scholarly journals Isoflavone diet ameliorates experimental autoimmune encephalomyelitis through modulation of gut bacteria depleted in patients with multiple sclerosis

2021 ◽  
Vol 7 (28) ◽  
pp. eabd4595
Author(s):  
Samantha N. Jensen ◽  
Nicole M. Cady ◽  
Shailesh K. Shahi ◽  
Stephanie R. Peterson ◽  
Arnav Gupta ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
Mouse Model ◽  
Experimental Autoimmune Encephalomyelitis ◽  
Gut Microbiota ◽  
Gut Microbiome ◽  
Healthy Individuals ◽  
Autoimmune Encephalomyelitis ◽  
Healthy Human ◽  
Ms Pathogenesis ◽  
Experimental Autoimmune

The gut microbiota is a potential environmental factor that influences the development of multiple sclerosis (MS). We and others have demonstrated that patients with MS and healthy individuals have distinct gut microbiomes. However, the pathogenic relevance of these differences remains unclear. Previously, we showed that bacteria that metabolize isoflavones are less abundant in patients with MS, suggesting that isoflavone-metabolizing bacteria might provide protection against MS. Here, using a mouse model of MS, we report that an isoflavone diet provides protection against disease, which is dependent on the presence of isoflavone-metabolizing bacteria and their metabolite equol. Notably, the composition of the gut microbiome in mice fed an isoflavone diet exhibited parallels to healthy human donors, whereas the composition in those fed an isoflavone-free diet exhibited parallels to patients with MS. Collectively, our study provides evidence that dietary-induced gut microbial changes alleviate disease severity and may contribute to MS pathogenesis.

scholarly journals Human gut derived Anaerotruncus colihominis ameliorates experimental autoimmune encephalomyelitis

2021 ◽  
Author(s):  
Paola Bianchimano ◽  
Graham J Britton ◽  
david Wallach ◽  
Emma Smith ◽  
Laura Cox ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
T Cells ◽  
Regulatory T Cells ◽  
Mouse Model ◽  
Experimental Autoimmune Encephalomyelitis ◽  
Gut Microbiota ◽  
Human Gut ◽  
Autoimmune Encephalomyelitis ◽  
Multiple Sclerosis Patients ◽  
Experimental Autoimmune

The gut microbiome plays an important role in autoimmunity including multiple sclerosis and its mouse model called experimental autoimmune encephalomyelitis (EAE). The gut-brain axis refers to the complex interactions between the gut microbiota and the nervous and immune systems linking brain and gut functions. Prior studies have demonstrated that the multiple sclerosis gut microbiota can contribute to disease hence making it a potential therapeutic target. Other studies have reported that long-term antibiotic therapy in multiple sclerosis patients reduces relapse rate and gadolinium enhancing lesions as well as improves measures of disability. In addition, antibiotic treatment has been shown to ameliorate disease in the EAE mouse model of multiple sclerosis. Yet, to this date, the mechanisms mediating these antibiotics effects are not understood. Furthermore, there is no consensus on the gut derived bacterial strains that drive neuroinflammation in multiple sclerosis. Hence, it remains unclear how the gut microbiota can be targeted for therapeutic purposes in multiple sclerosis patients. Here we characterized the gut microbiome of untreated and vancomycin treated EAE mice over time to identify bacteria with neuroimmunomodulatory potential. We observed alterations in the gut microbiota composition following EAE induction. We found that vancomycin treatment ameliorates EAE and that this protective effect is mediated via the microbiota. Notably, we observed increase abundance of bacteria known to be strong inducers of regulatory T cells including members of Clostridium clusters XIVa and XVIII in vancomycin-treated mice during the presymptomatic phase of EAE as well as at disease peak. We identified 50 bacterial taxa that correlate with EAE severity. Interestingly, several of these taxa exist in the human gut and some of them have been implicated in multiple sclerosis including Anaerotruncus colihominis which had a positive correlation with disease severity. Unexpectedly, we found that Anaerotruncus colihominis ameliorates EAE and this is associated with induction of RORγt+ regulatory T cells in the mesenteric lymph nodes. Together, our results identify vancomycin as a potent modulator of the gut-brain axis by promoting the proliferation of bacterial species that induce regulatory T cells. In addition, our findings reveal 50 gut commensals as regulator of the gut-brain axis that can be used to further characterize pathogenic and beneficial host-microbiota interactions in multiple sclerosis patients. Our findings suggest that elevated Anaerotruncus colihominis in multiple sclerosis patients may represent a protective mechanism associated with recovery from the disease.

scholarly journals Gut Microbiota in Multiple Sclerosis and Experimental Autoimmune Encephalomyelitis: Current Applications and Future Perspectives

2018 ◽  
Vol 2018 ◽  
pp. 1-17 ◽  
Author(s):  
Fengna Chu ◽  
Mingchao Shi ◽  
Yue Lang ◽  
Donghui Shen ◽  
Tao Jin ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
Experimental Autoimmune Encephalomyelitis ◽  
Gut Microbiota ◽  
Gut Microbiome ◽  
Gastrointestinal Microbiota ◽  
Autoimmune Encephalomyelitis ◽  
Extrinsic Factors ◽  
The Central Nervous System ◽  
Future Direction ◽  
Experimental Autoimmune

The gut environment and gut microbiome dysbiosis have been demonstrated to significantly influence a range of disorders in humans, including obesity, diabetes, rheumatoid arthritis, and multiple sclerosis (MS). MS is an autoimmune disease affecting the central nervous system (CNS). The etiology of MS is not clear, and it should involve both genetic and extrinsic factors. The extrinsic factors responsible for predisposition to MS remain elusive. Recent studies on MS and its animal model, experimental autoimmune encephalomyelitis (EAE), have found that gastrointestinal microbiota may play an important role in the pathogenesis of MS/EAE. Thus, gut microbiome adjustment may be a future direction of treatment in MS. In this review, we discuss the characteristics of the gut microbiota, the connection between the brain and the gut, and the changes in gut microbiota in MS/EAE, and we explore the possibility of applying microbiota therapies in patients with MS.

scholarly journals Protection of Fecal Microbiota Transplantation in a Mouse Model of Multiple Sclerosis

2020 ◽  
Vol 2020 ◽  
pp. 1-13
Author(s):  
Kanglan Li ◽  
Shouchao Wei ◽  
Li Hu ◽  
Xiaojian Yin ◽  
Yingren Mai ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
Mouse Model ◽  
Experimental Autoimmune Encephalomyelitis ◽  
Gut Microbiota ◽  
Effective Treatment ◽  
Therapeutic Approach ◽  
Fecal Microbiota Transplantation ◽  
Fecal Microbiota ◽  
Autoimmune Encephalomyelitis ◽  
Experimental Autoimmune

Given the growing evidence of a link between gut microbiota (GM) dysbiosis and multiple sclerosis (MS), fecal microbiota transplantation (FMT), aimed at rebuilding GM, has been proposed as a new therapeutic approach to MS treatment. To evaluate the viability of FMT for MS treatment and its impact on MS pathology, we tested FMT in mice with experimental autoimmune encephalomyelitis (EAE), a mouse model of MS. We provide evidence that FMT can rectify altered GM to some extent with a therapeutic effect on EAE. We also found that FMT led to reduced activation of microglia and astrocytes and conferred protection on the blood-brain barrier (BBB), myelin, and axons in EAE. Taken together, our data suggest that FMT, as a GM-based therapy, has the potential to be an effective treatment for MS.

scholarly journals The S100B Inhibitor Pentamidine Ameliorates Clinical Score and Neuropathology of Relapsing—Remitting Multiple Sclerosis Mouse Model

Cells ◽  
2020 ◽  
Vol 9 (3) ◽  
pp. 748 ◽  
Author(s):  
Gabriele Di Sante ◽  
Susanna Amadio ◽  
Beatrice Sampaolese ◽  
Maria Elisabetta Clementi ◽  
Mariagrazia Valentini ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
Mouse Model ◽  
Experimental Autoimmune Encephalomyelitis ◽  
Clinical Score ◽  
Autoimmune Encephalomyelitis ◽  
Experimental Autoimmune Encephalomyelitis Mouse ◽  
Extracellular Signaling ◽  
Relapsing Remitting ◽  
Inflammatory Processes ◽  
Experimental Autoimmune

S100B is an astrocytic protein acting either as an intracellular regulator or an extracellular signaling molecule. A direct correlation between increased amount of S100B and demyelination and inflammatory processes has been demonstrated. The aim of this study is to investigate the possible role of a small molecule able to bind and inhibit S100B, pentamidine, in the modulation of disease progression in the relapsing–remitting experimental autoimmune encephalomyelitis mouse model of multiple sclerosis. By the daily evaluation of clinical scores and neuropathologic-molecular analysis performed in the central nervous system, we observed that pentamidine is able to delay the acute phase of the disease and to inhibit remission, resulting in an amelioration of clinical score when compared with untreated relapsing–remitting experimental autoimmune encephalomyelitis mice. Moreover, we observed a significant reduction of proinflammatory cytokines expression levels in the brains of treated versus untreated mice, in addition to a reduction of nitric oxide synthase activity. Immunohistochemistry confirmed that the inhibition of S100B was able to modify the neuropathology of the disease, reducing immune infiltrates and partially protecting the brain from the damage. Overall, our results indicate that pentamidine targeting the S100B protein is a novel potential drug to be considered for multiple sclerosis treatment.

scholarly journals Neural stem cells reversed disease symptoms in an experimental autoimmune encephalomyelitis mouse model of multiple sclerosis

2021 ◽  
Author(s):  
Christina Brown ◽  
Christina McKee ◽  
Sophia Halassy ◽  
Suleiman Kojan ◽  
Douglas Feinstein ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
Stem Cells ◽  
Mouse Model ◽  
Experimental Autoimmune Encephalomyelitis ◽  
Neural Stem Cells ◽  
Cell Transplantation ◽  
Blue Staining ◽  
Autoimmune Encephalomyelitis ◽  
Disease Symptoms ◽  
Experimental Autoimmune

Abstract Background Multiple sclerosis (MS) is an autoimmune inflammatory disease of the central nervous system (CNS). MS affects millions of people and causes a great economic and societal burden. Currently used treatment drugs have side effects and only address the symptoms but not the causes of MS. In this study, a novel approach of transplanting neural stem cells (NSCs) derived from human primitive mesenchymal stem cells (MSCs) was investigated in an experimental autoimmune encephalomyelitis (EAE) mouse model of MS. Methods Primitive MSCs were differentiated into NSCs using selective media. The cells were labeled with PKH26 and injected into the tail vein of EAE mice. The animals were evaluated for changes in neurobehavior and weight twice daily. Two weeks following cell transplantation, the animals were sacrificed to collect the blood, lymphatic and CNS tissues for analysis. FACS analysis was used to track labeled cells and infiltrates. Histochemical analysis was performed to determine the levels of myelination. Expression of inflammation, neural, astrogliosis, neuroprotection, and myelination markers was investigated by using immunohistochemical and qRT-PCR analyses. Results Neurobehavioral assays showed that EAE disease process was halted by transplantation of both MSCs and NSCs. However, NSCs showed greater efficacy in reversing the disease symptoms, which resulted in near complete recovery of EAE animals. Post-transplantation analyses also showed homing of transplanted cells into the CNS with concomitant induction of anti-inflammatory response resulting in reduction of immune infiltrates. Luxol fast blue staining intensity of CNS tissues was significantly improved in treated mice as compared to EAE animals, suggesting endogenous remyelination. NSC transplantation also modulated Treg and Th17 cells in EAE mice to levels comparable to healthy controls. In addition, several of the markers associated with neuroprotection (i.e. Igf, Bdnf, and Trkb), myelination (i.e. Erk2, Krox-20, Oct-6, Mpz, Mbp, and Mog) and neurogenesis (i.e. Tuj1 and Nestin) were upregulated, suggesting endogenous regeneration in treated animals. Conclusions Cell transplantation was more effective at an earlier point of EAE disease (EAE stage 1) than later (EAE stage 2). These promising results provide basis for large-scale clinical studies to treat MS using NSCs derived from primitive MSCs.

scholarly journals Loss of HDAC11 ameliorates clinical symptoms in a multiple sclerosis mouse model

2018 ◽  
Vol 1 (5) ◽  
pp. e201800039 ◽  
Author(s):  
Lei Sun ◽  
Elphine Telles ◽  
Molly Karl ◽  
Fengdong Cheng ◽  
Noreen Luetteke ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
Mouse Model ◽  
Experimental Autoimmune Encephalomyelitis ◽  
Immune Cell ◽  
Demyelinating Disease ◽  
Demyelinating Diseases ◽  
Clinical Severity ◽  
Autoimmune Encephalomyelitis ◽  
Immune Mediated ◽  
Experimental Autoimmune

Multiple sclerosis (MS) is a chronic, immune-mediated, demyelinating disease of the central nervous system (CNS). There is no known cure for MS, and currently available drugs for managing this disease are only effective early on and have many adverse side effects. Results from recent studies suggest that histone deacetylase (HDAC) inhibitors may be useful for the treatment of autoimmune and inflammatory diseases such as MS. However, the underlying mechanisms by which HDACs influence immune-mediated diseases such as MS are unclear. More importantly, the question of which specific HDAC(s) are suitable drug targets for the potential treatment of MS remains unanswered. Here, we investigate the functional role of HDAC11 in experimental autoimmune encephalomyelitis, a mouse model for MS. Our results indicate that the loss of HDAC11 in KO mice significantly reduces clinical severity and demyelination of the spinal cord in the post-acute phase of experimental autoimmune encephalomyelitis. The absence of HDAC11 leads to reduced immune cell infiltration into the CNS and decreased monocytes and myeloid DCs in the chronic progressive phase of the disease. Mechanistically, HDAC11 controls the expression of the pro-inflammatory chemokine C–C motif ligand 2 (CCL2) gene by enabling the binding of PU.1 transcription factor to the CCL2 promoter. Our results reveal a novel pathophysiological function for HDAC11 in CNS demyelinating diseases, and warrant further investigations into the potential use of HDAC11-specific inhibitors for the treatment of chronic progressive MS.

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