The Role of Intestinal Microbiota and Probiotics Supplementation in Multiple Sclerosis Management.

Multiple sclerosis (MS) is a neurological autoimmune disorder predominantly afflicting young adults. The etiology of MS is intricate, involving a variety of environmental and genetic factors. Current research increasingly focuses on the substantial contribution of gut microbiota in MS pathogenesis. The commensal microbiota resident within the intestinal milieu assumes a central role within the intricate network recognized as the gut-brain axis (GBA), wielding beneficial impact in neurological and psychological facets. As a result, the modulation of gut microbiota is considered a pivotal aspect in the management of neural disorders, including MS. Recent investigations have unveiled the possibility of using probiotic supplements as a promising strategy for exerting a positive impact on the course of MS. This therapeutic approach operates through several mechanisms, including the reinforcement of gut epithelial integrity, augmentation of the host's resistance against pathogenic microorganisms, and facilitation of mucosal immunomodulatory processes. The present study comprehensively explains the gut microbiome's profound influence on the central nervous system (CNS). It underscores the pivotal role played by probiotics in forming the immune system and modulating neurotransmitter function. Furthermore, the investigation elucidates various instances of probiotic utilization in MS patients, shedding light on the potential therapeutic advantages afforded by this intervention.

Association between insulin resistance and multiple sclerosis: a systematic review and meta-analysis.

There is increasing evidence of metabolic perturbations in multiple sclerosis (MS) patients, and insulin is an important parameter that has controversial effects on neurological disease. Therefore, this systematic review and meta-analysis study aimed to explore the association between insulin resistance (IR) and MS as well as insulin levels and MS. Three electronic databases, including Medline, Scopus, and the Web of Science, were examined up to 26 May 2023 for observational studies. Two independent reviewers assessed the studies according to a pre-specified protocol. Random-effects model using a Restricted-maximum Likelihood (REML) estimator was used to meta-analyze the association between IR [assessed by Homeostatic Model Assessment (HOMA-IR)], insulin and MS. Eighteen datasets from 2012 to 2022 were included in this meta-analysis. The standardized mean difference (SMD) for comparison IR and insulin between MS and healthy control group as outcomes 1 and 2 were 0.78 and 0.72 respectively. Furthermore, for outcome 1, we observed a greater effect size in studies that recruited different types of MS (Mix) (SMD: 1.09) than in those that included only relapsing-remitting MS (RRMS) (SMD: 0.59). The meta-analysis revealed a significant association between IR, insulin and MS, with stronger associations in studies that recruited mixed patients. However, high heterogeneity has been observed in the present study. Therefore, more studies are needed to confirm the association between these parameters and MS.

Potential therapeutic and diagnostic approaches of exosomes in multiple sclerosis pathophysiology.

Exosomes are bilayer lipid vesicles that are released by cells and contain proteins, nucleic acids, and lipids. They can be internalized by other cells, inducing inflammatory responses and instigating toxicities in the recipient cells. Exosomes can also serve as therapeutic vehicles by transporting protective cargo to maintain homeostasis. Multiple studies have shown that exosomes can initiate and participate in the regulation of neuroinflammation, improve neurogenesis, and are closely related to the pathogenesis of central nervous system (CNS) diseases, including multiple sclerosis (MS). Exosomes can be secreted by both neurons and glial cells in the CNS, and their contents change with disease occurrence. Due to their ability to penetrate the blood-brain barrier and their stability in peripheral fluids, exosomes are attractive biomarkers of CNS diseases. In recent years, exosomes have emerged as potential therapeutic agents for CNS diseases, including MS. However, the molecular pathways in the pathogenesis of MS are still unknown, and further research is needed to fully understand the role of exosomes in the occurrence or improvement of MS disease. Thereby, in this review, we intend to provide a more complete understanding of the pathways in which exosomes are involved and affect the occurrence or improvement of MS disease.

Bifidobacterium breve Probiotic Compared to Lactobacillus casei Causes a Better Reduction in Demyelination and Oxidative Stress in Cuprizone-Induced Demyelination Model of Rat.

Despite the anatomical separation, strong evidence suggested a bidirectional association between gut microbiota and central nervous system. Cross-talk between gut microbiota and brain has an important role in the pathophysiology of neurodegenerative disorders and regenerative processes. However, choosing the appropriate probiotics and combination therapy of probiotics to provide a synergistic effect is very crucial. In the present study, we investigated the effect of Lactobacillus casei (L. casei) and Bifidobacterium breve (B. breve) on alternation performance, oxidant/antioxidant biomarkers, the extent of demyelination, and the expression level of HO-1, Nrf-2, Olig2, MBP, PDGFRα, and BDNF in cuprizone (CPZ)-induced demyelination model of rat corpus callosum. In order to induce this model, rats received oral administration of CPZ 0.6% w/w in corn oil for 28 days. Then, L. casei, B. breve, or their combinations were orally administrated for 28 days. Y maze test was performed to investigate the alternation performance. Oxidant/antioxidant biomarkers were determined by colorimetric methods. Extent of demyelination was investigated using FluoroMyelin staining. The genes' expression levels of antioxidant and myelin lineage cells were assessed by quantitative real time PCR. The results showed the probiotics supplementation significantly improve the alternation performance and antioxidant capacity in demyelinated corpus callosum. Interestingly, B. breve supplementation alleviated demyelination and oxidative stress levels more than the administration of L. casei alone or the combination of two probiotics. These observations suggest that B. breve could provide a supplementary strategy for the treatment of multiple sclerosis by increasing antioxidant capacity and remyelination.

Does vitamin D reduce the mortality rate of Plasmodium infection?: a systematic review and meta-analysis.

BACKGROUND: Vitamin D supplementation is recommended as an effective adjunct to counteract malaria pathogenesis, but the evidence on this point is limited and controversial. This systematic review and meta-analysis aimed to investigate the effect of vitamin D administration on the survival rate of Plasmodium-infected animals in experimentally-induced malaria on days 6 and 10 post-infection. METHODS: Five electronic databases were searched up to 20 December 2021. The pooled risks ratio (RR) and associated 95% confidence interval were estimated using the Restricted-maximum likelihood (REML) random-effects model. Heterogeneity was assessed by Cochran's Q test and I2 value. Sub-group analyses were used to identify the sources of heterogeneity for several variables, such as type of vitamin D, type of intervention, and dose of vitamin D. RESULTS: Out of 248 articles found in the electronic database, six were eligible for inclusion in the meta-analysis. The current study found that the pooled random effect of risks ratio favored a statistically significant effect of vitamin D administration on survival rate in infected mice on day 6 post Plasmodium infection (RR = 1.08, 95%CI 1.03, 1.15, p < 0.99; I2 = 0%). It also found that vitamin D administration significantly affected the survival rate on day 10 post-infection (RR = 1.94, 95%CI 1.39, 2.71, p < 0.001; I2 = 69.02%). Subgroup analyses demonstrated a significant pooled RRs of the positive effect of vitamin D administration for cholecalciferol (RR = 3.11, 95%CI 2.41, 4.03, p < 0.001; I2 = 0%), doses higher than 50 µg/kg (RR = 3.37, 95%CI 2.55, 4.27, p < 0.001; I2 = 0%), and oral administration (RR = 3.01, 95%CI 2.37, 3.82, p < 0.001; I2 = 0%). CONCLUSION: This systematic review and meta-analysis showed that vitamin D administration positively affects the survival rate in Plasmodium-infected mice. Since, the mouse model may not accurately reproduce the clinical and pathological features of human malaria, future research should investigate the impact of vitamin D in human malaria.

Intranasal administration of fingolimod (FTY720) attenuates demyelination area in lysolecithin-induced demyelination model of rat optic chiasm.

BACKGROUND: Fingolimod (FTY720) is an oral immunosuppressive compound that has been prescribed to multiple sclerosis (MS) patients since 2010. The lipophilicity and low molecular weight of FTY720 allows it to cross blood brain barrier (BBB) and exert both peripheral and central effects. Previous reports showed that intranasal (IN) administration of drugs are the preferred non-invasive route, which bypasses BBB and improves their delivery and bioavailability in the central nervous system (CNS). Therefore, we aimed to compare the effects of IN and oral administrations of FTY720 on astrocyte activation and demyelination levels of optic chiasm in a focal demyelination model. METHODS: The experimental model was induced by injection of 2 µL lysolecithin 1% into the optic chiasm of male Wistar rats. The rats were treated by oral gavage or intranasal drop of FTY720 at dose of 0.3 mg/kg for 14 days. Astrocyte activation was analyzed using GFAP immunostaining, extent of demyelination, and myelination levels were measured by fluoromyelin staining, and MOG immunostaining, respectively. Then, the concentration of FTY720 was measured by high performance liquid chromatography (HPLC) method in brain tissues. RESULTS: Our data showed that IN administration of FTY720 significantly decreases astrocyte activation and demyelination levels in the optic chiasm compared to the oral administration route. In addition, the concentration of FTY720 was higher in the brain tissue of IN receiving rats compared to the oral treated group. CONCLUSION: It seems that IN administration of FTY720 may be a preferred route to decline the central inflammation and demyelination levels in the MS patients.

Modulation of mRNA Expression of Monoacylglycerol Lipase, Diacylglycerol Lipase and Cannabinoid Receptor-1 in Mice Experimentally Infected with T. gondii.

Toxoplasma gondii, an obligate intracellular parasite, infects more than 30% of world's population. This parasite is considered to be neurotropic, and has high tropism for the central nervous system, and potentially induces cryptogenic epilepsy by no clear mechanism. The current study aimed to investigate the alteration of the main components of the endocannabinoid signaling systems in T. gondii-infected mice. For this purpose, the levels of mRNA expression of monoacylglycerol lipase (MAGL), diacylglycerol lipase (DAGL) and cannabinoid receptor-1 (CB1), were measured by quantitative real time PCR.The mRNA expression level of MAGL was increased by ~ 8-fold in the brains of the Toxoplasma-infected group in comparison with non-infected mice (P<0.0001). The mRNA expression of CB1 gene in the brain of the infected mice was ~ 2 times higher than that measured in control group (P<0.01). The mRNA expression level of DAGL remained unchanged in the infected mice. Overall a substantial increase in MAGL and CB1 expression without any changes in DAGL, in the brain of infected mice suggests that T. gondii disturbs the endocannabinoid signaling pathways, which are known as neurotransmitter modulators involved in epilepsy.

Impact of disease-modifying drugs on the severity of COVID-19 infection in multiple sclerosis patients.

Recent evidence suggested that neurological manifestations occur in patients with a severe form of coronavirus disease (COVID-19). On the basis of this issue, neurologists are very concerned about patients with neurological disorders, especially multiple sclerosis (MS), as consumers of immunosuppressive or immune-modulating drugs. Therefore, the administration of proper disease-modifying therapies (DMTs) in MS patients is critical during the pandemic status. On the one hand, both the autoimmune diseases and immunosuppressive drugs increase the risk of infection due to impairment in the immune system, and on the other hand, postponing of MS treatment has serious consequences on the central nervous system. In the present study, we discussed recent literature about the effect of DMTs administration on the severity of COVID-19 in the MS patients. Overall, it seems that DMTs do not provoke the COVID-19 infection in the MS patients by declining immune responses and cytokine storm. However, as a precaution, the supervision of a neurologist is highly recommended.

An Apparent Correlation Between Central Nervous System and Kidney's Erythropoietin and TNF Alpha Expression at Peak Experimental Autoimmune Encephalomyelitis Disease.

Experimental autoimmune encephalomyelitis (EAE) is an inflammatory demyelination disease associated with inflammatory reactions and attenuation of antioxidant capacity. Several lines of evidence show that organs such as the liver and kidneys can share their antioxidant activity to protect the central nervous system (CNS) against neurodegenerative diseases. The aim of this study was to examine the possible interplay of the kidneys and CNS in pathogenesis of EAE. For this purpose, EAE model was induced in C57BL/6 mice, and expression of erythropoietin (EPO), TNF-α, and NFκB-1 was determined in the kidney and CNS at early and peak stages of the disease. Besides, changes in serum level of EPO and total antioxidant capacity (TAC) were measured by different clinical scores. Real-time PCR (qPCR) results showed a substantial increase in TNF-α and NFκB-1 expression in mice at EAE peak stage compared to sham (control). There was a positive correlation between kidney-EPO and CNS-inflammatory factor expression in EAE-induced mice. In general, EPO expression was relatively higher in the kidneys compared to CNS tissue in sham group. There was a significant upregulation in expression of EPO in the brain, spinal cord, and kidneys particularly at peak stage. Accordingly, changes in serum TAC were consistent with serum EPO concentration. This data may suggest that there is an EPO-mediated cross-talk between the kidney and CNS during EAE pathogenesis.