Background
Multiple Sclerosis (MS) is a chronic immune‐mediated neurological disease of the central nervous system with a complex and still not fully understood aetiology. In recent years, the gut ...microbiota and fermentative metabolites like short‐chain fatty acids (SCFAs) have received increased attention in relation to the development and disease course of MS. This systematic review highlights and summarizes the existing literature within this field.
Methods
A systematic search in PubMed was conducted on 12 October 2017, to find published original studies on SCFAs and their impact on MS and the animal model of MS experimental autoimmune encephalomyelitis (EAE). Furthermore, all studies analysing the gut microbiota in MS patients were included. A total of 14 studies were eligible for this review.
Results
Short‐chain fatty acids have been shown to ameliorate the disease course in EAE, but no studies specifically addressing the role of SCFAs in human MS patients were identified. However, some investigations have shown that the microbiota of MS patients is characterized by a reduction in SCFA‐producing bacteria.
Conclusions
Studies of EAE in mice suggest that SCFAs may play a role in the development and progression of EAE, but so far this has not been confirmed in humans. An aberrant gut microbiota in MS patients has been reported to be differentially abundant compared with healthy controls, although with little consistency in the bacterial taxa. Further investigations are required to elucidate the involvement of the gut microbiota and its metabolites, including potential beneficial effects of SCFAs, in the development and course of MS.
Multiple sclerosis (MS) is a chronic immune-mediated disease characterized by demyelination and neuroaxonal damage in the central nervous system. The etiology is complex and is still not fully ...understood. Accumulating evidence suggests that our gut microbiota and its metabolites influence the MS pathogenesis. Short-chain fatty acids (SCFAs), such as acetate, propionate and butyrate, are metabolites produced by gut microbiota through fermentation of indigestible carbohydrates. SCFAs and kynurenine metabolites have been shown to have important immunomodulatory properties, and propionate supplementation in MS patients has been associated with long-term clinical improvement. However, the underlying mechanisms of action and its importance in MS remain incompletely understood. We analyzed serum levels of SCFAs and performed targeted metabolomics in relation to biomarkers of inflammation, and clinical and MRI measures in newly diagnosed patients with relapsing-remitting MS before their first disease modifying therapy and healthy controls (HCs). We demonstrated that serum acetate levels were nominally reduced in MS patients compared with HCs. The ratios of acetate/butyrate and acetate/(propionate + butyrate) were significantly lower in MS patients in a multivariate analysis (orthogonal partial least squares discriminant analysis; OPLS-DA). The mentioned ratios and acetate levels correlated negatively with the pro-inflammatory biomarker
IFNG
, indicating an inverse relation between acetate and inflammation. In contrast, the proportion of butyrate was found higher in MS patients in the multivariate analysis, and both butyrate and valerate correlated positively with proinflammatory cytokines (
IFNG
and
TNF
), suggesting complex bidirectional regulatory properties of SCFAs. Branched SCFAs were inversely correlated with clinical disability, at a nominal significance level. Otherwise SCFAs did not correlate with clinical variables or MRI measures. There were signs of an alteration of the kynurenine pathway in MS, and butyrate was positively correlated with the immunomodulatory metabolite 3-hydroxyanthranilic acid. Other variables that influenced the separation between MS and HCs were NfL,
ARG1
and
IL1R1
, D-ribose 5-phosphate, pantothenic acid and D-glucuronic acid. In conclusion, we provide novel results in this rapidly evolving field, emphasizing the complexity of the interactions between SCFAs and inflammation; therefore, further studies are required to clarify these issues before supplementation of SCFAs can be widely recommended.
A number of studies have reported flare-up of multiple sclerosis (MS) disease activity after cessation of natalizumab, increasing to a level beyond the pre-natalizumab treatment level. Our aim was to ...describe the development in clinical disease activity following cessation of natalizumab therapy in a large unselected cohort of highly active patients. We studied 375 highly active patients who had suffered at least two significant relapses within 1 year or three relapses within 2 years, or had been treated with mitoxantrone for highly active disease. All patients had discontinued therapy with natalizumab after at least 24 weeks on therapy, and had been followed 3–12 months (mean 8.9 months) after cessation of natalizumab therapy. The annualised relapse rate before start of natalizumab therapy was 0.94 (95 % confidence interval CI 0.88–1.00), 0.47 (95 % CI 0.43–0.52) during natalizumab therapy, 0.63 (95 % CI 0.51–0.76) 1–6 months after natalizumab and 0.55 (95 % CI 0.42–0.70) 7–12 months after natalizumab. However, 83 (22 %) of the patients could be classified as showing rebound of relapses, defined as a higher individual relapse rate after cessation of natalizumab than before natalizumab. These patients had a higher annualised relapse rate during natalizumab therapy. For the whole patient group, the relapse rate after discontinuation did not exceed the pre-natalizumab relapse rate at any time, but 22 % of the patients showed rebound of relapses after discontinuation of natalizumab.
OBJECTIVETo investigate whether smoking in patients with relapsing-remitting multiple sclerosis (RRMS) treated with interferon beta (IFN-β) is associated with the relapse rate and whether there is an ...interaction between smoking and human leukocyte antigen (HLA)–DRB1*15:01, HLA-A*02:01, and the N-acetyltransferase-1 (NAT1) variant rs7388368A.
METHODSDNA from 834 IFN-β–treated patients with RRMS from the Danish Multiple Sclerosis Biobank was extracted for genotyping. Information about relapses from 2 years before the start of treatment to either the end of treatment or the last follow-up visit was obtained from the Danish Multiple Sclerosis Treatment Register. Smoking information came from a comprehensive questionnaire.
RESULTSWe found that the relapse rate in patients with RRMS during IFN-β treatment was higher in smokers compared to nonsmokers, with an incidence rate ratio (IRR) of 1.20 (95% confidence interval CI 1.021–1.416, p = 0.027) and with an IRR increase of 27% per pack of cigarettes per day (IRR 1.27, 95% CI 1.056–1.537, p = 0.012). We found no association or interaction with HLA and the NAT1 variant.
CONCLUSIONIn this observational cohort study, we found that smoking is associated with increased relapse activity in patients with RRMS treated with IFN-β, but we found no association or interaction with HLA or the NAT1 variant.
Background:
Neurofilament light chain (NFL) and chitinase-3-like-1 (CHI3L1) concentrations in cerebrospinal fluid (CSF) may have prognostic value in clinically isolated syndromes (CIS) and ...relapsing–remitting multiple sclerosis (RRMS).
Objectives:
To compare the prognostic value of CSF concentrations of NFL and CHI3L1 in newly diagnosed CIS and RRMS patients.
Methods:
NFL and CHI3L1 were measured in CSF in 177 newly diagnosed patients with CIS or RRMS who were followed clinically for a mean of 5.7 years.
Results:
At baseline CSF concentrations of NFL correlated with CSF concentrations of CHI3L1, relapses in the previous year, time from last relapse, and the Expanded Disability Status Scale (EDSS) score. CSF concentrations of NFL and CHI3L1 were both associated with increased relapse risk during the first 2 years in univariate analyses, but only the CSF concentration of NFL was independently associated with relapse risk in a multivariable analysis. There was no relationship between CSF concentrations of NFL or CHI3L1 and risk of conversion to secondary progressive MS or development of disability.
Conclusion:
CSF concentrations of NFL are associated with 2-year relapse risk but not with disease progression or clinical worsening in newly diagnosed CIS and RRMS patients. This may be due to confounding by the effect of disease-modifying therapies.
The human leukocyte antigen (HLA) haplotype DRB1*15:01 is the major risk factor for multiple sclerosis (MS). Here, we find that DRB1*15:01 is hypomethylated and predominantly expressed in monocytes ...among carriers of DRB1*15:01. A differentially methylated region (DMR) encompassing HLA-DRB1 exon 2 is particularly affected and displays methylation-sensitive regulatory properties in vitro. Causal inference and Mendelian randomization provide evidence that HLA variants mediate risk for MS via changes in the HLA-DRB1 DMR that modify HLA-DRB1 expression. Meta-analysis of 14,259 cases and 171,347 controls confirms that these variants confer risk from DRB1*15:01 and also identifies a protective variant (rs9267649, p < 3.32 × 10−8, odds ratio = 0.86) after conditioning for all MS-associated variants in the region. rs9267649 is associated with increased DNA methylation at the HLA-DRB1 DMR and reduced expression of HLA-DRB1, suggesting a modulation of the DRB1*15:01 effect. Our integrative approach provides insights into the molecular mechanisms of MS susceptibility and suggests putative therapeutic strategies targeting a methylation-mediated regulation of the major risk gene.
Background:
Smoking has been associated with increased multiple sclerosis (MS) risk, disease worsening, and progression in MS patients. Furthermore, interactions between smoking and human leukocyte ...antigen (HLA) genes have been shown for MS risk. Recently, we found that smoking was associated with an increased relapse rate in interferon-beta-treated relapsing-remitting multiple sclerosis (RRMS) patients.
Objectives:
We examined the association between smoking and relapses in natalizumab-treated RRMS patients. Second, we investigated if an interaction between smoking and HLA-DRB1*15:01 or HLA-A*02:01 affected the number of relapses during treatment.
Methods:
In this observational cohort study, 355 natalizumab-treated RRMS patients were assessed. Prespecified criteria excluded 62 patients. Clinical data from the starting of treatment to the two-year follow-up visit were collected. Smoking status was obtained by a questionnaire survey. TaqMan allelic discrimination was used for genotyping of tag single-nucleotide polymorphisms (SNPs) for HLA-DRB1*15:01 and HLA-A*02:01. Negative binomial regression analysis was used to analyze the association between relapse rate and smoking intensity and HLA.
Results:
One pack of cigarettes (20 cigarettes) per day during natalizumab treatment increased the relapse rate during treatment with 38% (incidence rate ratio (IRR) = 1.38, 95% confidence interval (CI): 1.08–1.77, p = 0.01). No association or interaction was found between smoking and HLA-DRB1*15:01 or HLA-A*02:01, respectively.
Conclusion:
Smoking intensity was significantly associated with the number of relapses during natalizumab treatment.
Background:
Environmental factors are associated with acquiring multiple sclerosis (MS) particularly in adolescence.
Objective:
To test for association between MS and exposure to passive smoking at ...the age of 10–19.
Methods:
A total of 919 patients from the Danish MS Registry and Biobank and 3419 healthy blood donors who had not smoked before the age of 19 were targeted. We analyzed separately for each sex and for those never-smokers (cohort 1) and active smokers above the age of 19 (cohort 2). All participants completed standardized questionnaires about smoking and lifestyle. We matched cases and controls in the ratio of 1:2 by propensity scores discarding unmatchable individuals and used logistic regression adjusted for all covariates and interactions.
Results:
After matching, we included 110/213 male cases/controls and 232/377 female case/controls in cohort 1. In cohort 2, the numbers were 160/320 and 417/760, respectively. Among women in cohort 1, the odds ratio (OR) for MS by passive smoking at the age of 10–19 was 1.432 (p = 0.037) but in men it was 1.232 (p = 0.39). Among men in cohort 2, OR was 1.593 (p = 0.022) but among women it was only 1.102 (p = 0.44).
Conclusion:
Among never smokers, female MS cases were more often than female controls reported with passive smoking between the age of 10 and 19, and among smokers above the age of 19, male MS patients were more often than male controls reported with passive smoking.
Background and objective:
Due to the possible existence of a vulnerable period of multiple sclerosis (MS) susceptibility in adolescence and because Danish teenagers have a high alcohol consumption, ...we investigated the association between alcohol consumption at ages 15–19 and the risk of developing MS.
Methods:
A total of 1717 patients with MS and 4685 healthy blood donors filled in a comprehensive environmental and lifestyle questionnaire. Data were analysed by logistic regression models and adjusted for selected confounders.
Results:
We found an inverse association between alcohol consumption in adolescence and risk of developing MS in both women (p < 0.001) and men (p = 0.012). Women with low alcohol consumption had an odds ratio (OR) of 0.56 (95% confidence interval (CI): 0.47–0.66) compared with non-drinking women. The ORs were similar for women with moderate (OR = 0.49, 95% CI: 0.38–0.62) and high consumption (OR = 0.57, 95% CI: 0.38–0.84). Men with low alcohol consumption had an OR of 0.69 (95% CI: 0.53–0.89) compared with non-drinking men but no decreased risk was found for men with moderate and high consumption.
Conclusion:
Alcohol consumption in adolescence was associated with lower risk of developing MS among both sexes.
The endocannabinoid system (ECS) has been found altered in patients with multiple sclerosis (MS). However, whether the ECS alteration is present in the early stage of MS remains unknown. First, we ...aimed to compare the ECS profile between newly diagnosed MS patients and healthy controls (HCs). Next, we explored the association of the ECS, biomarkers of inflammation, and clinical parameters in newly diagnosed MS patients.
Whole blood gene expression of ECS components and levels of endocannabinoids in plasma were measured by real-time quantitative polymerase chain reaction and ultra-high-pressure liquid chromatography-mass spectrometry, respectively, in 66 untreated MS patients and 46 HCs.
No differences were found in the gene expression or plasma levels of the selected ECS components between newly diagnosed MS patients and HCs. Interferon-γ, encoded by the gene IFNG, correlated positively (ρ = 0.60) with the expression of G protein-coupled receptor 55 (GPR55), and interleukin1β (IL1B) correlated negatively (ρ = -0.50) with cannabinoid receptor 2 (CNR2) in HCs.
We found no alteration in the peripheral ECS between untreated patients with MS and HC. Furthermore, our results indicate that the ECS has a minor overall involvement in the early stage of MS on inflammatory markers and clinical parameters when compared with HCs.
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