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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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Safety of exercise training in multiple sclerosis: An updated systematic review and meta-analysis.
Learmonth, YC, P Herring, M, Russell, DI, Pilutti, LA, Day, S, Marck, CH, Chan, B, Metse, AP, Motl, RW
Multiple sclerosis (Houndmills, Basingstoke, England). 2023;29(13):1604-1631
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Exercise training represents a rehabilitation-based approach for reversing multiple sclerosis (MS) dysfunction and managing symptoms and should be promoted among persons with MS throughout the disease trajectory. The aim of this study was to quantify the rate of relapse, adverse events (AE) and serious adverse events (SAE) in randomised controlled trials of exercise training in persons with MS. This study was a systematic review and meta-analysis of forty-six exercise interventions. Results showed that in exercise trials with individuals diagnosed with MS, where safety measures were documented, aerobic, strength, or neuromotor exercises conducted under both supervised and unsupervised conditions were deemed safe for those with MS. This conclusion was drawn from two key observations: (1) there were no instances of serious adverse effects reported during exercise sessions, and (2) participants engaging in exercise interventions did not exhibit higher risks of relapse, AE or SAE compared to control participants. Authors concluded that exercise training may be promoted as safe and beneficial to persons with MS.
Abstract
BACKGROUND A review of the safety profile of exercise training in multiple sclerosis (MS) has not been conducted since 2013. OBJECTIVE We undertook a systematic review and meta-analysis of randomised controlled trials (RCTs) of exercise training published since 2013 and quantified estimated population risks of clinical relapse, adverse events (AE) and serious adverse event (SAE). METHODS Articles reporting safety outcomes from comparisons of exercise training with non-exercise among persons with MS were identified. The risk of bias was established from study's internal validity assessed using Physiotherapy Evidence Database (PEDro). Rates and estimated mean population relative risks (RRs; 95% confidence interval (CI)) of safety outcomes were calculated, and random-effects meta-analysis estimated the mean RR. RESULTS Forty-six interventions from 40 RCTs (N = 1780) yielded 46, 40 and 39 effects for relapse, AE, adverse effects and SAE, respectively. The mean population RRs ((95% CI), p-value) for relapse, AE and SAE were 0.95 ((0.61, 1.48), p = 0.82), 1.40 ((0.90, 2.19), p = 0.14) and 1.05 ((0.62, 1.80), p = 0.85), respectively. No significant heterogeneity is observed for any outcome. CONCLUSION In studies that reported safety outcomes, there was no higher risk of relapse, AE, adverse effects or SAE for exercise training than the comparator. Exercise training may be promoted as safe and beneficial to persons with MS.
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Lipid profile is associated with decreased fatigue in individuals with progressive multiple sclerosis following a diet-based intervention: Results from a pilot study.
Fellows Maxwell, K, Wahls, T, Browne, RW, Rubenstein, L, Bisht, B, Chenard, CA, Snetselaar, L, Weinstock-Guttman, B, Ramanathan, M
PloS one. 2019;14(6):e0218075
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Fatigue is a frequent and debilitating symptom of multiple sclerosis (MS) and is independent of level of disability. The authors previously reported that a 12 months diet and lifestyle intervention was effective at reducing fatigue in patients with progressive MS. The aims of this study were to characterise the changes in lipid and cholesterol biomarkers during the intervention, and to investigate whether these biomarkers were associated with fatigue outcomes. Data of 18 MS patients were analysed. The intervention consisted of a modified Paleolithic diet, supplemented with exercise, neuromuscular electrical stimulation (NMES) and stress reduction techniques (Wahl’s protocol). Fatigue was significantly decreased at 3, 6, 9 and 12 months compared to baseline, and more so in those having more of the recommended foods and less of the excluded foods. The exercise, NMES, and stress reduction components of the intervention were not associated with changes in fatigue. All variables of the lipid profiles improved during the 12 months intervention. These improvements were associated with the changes in nutrient intakes, in particular, with amounts and types of fat, carbohydrates and fibre. Changes in total and HDL cholesterol, but not LDL cholesterol or triglycerides were associated with a decrease in fatigue. The authors hypothesise that the benefits of the changes in lipid profile on fatigue may be mediated by the positive effects of HDL-cholesterol on mitochondrial function (mitochondria are the “power houses” of every cell, i.e. produce energy on the cellular level), in particular those in the muscles. Limitations of the study include the small sample size, lack of control group and randomisation. The authors conclude that diet-induced changes in HDL and total cholesterol may mediate the positive effects of a dietary and lifestyle intervention on fatigue in MS patients.
Abstract
PURPOSE To investigate associations between lipid profiles and fatigue in a cohort of progressive multiple sclerosis (MS) patients on a diet-based multimodal intervention. METHODS This pilot study included 18 progressive MS patients who participated in a prospective longitudinal study of fatigue following a diet-based multimodal intervention that included exercise, neuromuscular electrical stimulation and stress reduction. The diet recommended high intake of vegetables and fruits, encouraged consumption of animal and plant protein and excluded foods with gluten-containing grains, dairy and eggs. Fatigue was measured on the Fatigue Severity Scale (FSS) at baseline and every 3 months for 12 months. A lipid profile consisting of high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), total cholesterol (TC) and triglycerides (TG) was obtained on fasting blood samples at baseline and 12 months. RESULTS FSS scores decreased from a baseline of 5.51 (95% CI: 4.86, 6.16) to a mean of 3.03 (95% CI: 2.23, 3.82) at 12 months (p < 0.001). At 12 months, increases in HDL-C (mean change: +6.0 mg/dl; 95% CI: 0.3, 12.0; p = 0.049) and decreases in BMI (mean change: -2.6 kg/m2; 95% CI: -3.6, -2.5; p < 0.001), LDL-C (mean change: -10.4 mg/dl; 95% CI:-19.7, -1.2; p = 0.029), TG (mean change: -29.2 mg/dl; 95% CI: -44.3, -14.2; p = 0.001), TG to HDL-C ratio (mean change: -0.6; 95% CI: -1.0, -0.3; p = 0.002) and TC to HDL-C ratio (mean change:-0.6; 95% CI: -1.0, -0.3; p = 0.003) were observed compared to baseline. Improvements in FSS were associated with increases in HDL-C (β = -0.05; 95% CI: -0.1, -0.0004; p = 0.048) and changes in TC (p = 0.005) from baseline to 12 months. CONCLUSIONS Lipid profile variables are associated with improvements in fatigue in progressive MS patients on a diet-based multimodal intervention.
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Influence of combined functional resistance and endurance exercise over 12 weeks on matrix metalloproteinase-2 serum concentration in persons with relapsing-remitting multiple sclerosis - a community-based randomized controlled trial.
Proschinger, S, Joisten, N, Rademacher, A, Schlagheck, ML, Walzik, D, Metcalfe, AJ, Oberste, M, Warnke, C, Bloch, W, Schenk, A, et al
BMC neurology. 2019;19(1):314
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Multiple Sclerosis (MS) is a degenerative autoimmune neuroinflammatory disease where the blood-brain barrier is compromised, causing inflammation. Regular exercise has been shown to support psychomotor symptoms and improve mobility. This trial examines the effects of resistance and endurance exercise in 64 patients, aged 18-45 years, with relapsing-remitting MS (RRMS). The patients are divided into an exercise group and a passive group. The exercise group will perform 60 min of combined functional resistance and endurance exercises 3x per week over a period of 12 weeks. Blood samples will be taken to measure proteolytic matrix metalloproteinases (MMP) as an indicator of neurological inflammation. Secondary measures will also be taken to evaluate patient-reported outcomes regarding gait, sleep, depression, anxiety, fatigue, and quality of life. The study is currently ongoing, so the results are not yet published. From an ethical perspective the passive group will also be offered the opportunity to perform the same exercises at the end of the trial.
Abstract
BACKGROUND The relevance of regular moderate to intense exercise for ameliorating psychomotor symptoms in persons with multiple sclerosis (pwMS) is becoming increasingly evident. Over the last two decades, emerging evidence from clinical studies and animal models indicate immune regulatory mechanisms in both periphery and the central nervous system that may underlie these beneficial effects. The integrity of the blood-brain barrier as the main structural interface between periphery and brain seems to play an important role in MS. Reducing the secretion of proteolytic matrix metalloproteinases (MMP), i.e. MMP-2, as disruptors of blood-brain barrier integrity could have profound implications for MS. METHODS In this two-armed randomized controlled trial 64 participants with relapsing-remitting MS (RRMS) (EDSS 0-4.0) will be allocated to either an intervention group or a passive wait list control group. The intervention group will perform 60 min of combined functional resistance and endurance exercises 3x per week over a period of 12 weeks in a community-based and publicly available setting. Changes in serum concentration of MMP-2 will be the primary outcome. Secondary outcomes are numbers of immune cell subsets, soluble (anti-) inflammatory factors, physical capacity, cognitive performance, physical activity behavior, gait performance, and patient-reported outcomes. All outcome measures will be assessed at baseline and after week 12 with an additional blood sampling before, during and immediately after a single training session in week 6. DISCUSSION To our knowledge, this will be the first RCT to investigate both the acute and chronic effects of a community-based intense functional resistance and endurance exercise regimen in persons with RRMS. Combining analysis of biological and cognitive or psychological outcomes may provide a better understanding of the MS-specific symptomology. TRIAL REGISTRATION DRKS00017091; 05th of April, 2019; International Clinical Trials Registry Platform.
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Satiating Effect of a Ketogenic Diet and Its Impact on Muscle Improvement and Oxidation State in Multiple Sclerosis Patients.
Benlloch, M, López-Rodríguez, MM, Cuerda-Ballester, M, Drehmer, E, Carrera, S, Ceron, JJ, Tvarijonaviciute, A, Chirivella, J, Fernández-García, D, de la Rubia Ortí, JE
Nutrients. 2019;11(5)
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Multiple sclerosis (MS) is an auto-immune condition that affects the brain and spinal cord. In MS, the coating that protects the nerves (myelin) is damaged, and this can lead to muscle wasting. The aim of this pilot study was to establish whether a low carbohydrate (‘ketogenic’) diet would lead to improvements in muscle mass in patients with MS. 27 MS patients were given instructions to follow a Mediterranean-style ketogenic diet that consisted of 20% total calories from protein, 40% of calories from carbohydrate and 40% of calories from fat, including 60ml of coconut oil per day. After four months on the diet, participants had gained muscle mass and lost fat. They also felt less hungry, and blood tests showed lower levels of inflammation and oxidation. The researchers concluded that a ketogenic diet has the potential to provide an additional therapy for patients with MS.
Abstract
BACKGROUND It was previously established that Multiple sclerosis (MS) generates energy alterations at the mitochondrial level related to the loss of muscle mass. Ketone bodies, mainly beta-hydroxybutyrate (BHB), re-establish this energy alteration causing satiety, changes in body composition and a decrease in hormone-dependant hunger, such as ghrelin. The aim of this study was to establish possible improvements in body composition and the level of oxidation in patients with MS, by means of the satiating effect of a ketogenic diet. METHODS A pilot study was carried out with 27 MS patients who were given a Mediterranean isocaloric and ketogenic diet for 4 months. Anthropometric measurements, as well as satiety and hunger perception (VAS scale), were taken. In addition, BHB and paraoxonase 1 (PON1), as an oxidation marker, were measured by spectrophotometric automated assays, and ghrelin was determined by an enzyme immunoassay in the serum. All measurements were taken before and after the intervention. RESULTS A significant increase in satiety perception at lunch and dinner and of BHB in the blood was obtained. Hunger perception decreased significantly at lunch and dinner with similar levels of ghrelin. In addition, an important increase in lean mass and PON1 was observed. To our knowledge, this is the first study addressing improvements in body composition, oxidation state and metabolism in MS patients, based on the satiating effect of a Mediterranean isocaloric diet. CONCLUSION A ketogenic diet increases lean mass and decreases inflammation and oxidation possibly as a consequence of an increase in satiety and decrease in hunger in MS patients.
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The microbiome and autoimmunity: a paradigm from the gut-liver axis.
Li, B, Selmi, C, Tang, R, Gershwin, ME, Ma, X
Cellular & molecular immunology. 2018;15(6):595-609
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The incidence of autoimmune and inflammatory diseases has been increasing worldwide. Changes in environmental factors, such as modern lifestyle, diet, antibiotics and hygiene are thought to play a critical role in the development of various autoimmune diseases. It is the mucosal microbial flora that is shaped by our environment and communicates with the innate and adaptive immune systems, and when disrupted, can lead to the loss of immune tolerance and dysregulated immune cells. This review paper provides an overview of the interactions between the intestinal microbiome and the immune system. It explains how these interactions affect host autoimmunity locally and systemically and sheds light on the molecular mechanisms, utilised by microbes that may contribute to systemic autoimmunity in genetically susceptible individuals. The links between the gut microbiome and various autoimmune diseases, such as rheumatoid arthritis, type 1 diabetes and multiple sclerosis, as well as the gut-liver axis, involving intestinal microbiome and autoimmune liver diseases, are discussed in more detail.
Abstract
Microbial cells significantly outnumber human cells in the body, and the microbial flora at mucosal sites are shaped by environmental factors and, less intuitively, act on host immune responses, as demonstrated by experimental data in germ-free and gnotobiotic studies. Our understanding of this link stems from the established connection between infectious bacteria and immune tolerance breakdown, as observed in rheumatic fever triggered by Streptococci via molecular mimicry, epitope spread and bystander effects. The availability of high-throughput techniques has significantly advanced our capacity to sequence the microbiome and demonstrated variable degrees of dysbiosis in numerous autoimmune diseases, including rheumatoid arthritis, type 1 diabetes, multiple sclerosis and autoimmune liver disease. It remains unknown whether the observed differences are related to the disease pathogenesis or follow the therapeutic and inflammatory changes and are thus mere epiphenomena. In fact, there are only limited data on the molecular mechanisms linking the microbiota to autoimmunity, and microbial therapeutics is being investigated to prevent or halt autoimmune diseases. As a putative mechanism, it is of particular interest that the apoptosis of intestinal epithelial cells in response to microbial stimuli enables the presentation of self-antigens, giving rise to the differentiation of autoreactive Th17 cells and other T helper cells. This comprehensive review will illustrate the data demonstrating the crosstalk between intestinal microbiome and host innate and adaptive immunity, with an emphasis on how dysbiosis may influence systemic autoimmunity. In particular, a gut-liver axis involving the intestinal microbiome and hepatic autoimmunity is elucidated as a paradigm, considering its anatomic and physiological connections.
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Intermittent Fasting Confers Protection in CNS Autoimmunity by Altering the Gut Microbiota.
Cignarella, F, Cantoni, C, Ghezzi, L, Salter, A, Dorsett, Y, Chen, L, Phillips, D, Weinstock, GM, Fontana, L, Cross, AH, et al
Cell metabolism. 2018;27(6):1222-1235.e6
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Calorie restriction (CR) has potent anti-inflammatory effects and has shown beneficial effects in an animal model for Multiple Sclerosis (MS). Intermittent Fasting (IF) has similar effects as CR and may be more acceptable long term than CR. This paper reports results from both an animal study and a pilot randomised controlled human clinical trial on IF and MS. The animal study showed that IF had beneficial effects on the MS animal model and that these effects were at least in part mediated by changes in the gut microbiome. 16 patients with relapsing remitting MS were enrolled during a relapse and randomised to either IF (6-7 fasting days during the two-week study) or normal eating. Changes in immune inflammatory parameters and gut flora were seen in the IF group which were similar to the beneficial changes in the animal model. The authors conclude that larger clinical studies to test IF and microbiome manipulation as a potential treatment in MS are warranted.
Abstract
Multiple sclerosis (MS) is more common in western countries with diet being a potential contributing factor. Here we show that intermittent fasting (IF) ameliorated clinical course and pathology of the MS model, experimental autoimmune encephalomyelitis (EAE). IF led to increased gut bacteria richness, enrichment of the Lactobacillaceae, Bacteroidaceae, and Prevotellaceae families and enhanced antioxidative microbial metabolic pathways. IF altered T cells in the gut with a reduction of IL-17 producing T cells and an increase in regulatory T cells. Fecal microbiome transplantation from mice on IF ameliorated EAE in immunized recipient mice on a normal diet, suggesting that IF effects are at least partially mediated by the gut flora. In a pilot clinical trial in MS patients, intermittent energy restriction altered blood adipokines and the gut flora resembling protective changes observed in mice. In conclusion, IF has potent immunomodulatory effects that are at least partially mediated by the gut microbiome.
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Effect of intermittent vs. daily calorie restriction on changes in weight and patient-reported outcomes in people with multiple sclerosis.
Fitzgerald, KC, Vizthum, D, Henry-Barron, B, Schweitzer, A, Cassard, SD, Kossoff, E, Hartman, AL, Kapogiannis, D, Sullivan, P, Baer, DJ, et al
Multiple sclerosis and related disorders. 2018;23:33-39
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Multiple sclerosis (MS) is a disease of the central nervous system. Dietary modification is emerging as a safe intervention to potentially modify disease course. The main aim of this study was to assess the safety and feasibility of an intermittent fasting diet in people with MS. Secondary outcomes explored the effects of calorie restriction (CR) diets on body weight and anthropometric characteristics as well as on patient-reported outcomes including fatigue, sleep and mood. The study is a pilot randomised controlled feeding study of three different types of diets. Each participant (n=36) was randomized to 1 of 3 diets: a control diet (placebo), a daily CR diet and intermittent CR diet. Results indicate that daily CR diet was associated with marginally greater weight loss than the intermittent CR diet. Both CR diets were associated with trends toward improvements in cardiometabolic outcomes. Furthermore, CR diets were associated with in improvements in emotional well-being. Authors conclude that CR and weight loss represent interventions for clinically relevant symptoms due to MS, such as emotional well-being, without adding meaningful risks or adverse outcomes.
Abstract
An intermittent fasting or calorie restriction diet has favorable effects in the mouse forms of multiple sclerosis (MS) and may provide additional anti-inflammatory and neuroprotective advantages beyond benefits obtained from weight loss alone. We conducted a pilot randomized controlled feeding study in 36 people with MS to assess safety and feasibility of different types of calorie restriction (CR) diets and assess their effects on weight and patient reported outcomes in people with MS. Patients were randomized to receive 1 of 3 diets for 8 weeks: daily CR diet (22% daily reduction in energy needs), intermittent CR diet (75% reduction in energy needs, 2 days/week; 0% reduction, 5 days/week), or a weight-stable diet (0% reduction in energy needs, 7 days/week). Of the 36 patients enrolled, 31 (86%) completed the trial; no significant adverse events occurred. Participants randomized to CR diets lost a median 3.4 kg (interquartile range [IQR]: -2.4, -4.0). Changes in weight did not differ significantly by type of CR diet, although participants randomized to daily CR tended to have greater weight loss (daily CR: -3.6 kg [IQR: -3.0, -4.1] vs. intermittent CR: -3.0 kg [IQR: -1.95, -4.1]; P = 0.15). Adherence to study diets differed significantly between intermittent CR vs. daily CR, with lesser adherence observed for intermittent CR (P = 0.002). Randomization to either CR diet was associated with significant improvements in emotional well-being/depression scores relative to control, with an average 8-week increase of 1.69 points (95% CI: 0.72, 2.66). CR diets are a safe/feasible way to achieve weight loss in people with MS and may be associated with improved emotional health.