Probiotic and commensal gut microbial therapies in multiple sclerosis and its animal models: a comprehensive review.
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ABSTRACT:
SUBMITTER: Blais LL
PROVIDER: S-EPMC8284149 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:An unmet but urgent medical need is the development of myelin repair promoting therapies for Multiple Sclerosis (MS). Many such therapies have been pre-clinically tested using different models of toxic demyelination such as cuprizone, ethidium bromide, or lysolecithin and some of the therapies already entered clinical trials. However, keeping track on all these possible new therapies and their efficacy has become difficult with the increasing number of studies. In this study, we aimed at summarizing the current evidence on such therapies through a systematic review and at providing an estimate of the effects of tested interventions by a meta-analysis. We show that 88 different therapies have been pre-clinically tested for remyelination. 25 of them (28%) entered clinical trials. Our meta-analysis also identifies 16 promising therapies which did not enter a clinical trial for MS so far, among them Pigment epithelium-derived factor, Plateled derived growth factor, and Tocopherol derivate TFA-12.We also show that failure in bench to bedside translation from certain therapies may in part be attributable to poor study quality. By addressing these problems, clinical translation might be smoother and possibly animal numbers could be reduced.
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Project description:Experimental autoimmune encephalomyelitis (EAE) is still the most widely accepted animal model of multiple sclerosis (MS). Different types of EAE have been developed in order to investigate pathogenetic, clinical and therapeutic aspects of the heterogenic human disease. Generally, investigations in EAE are more suitable for the analysis of immunogenetic elements (major histocompatibility complex restriction and candidate risk genes) and for the study of histopathological features (inflammation, demyelination and degeneration) of the disease than for screening of new treatments. Recent studies in new EAE models, especially in transgenic ones, have in connection with new analytical techniques such as microarray assays provided a deeper insight into the pathogenic cellular and molecular mechanisms of EAE and potentially of MS. For example, it was possible to better delineate the role of soluble pro-inflammatory (tumor necrosis factor-α, interferon-γ and interleukins 1, 12 and 23), anti-inflammatory (transforming growth factor-β and interleukins 4, 10, 27 and 35) and neurotrophic factors (ciliary neurotrophic factor and brain-derived neurotrophic factor). Also, the regulatory and effector functions of distinct immune cell subpopulations such as CD4+ Th1, Th2, Th3 and Th17 cells, CD4+FoxP3+ Treg cells, CD8+ Tc1 and Tc2, B cells and γδ+ T cells have been disclosed in more detail. The new insights may help to identify novel targets for the treatment of MS. However, translation of the experimental results into the clinical practice requires prudence and great caution.
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Project description:Multiple sclerosis (MS) is a demyelinating disease of the central nervous system. We and others have shown that there is enrichment or depletion of some gut bacteria in MS patients compared to healthy controls (HC), suggesting an important role of the gut bacteria in disease pathogenesis. Thus, specific gut bacteria that are lower in abundance in MS patients could be used as a potential treatment option for this disease. In particular, we and others have shown that MS patients have a lower abundance of Prevotella compared to HC, whereas the abundance of Prevotella is increased in patients that receive disease-modifying therapies such as Copaxone® (Glatiramer acetate-GA). This inverse correlation between the severity of MS disease and the abundance of Prevotella suggests its potential for use as a therapeutic option to treat MS. Notably we have previously identified a specific strain, Prevotella histicola (P. histicola), that suppresses disease in the animal model of MS, experimental autoimmune encephalomyelitis (EAE) compared with sham treatment. In the present study we analyzed whether the disease suppressing effects of P. histicola synergize with those of the disease-modifying drug Copaxone® to more effectively suppress disease compared to either treatment alone. Treatment with P. histicola was as effective in suppressing disease as treatment with Copaxone®, whereas the combination of P. histicola plus Copaxone® was not more effective than either individual treatment. P. histicola-treated mice had an increased frequency and number of CD4+FoxP3+ regulatory T cells in periphery as well as gut and a decreased frequency of pro-inflammatory IFN-γ and IL17-producing CD4 T cells in the CNS, suggesting P. histicola suppresses disease by boosting anti-inflammatory immune responses and inhibiting pro-inflammatory immune responses. In conclusion, our study indicates that the human gut commensal P. histicola can suppress disease as efficiently as Copaxone® and may provide an alternative treatment option for MS patients.
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Project description:Microglia play an essential role in maintaining central nervous system (CNS) homeostasis, as well as responding to injury and disease. Most neurological disorders feature microglial activation, a process whereby microglia undergo profound morphological and transcriptional changes aimed at containing CNS damage and promoting repair, but often resulting in overt inflammation that sustains and propagates the neurodegenerative process. This is especially evident in multiple sclerosis (MS), were microglial activation and microglia-driven neuroinflammation are considered key events in the onset, progression, and resolution of the disease. Our understanding of microglial functions in MS has widened exponentially in the last decade by way of new tools and markers to discriminate microglia from other myeloid populations. Consequently, the complex functional and phenotypical diversity of microglia can now be appreciated. This, in combination with a variety of animal models that mimic specific features and processes of MS, has contributed to filling the gap of knowledge in the cascade of events underlying MS pathophysiology. The purpose of this review is to present the most up to date knowledge of the dynamic responses of microglia in the commonly used animal models of MS, specifically the immune-mediated experimental autoimmune encephalomyelitis (EAE) model, and the chemically-induced cuprizone and lysolecithin models. Elucidating the spectrum of microglial functions in these models, from detrimental to protective, is essential to identify emerging targets for therapy and guide drug discovery efforts.
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Project description:Bacteria can be genetically engineered to kill specific pathogens or inhibit their virulence. We previously developed a synthetic genetic system that allows a laboratory strain of Escherichia coli to sense and kill Pseudomonas aeruginosa in vitro. Here, we generate a modified version of the system, including a gene encoding an anti-biofilm enzyme, and use the probiotic strain Escherichia coli Nissle 1917 as host. The engineered probiotic shows in vivo prophylactic and therapeutic activity against P. aeruginosa during gut infection in two animal models (Caenorhabditis elegans and mice). These findings support the further development of engineered microorganisms with potential prophylactic and therapeutic activities against gut infections.
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Project description:This article recapitulates the evidence on the role of mammalian targets of rapamycin (mTOR) complex pathways in multiple sclerosis (MS). Key biological processes that intersect with mTOR signaling cascades include autophagy, inflammasome activation, innate (e.g., microglial) and adaptive (B and T cell) immune responses, and axonal and neuronal toxicity/degeneration. There is robust evidence that mTOR inhibitors, such as rapamycin, ameliorate the clinical course of the animal model of MS, experimental autoimmune encephalomyelitis (EAE). New, evolving data unravel mechanisms underlying the therapeutic effect on EAE, which include balance among T-effector and T-regulatory cells, and mTOR effects on myeloid cell function, polarization, and antigen presentation, with relevance to MS pathogenesis. Radiologic and preliminary clinical data from a phase 2 randomized, controlled trial of temsirolimus (a rapamycin analogue) in MS show moderate efficacy, with significant adverse effects. Large clinical trials of indirect mTOR inhibitors (metformin) in MS are lacking; however, a smaller prospective, non-randomized study shows some potentially promising radiological results in combination with ex vivo beneficial effects on immune cells that might warrant further investigation. Importantly, the study of mTOR pathway contributions to autoimmune inflammatory demyelination and multiple sclerosis illustrates the difficulties in the clinical application of animal model results. Nevertheless, it is not inconceivable that targeting metabolism in the future with cell-selective mTOR inhibitors (compared to the broad inhibitors tried to date) could be developed to improve efficacy and reduce side effects.
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Project description:Remyelination biology and the therapeutic potential of restoring myelin sheaths to prevent neurodegeneration and disability in multiple sclerosis (MS) has made considerable gains over the past decade with many regeneration strategies undergoing tested in MS clinical trials. Animal models used to investigate oligodendroglial responses and regeneration of myelin vary considerably in the mechanism of demyelination, involvement of inflammatory cells, neurodegeneration and capacity for remyelination. The investigation of remyelination in the context of aging and an inflammatory environment are of considerable interest for the potential translation to progressive multiple sclerosis. Here we review how remyelination is assessed in mouse models of demyelination, differences and advantages of these models, therapeutic strategies that have emerged and current pro-remyelination clinical trials.
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Project description:Multiple sclerosis treatment faces tremendous changes owing to the approval of new medications, some of which are available as oral formulations. Until now, the four orally available medications, fingolimod, dimethylfumarate (BG-12), teriflunomide, and cladribine have received market authorization, whereas laquinimod is still under development. Fingolimod is a sphingosine-1-phosphate inhibitor, which is typically used as escalation therapy and leads to up to 60% reduction of the annualized relapse rate, but might also have neuroprotective properties. In addition, there are three more specific S1P agonists in late stages of development: siponimod, ponesimod, and ozanimod. Dimethylfumarate has immunomodulatory and cytoprotective functions and is used as baseline therapy. Teriflunomide, the active metabolite of the rheumatoid arthritis medication leflunomide, targets the dihydroorotate dehydrogenase, thus inhibiting the proliferation of lymphocytes by depletion of pyrimidines. Here we will review the mechanisms of action, clinical trial data, as well as data about safety and tolerability of the compounds.
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Project description:Multiple sclerosis (MS) is a chronic autoimmune disease of the central nervous system and a leading cause of neurological disability in young adults. Clinical presentation and disease course are highly heterogeneous. Typically, disease progression occurs over time and is characterized by the gradual accumulation of disability. The risk of developing MS is driven by complex interactions between genetic and environmental factors, including the gut microbiome. How the commensal gut microbiota impacts disease severity and progression over time remains unknown. In a longitudinal study, disability status and associated clinical features in 58 MS patients were tracked over 4.2 ± 0.98 years, and the baseline fecal gut microbiome was characterized via 16S amplicon sequencing. Progressor status, defined as patients with an increase in Expanded Disability Status Scale (EDSS), were correlated with features of the gut microbiome to determine candidate microbiota associated with risk of MS disease progression. We found no overt differences in microbial community diversity and overall structure between MS patients exhibiting disease progression and non-progressors. However, a total of 41 bacterial species were associated with worsening disease, including a marked depletion in Akkermansia, Lachnospiraceae, and Oscillospiraceae, with an expansion of Alloprevotella, Prevotella-9, and Rhodospirillales. Analysis of the metabolic potential of the inferred metagenome from taxa associated with progression revealed enrichment in oxidative stress-inducing aerobic respiration at the expense of microbial vitamin K2 production (linked to Akkermansia), and a depletion in SCFA metabolism (linked to Oscillospiraceae). Further, as a proof of principle, statistical modeling demonstrated that microbiota composition and clinical features were sufficient to predict disease progression. Additionally, we found that constipation, a frequent gastrointestinal comorbidity among MS patients, exhibited a divergent microbial signature compared with progressor status. These results demonstrate a proof of principle for the utility of the gut microbiome for predicting disease progression in MS in a small well-defined cohort. Further, analysis of the inferred metagenome suggested that oxidative stress, vitamin K2, and SCFAs are associated with progression, warranting future functional validation and mechanistic study.
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Project description:BackgroundThe gut microbiota (GM) constitutes a critical factor in the maintenance of physiological homeostasis. Numerous studies have empirically demonstrated that the GM is closely associated with the onset and progression of osteoporosis (OP). Nevertheless, the characteristics of the GM and its metabolites related to different forms of OP are poorly understood. In the present study, we examined the changes in the GM and its metabolites associated with various types of OP as well as the correlations among them.MethodsWe simultaneously established rat postmenopausal, disuse-induced, and glucocorticoid-induced OP models. We used micro-CT and histological analyses to observe bone microstructure, three-point bending tests to measure bone strength, and enzyme-linked immunosorbent assay (ELISA) to evaluate the biochemical markers of bone turnover in the three rat OP models and the control. We applied 16s rDNA to analyze GM abundance and employed untargeted metabolomics to identify fecal metabolites in all four treatment groups. We implemented multi-omics methods to explore the relationships among OP, the GM, and its metabolites.ResultsThe 16S rDNA sequencing revealed that both the abundance and alterations of the GM significantly differed among the OP groups. In the postmenopausal OP model, the bacterial genera g__Bacteroidetes_unclassified, g__Firmicutes_unclassified, and g__Eggerthella had changed. In the disuse-induced and glucocorticoid-induced OP models, g__Akkermansia and g__Rothia changed, respectively. Untargeted metabolomics disclosed that the GM-derived metabolites significantly differed among the OP types. However, a Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis showed that it was mainly metabolites implicated in lipid and amino acid metabolism that were altered in all cases. An association analysis indicated that the histidine metabolism intermediate 4-(β-acetylaminoethyl) imidazole was common to all OP forms and was strongly correlated with all bone metabolism-related bacterial genera. Hence, 4-(β-acetylaminoethyl) imidazole might play a vital role in OP onset and progression.ConclusionsThe present work revealed the alterations in the GM and its metabolites that are associated with OP. It also disclosed the changes in the GM that are characteristic of each type of OP. Future research should endeavor to determine the causal and regulatory effects of the GM and the metabolites typical of each form of OP.
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