The rate of symptom accumulation distinguishes between slowly and rapidly progressing forms of multiple sclerosis (MS). Given that a patient's genetics can affect the rate of disease progression, identification of genetic variants associated with rapid disease progression should provide valuable information for timely prognosis and development of optimal treatment plans. We hypothesized that the polymorphism rs2821557 in the human KCNA3 gene encoding a voltage‐gated potassium channel Kv1.3 might be one of these genetic variants, given the role of Kv1.3 in neuroinflammation, as well as the location and gain‐of‐function effect of this polymorphism. To test this hypothesis we performed an analytic study exploring the relationships between rs2821557 polymorphism and disease progression in a cohort of MS patients. The rs2821557 genotype and the rate of disease progression based on Multiple Sclerosis Severity Score (MSSS) were determined for 101 patients (68 females and 33 males). Peripheral blood CD4+ lymphocyte subpopulations (Tnaive, TCM, TEM) and the expression of chemokine receptors (CXCR5, CXCR3, CCR6, CCR4) were estimated by flow cytometry. The comparisons between groups by genotype (TT, TC, CC) and allelic approach analysis (T vs. C) revealed a significantly higher incidence of the rapid disease course (MSSS ≥ 7.5) among minor C allele carriers (CC and TC) compared to patients with the TT genotype. Furthermore, C allele carriers had higher counts of CXCR3+ TEM cells than homozygous T allele carriers. In conclusion, accelerated MS progression in C allele carriers is likely linked to enhanced Kv1.3‐mediated accumulation of pathogenic CXCR3+ TEM cells and exacerbated neuroinflammation.
At present, the role of intestinal microbiota in diverse diseases of the central nervous system, including of multiple sclerosis (MS) has been extensively investigated. Self-reactive CD4+ Th1 and Th17 cells specific to myelin-derived antigens play a key role in the MS pathogenesis. Taking into consideration pathogenetic features related to MS development, we examined a relation between intestinal microbiocenosis and abundance of various peripheral blood helper T (Th) cell subsets in MS patients. Objective of the study: to assess prevalence of individual members of the intestinal microbiota in MS patients and analyze a relation with peripheral blood Th cell subsets. Prevalence of symbiotic and opportunistic microbial species was estimated by bacteriological method and real time PCR in 112 MS patients (72 females, 40 males) of varying severity and duration. Th cell subsets (Th1, Th2, Th17, Th1/Th17, Th17/Th22, DP Th17) were analyzed by using multi-color flow cytometry based on Th cell subset-specific surface expression of chemokine receptors. A relationship between individual intestinal microbiota species and severity, duration and rate of MS progression, as well as with the phenotype of immune cells was assessed. It was found that the most significant correlation between percentage of peripheral blood Th cell subsets was observed with prevalence of Lactobacillus spp., Enterococcus spp. and Enterobacter spp. Moreover, prevalence of Enterococcus spp. Th cell composition influenced synergistically or antagonistically together with Enterobacter spp. or Lactobacillus spp., respectively. It is suggested that direct and indirect impact of intestinal microbiota composition on human immune system might contribute to developing novel strategies for treating MS.
BACKGROUND: Heterogeneous dysbiosis of the intestinal microbiome is a common hallmark of multiple sclerosis. In this pilot study, we compared the level of some gut bacteria in multiple sclerosis patients receiving oral disease-modifying therapy versus untreated. MATERIALS AND METHODS: Subjects were patients with relapsing-remitting or secondary and primary progressive multiple sclerosis. Multiple sclerosis patients were treated by Fingolimod (n = 31), Teriflunomide (n = 21) or were untreated (n = 31). The bacterial levels in stool samples were analyzed by cultivation method and real time PCR. RESULTS: The levels of symbiotic and opportunistic bacterial species in the fecal samples of multiple sclerosis patients receiving disease-modifying therapy were different from those in untreated patients. Also, there was a difference in the spectrum of gastrointestinal tract disorders between these patients. Fingolimod-treated patients showed decreased levels of some bacterial species compared to untreated subjects, including Escherichia coli with regular enzymatic activity, Sutterella wadsworthensis (phylum Proteobacteria), butyrate-producing bacteria Roseburia spp., Faecalibacterium prausnitzii, and Ruminococcus spp. (phylum Firmicutes, class Clostridia). Teriflunomide-treated patients demonstrated decreased levels of Lactobacillus spp. and Enterococcus spp. (phylum Firmicutes, class Bacilli) and Ruminococcus spp. Increased levels of Bifidobacterium spp. were observed in treated and untreated multiple sclerosis patients with higher EDSS scores. CONCLUSIONS: This study shows the negative effect of oral disease-modifying therapy on intestinal microbiota composition and gastrointestinal tract disorders. However, more extensive studies are needed to confirm these preliminary results and develop ways to normalize intestinal dysbiosis in multiple sclerosis patients.
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