the benefits of RF in healthy subjects on mood and health related to quality of life (QoL). Cortisol and brain-derived neurotrophic factor (BDNF) have been shown to play a role in mood, body composition parameters, and health-related QoL. This study aimed at elucidating the mechanism of the benefit of RF, particularly cortisol and BNDF and their association with mood and QoL. Insulin growth factor-1 (IGF-1), interleukin (IL)-8, matrix metalloproteinase (MMP)-9, and myoglobin were determined. Thirty-four healthy men and women were recruited. Serum from peripheral venous blood samples was collected at five time points: 1 week before RF (T1); mid of RF (T2), last days of RF (T3), 1 week after RF (T4), and 1 month after RF (T5). The amounts of biological mediators in the serum samples were determined by enzyme-linked immunosorbent assay (ELISA) and Luminex assays. BDNF and cortisol significantly decreased at T3 (p < 0.05) and T4 (p < 0.001) compared to T1, respectively. It seems the benefits of RF for mood-related symptoms are mediated by different biological mediators, particularly cortisol and BDNF.
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Differential Health Effects on Inflammatory, Immunological and Stress Parameters in Professional Soccer Players and Sedentary Individuals after Consuming a Synbiotic. A Triple-Blinded, Randomized, Placebo-Controlled Pilot Study.
Quero, CD, Manonelles, P, Fernández, M, Abellán-Aynés, O, López-Plaza, D, Andreu-Caravaca, L, Hinchado, MD, Gálvez, I, Ortega, E
Nutrients. 2021;13(4)
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Synbiotic, a mixture of prebiotics and probiotics, is known to improve neurotransmitter interactions, immune, inflammatory, and stress responses by modulating the gut microbial composition. It is also believed that physical activity plays an important role in the modulation of immune function and stress response. The purpose of this triple-blinded, randomized, placebo-controlled pilot study was to evaluate the health benefits of symbiotic intervention in fourteen sedentary students and thirteen soccer players, especially in terms of improving immunophysiological and metabolic parameters. The 300mg of symbiotic intervention contained Bifidobacterium lactis CBP-001010, Lactobacillus rhamnosus CNCM I-4036, Bifidobacterium longum ES1(109 colony-forming unit), and fructooligosaccharides (200 mg) plus 1.5 mg of zinc, 8.25 µg of selenium, 0.75 µg of vitamin, and maltodextrin. Following a one-month intervention with synbiotic formulation, soccer players showed improvements in anxiety, sleep quality and stress, a slight reduction in proinflammatory cytokine IL-1β, an exercise-induced significant increase in dopamine and a slight elevation of corticotropin-releasing hormone. For confirmation of results of this pilot study and to assess more significant effects of symbiotic intervention in athletes as well as in the general population, longer-term robust studies are required. The findings of this study can help healthcare professionals understand the extensive health benefits of synbiotic intervention and its relationship to physical activity.
Abstract
The main objective of this research was to carry out an experimental study, triple-blind, on the possible immunophysiological effects of a nutritional supplement (synbiotic, Gasteel Plus®, Heel España S.A.U.), containing a mixture of probiotic strains, such as Bifidobacterium lactis CBP-001010, Lactobacillus rhamnosus CNCM I-4036, and Bifidobacterium longum ES1, as well as the prebiotic fructooligosaccharides, on both professional athletes and sedentary people. The effects on some inflammatory/immune (IL-1β, IL-10, and immunoglobulin A) and stress (epinephrine, norepinephrine, dopamine, serotonin, corticotropin-releasing hormone (CRH), Adrenocorticotropic hormone (ACTH), and cortisol) biomarkers were evaluated, determined by flow cytometer and ELISA. The effects on metabolic profile and physical activity, as well as on various parameters that could affect physical and mental health, were also evaluated via the use of accelerometry and validated questionnaires. The participants were professional soccer players in the Second Division B of the Spanish League and sedentary students of the same sex and age range. Both study groups were randomly divided into two groups: a control group-administered with placebo, and an experimental group-administered with the synbiotic. Each participant was evaluated at baseline, as well as after the intervention, which lasted one month. Only in the athlete group did the synbiotic intervention clearly improve objective physical activity and sleep quality, as well as perceived general health, stress, and anxiety levels. Furthermore, the synbiotic induced an immunophysiological bioregulatory effect, depending on the basal situation of each experimental group, particularly in the systemic levels of IL-1β (increased significantly only in the sedentary group), CRH (decreased significantly only in the sedentary group), and dopamine (increased significantly only in the athlete group). There were no significant differences between groups in the levels of immunoglobulin A or in the metabolic profile as a result of the intervention. It is concluded that synbiotic nutritional supplements can improve anxiety, stress, and sleep quality, particularly in sportspeople, which appears to be linked to an improved immuno-neuroendocrine response in which IL-1β, CRH, and dopamine are clearly involved.
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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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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.