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The Effect of Probiotic Supplements on Metabolic Parameters of People with Type 2 Diabetes in Greece-A Randomized, Double-Blind, Placebo-Controlled Study.
Zikou, E, Dovrolis, N, Dimosthenopoulos, C, Gazouli, M, Makrilakis, K
Nutrients. 2023;15(21)
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Type 2 diabetes is a multifaceted disease caused by both genetic and environmental factors such as excessive energy intake and lack of exercise. The gut microbiome has been shown to contribute to many different diseases including diabetes through its effects on the immune system, appetite, and fat storage. Probiotics are living organisms that have health benefits to humans and they have been studied for their effects on individuals with type 2 diabetes. However, the studies that have been performed have shown inconsistent results due to poorly designed trials. This randomised control trial aimed to determine the effects of a probiotic supplement containing Lactobacillus, Bifidobacterium, and Saccharomyces species on measures of blood sugar control over a period of 6 months. The results showed that compared to controls, there were significant reductions in measures of blood sugar and total cholesterol. Interestingly the probiotics did not change the diversity of the subjects gut microbiome but did alter their function noting changes in enzymes and metabolites involved in diabetes. It was concluded that over a 6-month period, the supplementation of probiotics containing Lactobacillus, Bifidobacterium, and Saccharomyces was of benefit to blood sugar balance and cholesterol levels. This study could be used by healthcare professionals to recommend a specific probiotic to individuals with type 2 diabetes.
Abstract
The role of probiotic supplementation in type 2 diabetes (T2D) treatment is controversial. The present study aimed to assess the effects of a multi-strain probiotic supplement (LactoLevureR (containing Lactobacillus acidophilus, Lactobacillus plantarum, Bifidobacterium lactis, and Saccharomyces boulardii)) over 6 months, primarily on glycemic control as well as on lipid levels and alterations in the gut microbiome, among individuals with T2D residing in Greece. A total of 91 adults with T2D (mean age [±SD] 65.12 ± 10.92 years, 62.6% males) were randomized to receive the probiotic supplement or a matching placebo capsule, once daily, for 6 months. Blood chemistries and anthropometric parameters were conducted every 3 months, and stool samples were collected at baseline and at 6 months. Significant reductions in HbA1c, fasting blood glucose, and total cholesterol were observed in participants treated with the probiotic supplement (n = 46) compared to the controls (n = 45), even after adjustment for a greater decrease in adiposity (waist circumference). Although there were no statistically significant differences in the diversity of the gut microbiome (α and β diversity), the administration of probiotics did influence several genera, metabolites, and key enzymes associated with diabetes. Overall, the administration of the multi-strain probiotic LactoLevureR over a 6-month period in individuals with T2D was well-tolerated and had a positive impact on metabolic parameters, alongside improvements in indices of adiposity.
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Effect of synbiotic supplementation on immune parameters and gut microbiota in healthy adults: a double-blind randomized controlled trial.
Li, X, Hu, S, Yin, J, Peng, X, King, L, Li, L, Xu, Z, Zhou, L, Peng, Z, Ze, X, et al
Gut microbes. 2023;15(2):2247025
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The gut microbiota is involved in regulating immunity and synbiotics, that is combinations of pro- and prebiotics, may therefore modulate immunity via the gut microbiota. The aim of this randomised, double-blind, placebo-controlled trial was to evaluate the immune-modulatory effects of a synbiotic supplement (containing Bifidobacterium lactis HN019, Lactobacillus rhamnosus HN001 and fructo-oligosaccharide) in healthy adults. Outcome measures included C-reactive protein (CRP, an inflammatory marker), various pro- and anti-inflammatory cytokines, stool and salivary secretory IgA (sIgA), leukocytes, microbial stool analysis and occurrence, duration, and severity of upper respiratory tract infections (URTI). Compared to the control group, a significant reduction in the inflammatory markers CRP and interferon-gamma and an increase in the anti-inflammatory interleukin-10 and stool sIgA were observed in the supplementation group. There were no differences in types of leukocytes or URTIs between groups. Significant favourable changes in microbiome analysis were observed in the supplemented group which correlated with the observed improvements in inflammatory markers. These changes were dependent on the baseline composition of the microbiome. No adverse events were reported. The authors conclude that the data show that synbiotics are of benefit to healthy adults and support the concept of personalised supplementation.
Abstract
Synbiotics are increasingly used by the general population to boost immunity. However, there is limited evidence concerning the immunomodulatory effects of synbiotics in healthy individuals. Therefore, we conducted a double-blind, randomized, placebo-controlled study in 106 healthy adults. Participants were randomly assigned to receive either synbiotics (containing Bifidobacterium lactis HN019 1.5 × 108 CFU/d, Lactobacillus rhamnosus HN001 7.5 × 107 CFU/d, and fructooligosaccharide 500 mg/d) or placebo for 8 weeks. Immune parameters and gut microbiota composition were measured at baseline, mid, and end of the study. Compared to the placebo group, participants receiving synbiotic supplementation exhibited greater reductions in plasma C-reactive protein (P = 0.088) and interferon-gamma (P = 0.008), along with larger increases in plasma interleukin (IL)-10 (P = 0.008) and stool secretory IgA (sIgA) (P = 0.014). Additionally, synbiotic supplementation led to an enrichment of beneficial bacteria (Clostridium_sensu_stricto_1, Lactobacillus, Bifidobacterium, and Collinsella) and several functional pathways related to amino acids and short-chain fatty acids biosynthesis, whereas reduced potential pro-inflammatory Parabacteroides compared to baseline. Importantly, alternations in anti-inflammatory markers (IL-10 and sIgA) were significantly correlated with microbial variations triggered by synbiotic supplementation. Stratification of participants into two enterotypes based on pre-treatment Prevotella-to-Bacteroides (P/B) ratio revealed a more favorable effect of synbiotic supplements in individuals with a higher P/B ratio. In conclusion, this study suggested the beneficial effects of synbiotic supplementation on immune parameters, which were correlated with synbiotics-induced microbial changes and modified by microbial enterotypes. These findings provided direct evidence supporting the personalized supplementation of synbiotics for immunomodulation.
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Alterations of gut microbiota are associated with blood pressure: a cross-sectional clinical trial in Northwestern China.
Lv, J, Wang, J, Yu, Y, Zhao, M, Yang, W, Liu, J, Zhao, Y, Yang, Y, Wang, G, Guo, L, et al
Journal of translational medicine. 2023;21(1):429
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Hypertension (HTN) is a complex and modifiable risk factor for cardiovascular diseases (CVDs) and stroke, while a diverse range of endogenous and environmental factors contribute to both HTN onset and progression. The adult gut microbiota (GM) consists of trillions of microorganisms and maintains the gut immunity and whole-body homeostasis. The aim of this study was to investigate the GM characteristics in HTN subjects in Northwestern China, and evaluate the associations of GM with blood pressure levels based on sex differences. This study was a cross-sectional study. Participants were randomly selected for the HTN and control groups. A total of 36 HTN subjects (24 females and 12 males) and 18 controls (9 females and 9 males) were randomly selected for metagenomic analysis. Results showed a positive association between GM characteristics and alterations and HTN in both females and males. Thus, GM dysbiosis underlies HTN pathogenesis. Authors conclude that further studies are needed to elucidate the underlying mechanisms and potential therapeutic interventions targeting GM for HTN prevention and management
Abstract
BACKGROUND The human gut microbiota (GM) is involved in the pathogenesis of hypertension (HTN), and could be affected by various factors, including sex and geography. However, available data directly linking GM to HTN based on sex differences are limited. METHODS This study investigated the GM characteristics in HTN subjects in Northwestern China, and evaluate the associations of GM with blood pressure levels based on sex differences. A total of 87 HTN subjects and 45 controls were recruited with demographic and clinical characteristics documented. Fecal samples were collected for 16S rRNA gene sequencing and metagenomic sequencing. RESULTS GM diversity was observed higher in females compared to males, and principal coordinate analysis showed an obvious segregation of females and males. Four predominant phyla of fecal GM included Firmicutes, Bacteroidetes, Actinobacteria and Proteobacteria. LEfSe analysis indicated that phylum unidentified_Bacteria was enriched in HTN females, while Leuconostocaceae, Weissella and Weissella_cibaria were enriched in control females (P < 0.05). Functionally, ROC analysis revealed that Cellular Processes (0.796, 95% CI 0.620 ~ 0.916), Human Diseases (0.773, 95% CI 0.595 ~ 0.900), Signal transduction (0.806, 95% CI 0.631 ~ 0.922) and Two-component system (0.806, 95% CI 0.631 ~ 0.922) could differentiate HTN females as effective functional classifiers, which were also positively correlated with systolic blood pressure levels. CONCLUSIONS This work provides evidence of fecal GM characteristics in HTN females and males in a northwestern Chinese population, further supporting the notion that GM dysbiosis may participate in the pathogenesis of HTN, and the role of sex differences should be considered. Trial registration Chinese Clinical Trial Registry, ChiCTR1800019191. Registered 30 October 2018 - Retrospectively registered, http://www.chictr.org.cn/ .
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Increased kynurenine-to-tryptophan ratio in the serum of patients infected with SARS-CoV2: An observational cohort study.
Lionetto, L, Ulivieri, M, Capi, M, De Bernardini, D, Fazio, F, Petrucca, A, Pomes, LM, De Luca, O, Gentile, G, Casolla, B, et al
Biochimica et biophysica acta. Molecular basis of disease. 2021;1867(3):166042
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Covid-19 infection may alter the immune system, but exactly how is still unclear. A key pathway in the regulation of the immune system is the kynurenine pathway of tryptopham. This observational cohort study aimed to determine how this pathway was affected following infection with Covid-19. The results showed that compared to healthy patients, individuals who tested positive to Covid-19 had an increased ratio of kynurenine:tryptopham and the increase was more pronounced in those who had severe infection and if they were male. It was concluded that the kynurenin:tryptopham ratio could be used as a marker for disease severity and useful for treatments. This study could be used by healthcare professionals to use the kynurenine:tryptopham ratio as a marker for disease severity and stratify patients accordingly for treatments.
Abstract
Immune dysregulation is a hallmark of patients infected by SARS-CoV2 and the balance between immune reactivity and tolerance is a key determinant of all stages of infection, including the excessive inflammatory state causing the acute respiratory distress syndrome. The kynurenine pathway (KP) of tryptophan (Trp) metabolism is activated by pro-inflammatory cytokines and drives mechanisms of immune tolerance. We examined the state of activation of the KP by measuring the Kyn:Trp ratio in the serum of healthy subjects (n = 239), and SARS-CoV2-negative (n = 305) and -positive patients (n = 89). Patients were recruited at the Emergency Room of St. Andrea Hospital (Rome, Italy). Kyn and Trp serum levels were assessed by HPLC/MS-MS. Compared to healthy controls, both SARS-CoV2-negative and -positive patients showed an increase in the Kyn:Trp ratio. The increase was larger in SARS-CoV2-positive patients, with a significant difference between SARS-CoV2-positive and -negative patients. In addition, the increase was more prominent in males, and positively correlated with age and severity of SARS-CoV2 infection, categorized as follows: 1 = no need for intensive care unit (ICU); 2 ≤ 3 weeks spent in ICU; 3 ≥ 3 weeks spent in ICU; and 4 = death. The highest Kyn:Trp values were found in SARS-CoV2-positive patients with severe lymphopenia. These findings suggest that the Kyn:Trp ratio reflects the level of inflammation associated with SARS-CoV2 infection, and, therefore, might represent a valuable biomarker for therapeutic intervention.
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Persistent fatigue following SARS-CoV-2 infection is common and independent of severity of initial infection.
Townsend, L, Dyer, AH, Jones, K, Dunne, J, Mooney, A, Gaffney, F, O'Connor, L, Leavy, D, O'Brien, K, Dowds, J, et al
PloS one. 2020;15(11):e0240784
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Tiredness is a common symptom of Covid-19; however, it is unknown if this fatigue persists once recovered. This observational study of 128 recovered Covid-19 patients aimed to determine if fatigue persisted after recovery and whether severity of disease could predict fatigue. The results showed that post Covid-19 fatigue was reported in more than half of the participants and was particularly pronounced in females and in those with depression. Severity of disease did not predict fatigue. It was concluded that fatigue appears to outlast infection and fatigue was independent of disease severity. This study could be used by health care practitioners to understand that fatigue is common even after recovery from Covid-19 infection and women and sufferers of depression are the most susceptible.
Abstract
Fatigue is a common symptom in those presenting with symptomatic COVID-19 infection. However, it is unknown if COVID-19 results in persistent fatigue in those recovered from acute infection. We examined the prevalence of fatigue in individuals recovered from the acute phase of COVID-19 illness using the Chalder Fatigue Score (CFQ-11). We further examined potential predictors of fatigue following COVID-19 infection, evaluating indicators of COVID-19 severity, markers of peripheral immune activation and circulating pro-inflammatory cytokines. Of 128 participants (49.5 ± 15 years; 54% female), more than half reported persistent fatigue (67/128; 52.3%) at median of 10 weeks after initial COVID-19 symptoms. There was no association between COVID-19 severity (need for inpatient admission, supplemental oxygen or critical care) and fatigue following COVID-19. Additionally, there was no association between routine laboratory markers of inflammation and cell turnover (leukocyte, neutrophil or lymphocyte counts, neutrophil-to-lymphocyte ratio, lactate dehydrogenase, C-reactive protein) or pro-inflammatory molecules (IL-6 or sCD25) and fatigue post COVID-19. Female gender and those with a pre-existing diagnosis of depression/anxiety were over-represented in those with fatigue. Our findings demonstrate a significant burden of post-viral fatigue in individuals with previous SARS-CoV-2 infection after the acute phase of COVID-19 illness. This study highlights the importance of assessing those recovering from COVID-19 for symptoms of severe fatigue, irrespective of severity of initial illness, and may identify a group worthy of further study and early intervention.
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Unusual Early Recovery of a Critical COVID-19 Patient After Administration of Intravenous Vitamin C.
Waqas Khan, HM, Parikh, N, Megala, SM, Predeteanu, GS
The American journal of case reports. 2020;21:e925521
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Coronavirus disease (Covid-19) continues to spread globally and to date there are no proven treatments. Current treatment focuses on the management of the associated acute respiratory distress syndrome (ARDS). There are many studies demonstrating that in severe sepsis and ARDS; Vitamin C reduces systemic inflammation, prevents lung damage, reduces the duration of mechanical ventilation (MV) and the length of intensive care unit (ICU) stay in patients. This is a case report where a critically ill patient received high-dose Vitamin C intravenous (IV) infusions and recovered. A 74 year-old woman with Covid-19, developed ARDS and septic shock. Usual medications were given. She needed MV and deteriorated rapidly. On Day 7 she was administered Vitamin C (11g per 24 hours as a continuous IV infusion). Her clinical condition improved slowly after this. In this case, high dose IV Vitamin C was associated with fewer days on mechanical intervention, a shorter ICU stay and earlier recovery. These results show the importance of further investigation of IV Vitamin C to assess its efficacy in critically ill Covid-19 patients requiring mechanical ventilation and ICU care.
Abstract
BACKGROUND Coronavirus disease 2019 (COVID-19) continues to spread, with confirmed cases now in more than 200 countries. Thus far there are no proven therapeutic options to treat COVID-19. We report a case of COVID-19 with acute respiratory distress syndrome who was treated with high-dose vitamin C infusion and was the first case to have early recovery from the disease at our institute. CASE REPORT A 74-year-old woman with no recent sick contacts or travel history presented with fever, cough, and shortness of breath. Her vital signs were normal except for oxygen saturation of 87% and bilateral rhonchi on lung auscultation. Chest radiography revealed air space opacity in the right upper lobe, suspicious for pneumonia. A nasopharyngeal swab for severe acute respiratory syndrome coronavirus-2 came back positive while the patient was in the airborne-isolation unit. Laboratory data showed lymphopenia and elevated lactate dehydrogenase, ferritin, and interleukin-6. The patient was initially started on oral hydroxychloroquine and azithromycin. On day 6, she developed ARDS and septic shock, for which mechanical ventilation and pressor support were started, along with infusion of high-dose intravenous vitamin C. The patient improved clinically and was able to be taken off mechanical ventilation within 5 days. CONCLUSIONS This report highlights the potential benefits of high-dose intravenous vitamin C in critically ill COVID-19 patients in terms of rapid recovery and shortened length of mechanical ventilation and ICU stay. Further studies will elaborate on the efficacy of intravenous vitamin C in critically ill COVID-19.
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Vitamin C levels in patients with SARS-CoV-2-associated acute respiratory distress syndrome.
Chiscano-Camón, L, Ruiz-Rodriguez, JC, Ruiz-Sanmartin, A, Roca, O, Ferrer, R
Critical care (London, England). 2020;24(1):522
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Sepsis related acute respiratory disease (ARDS) is associated with Covid-19. ARDS patients can present with decreased levels of vitamin C and so by association Covid-19 patients may also have low vitamin C levels. In this cohort study, 18 Covid-19 ARDS patients of which all survived were assessed for vitamin C levels. 17 patients had undetectable levels of vitamin C and one had low levels. It was concluded that more than 90% of the patients in this study had undetectable levels of vitamin C, which may be due to several reasons, such as reduced absorption of vitamin C in the gut and decreased production. Clinicians could use this study to understand the importance of monitoring vitamin C levels in patients with Covid-19.
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'The long tail of Covid-19' - The detection of a prolonged inflammatory response after a SARS-CoV-2 infection in asymptomatic and mildly affected patients.
Doykov, I, Hällqvist, J, Gilmour, KC, Grandjean, L, Mills, K, Heywood, WE
F1000Research. 2020;9:1349
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‘Long COVID’ or the persistence of symptoms after SARS-CoV-2 infection, such as fatigue, is becoming increasingly common. As the emergence of the virus is still relatively recent in research terms, little is known about the long-term impact of the viruses infection. This study sought to generate further insights into the management and diagnostic of long COVID, by assessing a range of inflammatory markers from blood serum samples. Examined were 10 samples of health care workers with previous asymptomatic or moderate SARS-CoV-2 infections, compared to 10 samples of SARS-CoV-2 naive health care workers. The serum was analyzed by mass spectrometry using a customized panel of the 96 immune response associated proteins. Despite being mild to moderate cases, the results showed that even 40-60 days after infection, significant disturbance in the immune systems inflammatory response could be observed. Particularly markers that reflect anti-inflammatory pathways and mitochondrial stress. The study highlighted six of the most noteworthy proteins and included a brief description of their role. The authors suggest that analysing proteins by using targeted proteomic technology, could serve as a cost-effective strategy to further investigate the changes in inflammatory responses post SARS-CoV-2 infection. Which could help to aid the identification of potential treatment targets in the future. Relevant findings from this small study for clinical practice are that even mild to moderate SARS-CoV-2 infection can alter the inflammatory responses for months afterwards.
Abstract
'Long Covid', or medical complications associated with post SARS-CoV-2 infection, is a significant post-viral complication that is being more and more commonly reported in patients. Therefore, there is an increasing need to understand the disease mechanisms, identify drug targets and inflammatory processes associated with a SARS-CoV-2 infection. To address this need, we created a targeted mass spectrometry based multiplexed panel of 96 immune response associated proteins. We applied the multiplex assay to a cohort of serum samples from asymptomatic and moderately affected patients. All patients had tested positive for a SARS-CoV-2 infection by PCR and were determined to be subsequently positive for antibodies. Even 40-60 days post-viral infection, we observed a significant remaining inflammatory response in all patients. Proteins that were still affected were associated with the anti-inflammatory response and mitochondrial stress. This indicates that biochemical and inflammatory pathways within the body can remain perturbed long after SARS-CoV-2 infections have subsided even in asymptomatic and moderately affected patients.
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Clinical symptoms and markers of disease mechanisms in adolescent chronic fatigue following Epstein-Barr virus infection: An exploratory cross-sectional study.
Kristiansen, MS, Stabursvik, J, O'Leary, EC, Pedersen, M, Asprusten, TT, Leegaard, T, Osnes, LT, Tjade, T, Skovlund, E, Godang, K, et al
Brain, behavior, and immunity. 2019;80:551-563
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Epstein-Barr virus (EBV) can trigger chronic fatigue (CF) and chronic fatigue syndrome (CFS) in individuals who are predisposed. However, how fatigue develops and how infections may trigger this is not fully understood. This exploratory cross-sectional study of 200 fatigued and non-fatigued adolescents 6 months after EBV aimed to understand symptoms and potential markers for disease. The results showed that all symptoms (not just fatigue) were more pronounced in those individuals suffering from fatigue, despite no increases in viral load. Those with fatigue only had slight changes in immune, nerve and hormonal markers and none correlated with severity of symptoms. It was concluded that there is a discrepancy between symptoms and viral load and alterations to several markers were only marginal. This study could be used by healthcare professionals to understand the possible limitations of using several biomarkers as a diagnostic tool for CF and CFS.
Abstract
INTRODUCTION Acute Epstein-Barr virus (EBV) infection is a trigger of chronic fatigue (CF) and Chronic Fatigue Syndrome (CFS). The aim of this cross-sectional study was to explore clinical symptoms as well as markers of disease mechanisms in fatigued and non-fatigued adolescents 6 months after EBV-infection, and in healthy controls. MATERIALS AND METHODS A total of 200 adolescents (12-20 years old) with acute EBV infection were assessed 6 months after the initial infectious event and divided into fatigued (EBV CF+) and non-fatigued (EBV CF-) cases based on questionnaire score. The EBV CF+ cases were further sub-divided according to case definitions of CFS. In addition, a group of 70 healthy controls with similar distribution of sex and age was included. Symptoms were mapped with a questionnaire. Laboratory assays included EBV PCR and serology; detailed blood leukocyte phenotyping and serum high-sensitive C-reactive protein; and plasma and urine cortisol and catecholamines. Assessment of autonomic activity was performed with continuous, non-invasive monitoring of cardiovascular variables during supine rest, controlled breathing and upright standing. Differences between EBV CF+ and EBV CF- were assessed by simple and multiple linear regression adjusting for sex as well as symptoms of depression and anxiety. A p-value ≤ 0.05 was considered statistically significant. This study is part of the CEBA-project (Chronic fatigue following acute Epstein-Barr virus infection in adolescents). RESULTS The EBV CF+ group had significantly higher scores for all clinical symptoms. All markers of infection and most immune, neuroendocrine and autonomic markers were similar across the EBV CF+ and EBV CF- group. However, the EBV CF+ group had slightly higher serum C-reactive protein (0.48 vs 0.43 mg/L, p = 0.031, high-sensitive assay), total T cell (CD3+) count (median 1573 vs 1481 × 106 cells/L, p = 0.012), plasma norepinephrine (1420 vs 1113 pmol/L, p = 0.01) and plasma epinephrine (363 vs 237 nmol/L, p = 0.032); lower low-frequency:high frequency (LF/HF) ratio of heart rate variability at supine rest (0.63 vs 0.76, p = 0.008); and an attenuated decline in LF/HF ratio during controlled breathing (-0.11 vs -0.25, p = 0.002). Subgrouping according to different CFS diagnostic criteria did not significantly alter the results. Within the EBV CF+ group, there were no strong correlations between clinical symptoms and markers of disease mechanisms. In a multiple regression analysis, serum CRP levels were independently associated with serum cortisol (B = 4.5 × 10-4, p < 0.001), urine norepinephrine (B = 9.6 × 10-2, p = 0.044) and high-frequency power of heart rate variability (B = -3.7 × 10-2, p = 0.024). CONCLUSIONS In adolescents, CF and CFS 6 months after acute EBV infection are associated with high symptom burden, but no signs of increased viral load and only subtle alterations of immune, autonomic, and neuroendocrine markers of which no one is strongly correlated with symptom scores. A slight sympathetic over parasympathetic predominance is evident in CF and might explain slightly increased CRP levels.
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Vitamin D Supplementation in Central Nervous System Demyelinating Disease-Enough Is Enough.
Häusler, D, Weber, MS
International journal of molecular sciences. 2019;20(1)
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Vitamin D is associated with a reduced risk and severity of multiple sclerosis (MS). However, whether supplementing vitamin D level alters disease severity, is a matter of ongoing debate. This review looks at both clinical and pre-clinical evidence for supplementing vitamin D in people with MS. In vitro experiments show that vitamin D and its metabolites can alter function of various immune cells, mostly via interaction with vitamin D receptors (VDR). Results from human clinical trials, however, are mixed. Preclinical evidence suggests that high dose vitamin D supplementation, when leading to hypercalcaemia, a potentially serious side effect of excessive vitamin D intake, may worsen MS. The authors also review research which suggests mechanisms by which sun exposure can improve MS symptoms independent of vitamin D production. The authors conclude that moderate sun exposure, combined with adequate dietary intake of vitamin D, and in conjunction with a regular assessment of vitamin D serum levels (to avoid hypercalcaemia), might be the best strategy for patients with MS.
Abstract
The exact cause of multiple sclerosis (MS) remains elusive. Various factors, however, have been identified that increase an individual's risk of developing this central nervous system (CNS) demyelinating disease and are associated with an acceleration in disease severity. Besides genetic determinants, environmental factors are now established that influence MS, which is of enormous interest, as some of these contributing factors are relatively easy to change. In this regard, a low vitamin D status is associated with an elevated relapse frequency and worsened disease course in patients with MS. The most important question, however, is whether this association is causal or related. That supplementing vitamin D in MS is of direct therapeutic benefit, is still a matter of debate. In this manuscript, we first review the potentially immune modulating mechanisms of vitamin D, followed by a summary of current and ongoing clinical trials intended to assess whether vitamin D supplementation positively influences the outcome of MS. Furthermore, we provide emerging evidence that excessive vitamin D treatment via the T cell-stimulating effect of secondary hypercalcemia, could have negative effects in CNS demyelinating disease. This jointly merges into the balancing concept of a therapeutic window of vitamin D in MS.