Mini Review

Combination of Probiotics and Natural Compounds to Treat Multiple Sclerosis via Warburg Effect

Introduction

Multiple sclerosis (MS) is an auto-immune disorder, in which our immune system attacks our healthy myelin sheath in the brain, spinal cord and the optic nerves get degraded. It alters the signal transduction of the brain. Approximately, 2.5 million people are typically affected by MS worldwide. ¹ Epidemiologic researches have revealed precisely that females are more affected by MS than males. ² MS arises with relapsing-remitting MS and drives to a chronic neuro-degenerative condition, known as primary and secondary progressive MS. ³ Due to the unique characteristics of MS, its symptoms are diverse. 80% of MS patients experience fatigue, unusual or excessive whole-body tiredness. It can severely affect a person’s fundamental quality of successful life. This prominently includes the somatic symptoms such as motility difficulties, fatigue, weakness, visual dilemmas, reproductive problems, psychological symptoms such as depression, anxiety, mental issues and neuro-cognitive symptoms such as: lack of attentiveness, memory, language and processing speed. ⁴ The pathology of MS include various factors. ⁵ The activated cytotoxic T cells infiltrate into the blood-brain barrier (BBB) and react defensively against the myelin sheath due to the activation of microglia and macrophages. ⁶ When the myelin steadily and continuously gets destroyed, nerve signals become moderate or may even cease, which prompt neurological problems. BBB is designed by a specific endothelial cell without membrane pores which are sealed with tight junctions. ⁷ In MS, the stimulated leukocytes can enhance the membrane permeability of the BBB by the expression and secretion of inflammatory cytokines, soluble constituents, reactive oxygen species and matrix metalloproteinase. ⁸ Warburg effect plays a chief role in demyelination and disease progression. Wnt-signaling pathway (especially β-catenin, Wnt3a and APC protein expression), ⁹ JAK/STAT signaling pathway, ¹⁰ NF-kB signaling pathway ¹¹ and PImT3K/Akt/mTOR pathway ¹² are highly expressed in MS lesions.

Different medications are available for the treatment of MS which includes: orals (fingolimod, teriflunomide and dimethyl fumarate), injectable-(interferons, glatiramer acetate and mitoxantrone), monoclonal antibodies (natalizumab, alemtuzumab, daclizumab and ocrelizumab). ¹³ Although, certain medicines are not safe in the long-term as they cause severe side effects. Herbal therapies and probiotic supplements seem to be more efficient in the treatment of MS. The medicinal plants reduce neuronal inflammation and improve the quality of sleep, ease muscle stiffness and reduce bladder trouble. ¹⁴ Probiotics in turn, equally possess significant functions in defeating autoimmune disorder and gut dysbiosis. ¹⁵ Hence, the use of sufficient Probiotics and herbal medicine can reduce the inflammation in the central nervous system (CNS) without any severe side effects. Phytochemicals in the plants act as prebiotics. In this review, we seek to discuss the possibilities of combination therapy using probiotics and medicinal plants as prebiotics for the treatment of MS.

Warburg effect in multiple sclerosis

The human brain uses one half of all the glucose in the body for the growth of nerve cells. Glucose molecules are delivered to astrocytes and oligodendrocytes by glucose transport protein (Glut-1). If the glucose levels get reduced, the signal transduction will be interrupted. Oligodendrocytes, the myelin precursor cells, oxidize glucose into lactate through a lactate shuttle system. It is then converted into pyruvate by the enzyme lactate dehydrogenase. Later, pyruvate molecules get oxidized in mitochondria by oxidative phosphorylation for the synthesis of high-energy ATP molecules. ¹⁶ However, in MS cells, an enormous volume of cytosolic pyruvate is transformed into lactate, even in the presence of sufficient oxygen. This metabolic shift is defined as the Warburg effect. ¹⁷ Aerobic glycolysis produce two molecules of ATP per cycle when compared to oxidative phosphorylation. Studies reveal that ATP generation per cycle in aerobic glycolysis is extremely quicker than the mitochondrial oxidative phosphorylation and produces more ATP which can be utilized for the activation of T-cells. ¹⁸ Activated T-cells infiltrate into BBB and stimulates the autoimmune mechanism and hence causes the myelin degeneration and axonal destruction.

The brain occupies 2% of total body weight and utilizes about 20% of the entire glucose and oxygen. Glucose transporters will adequately provide ample glucose molecules to the nerve cells. ¹⁹ Cytosolic pyruvate cannot oxidize further and becomes reduced to lactate under hypoxia. ²⁰ Hypoxia inducing factor-α (HIF-1α) induces pyruvate dehydrogenase kinase1 for inhibiting the catalytic activity of PDH by phosphorylating it, utilizing active ATP molecule. The activated immune cells stimulates the autoimmune mechanism of the transcription factor NF-κB for the continuous production of pro-inflammatory cytokines, interleukin-1β (IL-1β) and tumor necrosis factor-α (TNF). ²¹ These cytokines trigger the metabolic shift from oxidative phosphorylation to aerobic glycolysis. ²² The membrane-bound receptors TLR2, TLR4 and TLR9 properly promote the glucose transporter GLUT1 for more glucose uptake for the lactate production. ²³ The bulk production of lactate leads to neuronal death and myelin damage in MS. ²⁴ During the MS condition, the homeostasis of energy metabolism is impaired by mitochondrial dysfunction with limiting oxidative-phosphorylation. ²⁵ The precipitous rise in lactate molecules, may typically trigger the progression of MS cells. In investigations, it is evident that the lactate levels are increased in MS lesions. It is undoubtedly the reason for mitochondrial dysfunction and neuroinflammation. ^26,27 The Warburg effect mediated demyelinating process in MS is explained in .

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Figure 1. Warburg effect in MS.

Altered immune mechanism via Warburg effect

In MS, the immune cells (specialized CD4+T cells and B cells) become stimulated in the peripheral lymph tissues and penetrate into the CNS through BBB. Activated immune cells secrete cytokines to induce inflammation in CNS. The stimulated immune cells precisely require more energy in the form of ATP. For getting sufficient quantities of energy, T-cells modify their energy metabolism through Warburg effect which instantly follows aerobic glycolysis for the rapid production of ATP and other metabolic intermediates. ²³ Activated T-cells in MS convert pyruvate into lactate. ²⁸ Normal T-cells generate ATP through catabolism of glucose, amino acids and lipids and mainly oxidative phosphorylation. But the activated T cells shift the glucose metabolism to aerobic glycolysis (Warburg effect) for energy production. ²⁹ Immune activated T cells are divided into several subunits which includes cell-mediated immune response (specialized Th1 cells), humoral immunity (specialized Th2 cells), active inflammation (specialized Th17 cells) and regulatory T cells. Specialized Th17 cells participate in neuroinflammation and secrete cytokine IL-17. ³⁰ Bulk production of lactate provoke the gene modification of cytotoxic T-cells as illustrated in . Pro-inflammatory mediators, such as cytokines, interleukins (IL-6, IL-17, IL-22), TNF-α are synthesized by T-cells.

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Figure 2. Factors involving demyelination process. 31

Each stimulated B-cell acts as the antigen-presenting cells and later they will be transformed into plasmacytes for the secretion of demyelinating antibodies. Gradual infiltration of B cells and specific T cells into the CNS provoke the immune response of TLR receptors. ³² These receptors, TLR2 and TLR4 enhance the functional differentiation of T-cells into Th-1. Specialized Th-17 cells secrete IL1, IL6 and IL12. Th1 and specialized Th17 cells are liable for the secretion of the cytokines Interferon gamma (IFN-γ) and IL17, which leads to the neuronal inflammation. ³³ TLR3 induces NF-kB pathway through the expressed TRIF protein for the secretion of type 1 IFNs. ³⁴ IFN-β represents a distinct type-1 IFN which is reliably used for the treatment of relapsing-remitting MS, upon the cognitive stimulation of innate immune responses. ³⁵

Signaling pathways in MS

During MS the Wnt/Catenin, JAK/STAT, NF-kB and PI3/AKT/mTOR signaling pathways are over expressed. Wnt signaling pathway inhibits the pyruvate oxidation by delivering the factors such as PDK1, Myc gene and the lactate transporter MCT-1. ¹⁵ Wnt/Catenin and PI3/AKT/mTOR pathways elevate the glucose uptake for sustaining the aerobic glycolysis. ¹⁷ The stimulated PI3/AKT/mTOR pathway induces HIF-1α, which defeats oxidative phosphorylation. ¹³ PPARγ, a transcription factor, which regulates glucose metabolism and cellular homeostasis. WNT ligands belong to the family of glycoproteins concurring in the chief regulator of the cell cycle, cell regulation and embryogenesis. ³⁶ Altered PPAR ³⁷ and WNT/catenin ³⁸ signaling pathways trigger demyelination through the Warburg effect. ³⁹ The JAK/STAT pathway is important for the potential development of both adaptive and innate immunity. ^40,41 This specific pathway, abnormally expressed in MS, particularly STAT3 and STAT4 which releases cytokines for the extensive development of lesions on myelin sheath. ^42-45 IL-1β and TNF-α elevates the optimum levels of NF-kB in MS. ^46,47 INF-γ is one of the major pro-inflammatory cytokines observed in MS lesions secreted by T cells, NK cells and macrophages. ⁴⁸ By targeting the NF-kB along with its novel inhibitors, it can diminish the pro-inflammatory T-cell responses and thus resist MS. ⁴⁹

Enhanced levels of PI3/AKT/mTOR pathway remains a prominent sign of adaptive auto-immunity because it regulates the T-cell activation, proliferation, and apoptosis. ^50,51 The apparent magnitude of mTOR immune activation is directly proportional to the communication between immune T cells and dendritic cells. ⁵² The enhanced mTOR signaling is observed only in the initial states of oligodendrocytes formation and not during the maturation phases. ⁵³ Hence, targeting the PI3K/mTOR pathway might not represent a beneficial strategy for the remyelination method, however, it could slow down/ reduce the MS progression. ¹² These signaling pathways are summarized in Table 1.

Use of natural compounds in the treatment of MS

Herbal therapies used for the treatment of MS, are effectively tested in animals and humans. ⁵⁴ It is possible to treat the usualsymptoms of MS effectively by practicing herbal medicines which have anti-inflammatory and antioxidant qualities to stop the myelin sheath destruction without side effects. Phytochemicals are the bio-active compounds naturally found in plants and act as prebiotics. Some of the bioactive compounds present in medicinal plants are listed in Table 2.

Polymerized form of Nano-curcumin reduces the BBB damage, active inflammation and demyelination through enhanced remyelination and reduced oxidative stress. ⁵⁵ Cannabis extract reduces the pain, and spasticity associated challenges in MS. ⁵⁶ Oral administration of epigallocatechin-3-gallate, a naturally derived Catechin of green tea, along with regular exercise improves the muscular metabolism in MS patients. ⁵⁷ Crocus sativus L. extracts inhibit MS progression by restraining oxidative stress and leukocyte infiltration to CNS. ⁵⁸ Ginger extract modulates the expression of IL-27 and IL-33 for the reduced infiltration of inflammatory immune cells into the CNS. ⁵⁹ Andrographis paniculata minimizes the fatigue associated with MS. ⁶⁰ The treatment using Dendropanaxmorbiferus leaf extract enhances the oligodendrocyte regeneration in MS patients. ⁶¹ The fruit extracts of Terminalia ferdinandiana inhibit the growth of bacterial species which triggers autoimmune response. ⁶² Treatment using Boswellia papyrifera improves the visual and spatial memory of MS patients. ⁶³ Scrophulariamegalantha extract inhibits the secretion of IFN-γ and IL-17 and increases the formation of IL-10. ⁶⁴ The treatment using ethanolic extract of saffronagainst memory loss and oxidative stress, improves the cognitive performance of learning and memory in animal MS models. ⁶⁵ The active treatment of MS mice model using resveratrol ameliorates mitochondrial function, reduces oxidative stress, enhances motor co-ordination, activates remyelination through boosting the expression of Olig1 gene and irreversibly inhibits the signaling pathway of NF-κB. ⁶⁶ Another study of resveratrolexhibits higher neuro protection and improved mitochondrial function by the activation of novel SIRT1 mechanism and NAD⁺ dependent deacetylase pathway. ⁶⁷ Cannabis extract shows relief from pain and muscle stiffness in MS patients. ⁶⁸ Curcumin extracts protects axons from degeneration by inhibiting microglial MyD88/p38 MAPK signaling. ⁶⁹

Probiotics for the treatment of MS

Probiotics comprise vital microbial species which can modulate the immune responses of the host organism healthily by producing antimicrobial agents as bacteriocins. ⁷⁰ There are thousands of microbial species in the human gut. Bacteroidetes and Firmicutes are the two principal phyla of healthy gut microbiome. The gut microbiome altered in MS. Probiotics can naturally provoke the anti-inflammatory peripheral immune response in MS patients. Modulating the gut microbiome using probiotics is beneficial to MStreatment. ⁷¹ Some of them are noted in Table 3.

Administration of VSL3 probiotics mixture comprising of Lactobacillus, Bifidobacterium and Streptococcus in MS patients, switches their gut microbiota to modulate the anti-inflammatory peripheral innate immune response by regulating the intermediate monocytes. ⁷² Lactobacillus paracasei and L. Plantarum reduces the CNS inflammation by inhibition of pro-inflammatory Th1 and Th17 cytokines in MS. ⁷³ Lactobacillus reuteri mediated treatment of MS changes the gut microbiota and modulates Th1 and Th17 and their associated cytokines. ⁷⁴ The combined effect of Lactobacillus plantarum A7 and Bifidobacterium animalis strains inhibit MS progression by regulating the inflammatory T-cells infiltration into the CNS. ⁷⁵ Saccharomyces boulardii, a yeast-derived probiotic reduces the CNS inflammation, fatigue, pain and oxidative stress in MS patients. ²⁴ Oral administration of Lactobacillus acidophilus, Lactobacillus casei, Bifidobacterium bifidum and Lactobacillus fermentum probiotics inhibits the gene expressions of IL-8 and TNF-α in MS patients. ⁷⁶ Lactobacillus casei, Lactobacillus acidophilus, Lactobacillus reuteri, Bifidobacterium bifidum and Streptococcus thermophilus which slows down the pro-inflammatory Th1/Th17 polarization. ⁷⁷

Lactobacillus plantarum and Bifidobacterium B94 combined treatment promote spatial memory in MS. ⁷⁸ Treatment using probiotic capsules which contain Lactobacillus acidophilus, Lactobacillus casei, Bifidobacterium bifidum and Lactobacillus fermentum shows improvement in mental health and elevated HDL- cholesterol levels. ⁷⁹ A clinical trial treatment using probiotics capsule containing Bifidobacterium infantis, Bifidobacterium lactis, Lactobacillus reuteri, Lactobacillus casei, Lactobacillus plantarum and Lactobacillus fermentum progressively reduced the clinical symptoms and decreased the levels of high‐sensitivity C‐reactive protein and IL-6. Probiotics irreversibly inhibit the inflammatory cytokines and simultaneously increase the anti-inflammatory cytokine IL-10. ⁸⁰ Treatment using Streptococcus thermophilus as probiotics inhibited the secretion of pro-inflammatory cytokines IL-1β and IFN-γ and also enhanced the secretion of anti-inflammatory cytokines IL-4, IL-5, IL-10 in MS-induced mice model. ⁸¹

Prebiotics and probiotics in MS

MS is significantly associated with excess inflammation in the brain and spinal cord. Various studies sufficiently revealed, that gut microbiome is altered in MS patients. ^{24,72,76,79–81} It is proved that some bio-active compounds produce excessive neuro-protective activity against MS. ^{56,57,61,64,69} Prebiotics serve as good food for probiotics. Active inflammation in MS might be due to the profound alterations in the gut microbiome. Recently, various clinical trials were ongoing in this specialized field, and waiting for good results. ^82,83

Conclusion

The metabolic alterations in MS scientifically proved the significant role of Warburg effect in it. The demyelinating process is started by the immune activation of inflammatory CD4+ and CD8+ lymphocytes cells in the peripheral lymph nodes through the Warburg effect. The stimulated T-cells then differentiate into the Th1, Th17, Th2 and T regulatory cells. Cytotoxic Th1 lymphocytes are responsible for the continuous production of IL-2 and IFN-γ, which triggers cellular immune responses. Th17 lymphocytes trigger active inflammation through the secretion of cytokines IL-17. Cytotoxic Th2 lymphocytes and T regulatory cells secrete IL-4 and IL-10, which mediates humoral immune responses and generate anti-inflammatory cytokines. The activated B cells (antigen-presenting cells) are transformed into plasma cells for the production of demyelinating antibodies. When the immune cells become active, they forcibly displace oxidative phosphorylation to the aerobic glycolysis. Various metabolic pathways (Wnt/catenin, JAK/STAT pathway, NF-kB signaling pathway and direct PI3/AKT/mTOR pathway) are altered in MS.

The enhanced lactate production via aerobic glycolysis may induce T-cell activation. Activated T-cells are the major reason for myelin destruction. The BBB membrane permeability is progressively increased by these activated T-cells. Thus the reactive T-cells and B-cells migrate into the CNS through BBB and trigger the inflammation process on the myelin sheath. The inflammation process easily spreads by gradual infiltration of macrophages and monocytes into the CNS. The myelin attack leads to CNS damage. Gut microbiota can influence the brain. Any alteration in the gut microbiome can indirectly affect the immune system. Thus, probiotics can be used as an immunomodulatory substitute for the treatment of MS. Various studies, convincingly show that anti-inflammatory elements in the medicinal plants naturally have MS healing effect. Consequently, by this review, we can delicately suggest that more researches are needed for identifying the beneficial part of this combinational therapy of probiotics and medicinal plant extracts against MS. Prebiotics and Probiotics treatment can be prominently used as an efficient adjuvant therapy against MS.

Acknowledgments

The manuscript was not financed from any source.

Ethical Issues

This work does not contain any studies with animals or human participants conducted by any of the authors.

Conflict of Interest

The authors declare no conflict of interest in this study.

References

1. Browne P, Chandraratna D, Angood C, Tremlett H, Baker C, Taylor BV. Atlas of multiple sclerosis 2013: a growing global problem with widespread inequity. Neurology 2014; 83(11):1022-4. doi: 10.1212/wnl.0000000000000768 [Crossref]
2. Koch-Henriksen N, Sørensen PS. The changing demographic pattern of multiple sclerosis epidemiology. Lancet Neurol 2010; 9(5):520-32. doi: 10.1016/s1474-4422(10)70064-8 [Crossref]
3. Ebers GC. Prognostic factors for multiple sclerosis: the importance of natural history studies. J Neurol 2005; 252 Suppl 3:iii15-iii20. doi: 10.1007/s00415-005-2012-4 [Crossref]
4. Crespo-Bujosa HB, Gonzalez MJ. Phytochemicals for the treatment of multiple sclerosis? A review of scientific evidence. J Orthomol Med 2018; 33(1):1-8.
5. Baumann N, Pham-Dinh D. Biology of oligodendrocyte and myelin in the mammalian central nervous system. Physiol Rev 2001; 81(2):871-927. doi: 10.1152/physrev.2001.81.2.871 [Crossref]
6. Hohlfeld R, Wekerle H. Autoimmune concepts of multiple sclerosis as a basis for selective immunotherapy: from pipe dreams to (therapeutic) pipelines. Proc Natl Acad Sci U S A 2004; 101(Suppl 2):14599-606. doi: 10.1073/pnas.0404874101 [Crossref]
7. Loch-Neckel G, Koepp J. [The blood-brain barrier and drug delivery in the central nervous system]. Rev Neurol 2010; 51(3):165-74.
8. Larochelle C, Alvarez JI, Prat A. How do immune cells overcome the blood-brain barrier in multiple sclerosis?. FEBS Lett 2011; 585(23):3770-80. doi: 10.1016/j.febslet.2011.04.066 [Crossref]
9. Fünfschilling U, Supplie LM, Mahad D, Boretius S, Saab AS, Edgar J. Glycolytic oligodendrocytes maintain myelin and long-term axonal integrity. Nature 2012; 485(7399):517-21. doi: 10.1038/nature11007 [Crossref]
10. Pfeiffer T, Schuster S, Bonhoeffer S. Cooperation and competition in the evolution of ATP-producing pathways. Science 2001; 292(5516):504-7. doi: 10.1126/science.1058079 [Crossref]
11. Han MH, Hwang SI, Roy DB, Lundgren DH, Price JV, Ousman SS. Proteomic analysis of active multiple sclerosis lesions reveals therapeutic targets. Nature 2008; 451(7182):1076-81. doi: 10.1038/nature06559 [Crossref]
12. Benveniste EN, Liu Y, McFarland BC, Qin H. Involvement of the janus kinase/signal transducer and activator of transcription signaling pathway in multiple sclerosis and the animal model of experimental autoimmune encephalomyelitis. J Interferon Cytokine Res 2014; 34(8):577-88. doi: 10.1089/jir.2014.0012 [Crossref]
13. Leibowitz SM, Yan J. NF-κB pathways in the pathogenesis of multiple sclerosis and the therapeutic implications. Front Mol Neurosci 2016; 9:84. doi: 10.3389/fnmol.2016.00084 [Crossref]
14. Mammana S, Bramanti P, Mazzon E, Cavalli E, Basile MS, Fagone P. Preclinical evaluation of the PI3K/Akt/mTOR pathway in animal models of multiple sclerosis. Oncotarget 2018; 9(9):8263-77. doi: 10.18632/oncotarget.23862 [Crossref]
15. Bhatia R, Singh N. Multiple sclerosis: newer concepts on pathophysiology, diagnostic criteria and therapeutics. Astrocyte 2018; 5(1):43-54. doi: 10.4103/astrocyte.astrocyte_51_18 [Crossref]
16. Mojaverrostami S, Nazm Bojnordi M, Ghasemi-Kasman M, Ebrahimzadeh MA, Ghasemi Hamidabadi H. A review of herbal therapy in multiple sclerosis. Adv Pharm Bull 2018; 8(4):575-90. doi: 10.15171/apb.2018.066 [Crossref]
17. Jangi S, Gandhi R, Cox LM, Li N, von Glehn F, Yan R. Alterations of the human gut microbiome in multiple sclerosis. Nat Commun 2016; 7:12015. doi: 10.1038/ncomms12015 [Crossref]
18. Ngo DC, Ververis K, Tortorella SM, Karagiannis TC. Introduction to the molecular basis of cancer metabolism and the Warburg effect. Mol Biol Rep 2015; 42(4):819-23. doi: 10.1007/s11033-015-3857-y [Crossref]
19. Magistretti PJ, Allaman I. Lactate in the brain: from metabolic end-product to signalling molecule. Nat Rev Neurosci 2018; 19(4):235-49. doi: 10.1038/nrn.2018.19 [Crossref]
20. Otto AM. Warburg effect(s)-a biographical sketch of Otto Warburg and his impacts on tumor metabolism. Cancer Metab 2016; 4:5. doi: 10.1186/s40170-016-0145-9 [Crossref]
21. Dinarello CA, Simon A, van der Meer JW. Treating inflammation by blocking interleukin-1 in a broad spectrum of diseases. Nat Rev Drug Discov 2012; 11(8):633-52. doi: 10.1038/nrd3800 [Crossref]
22. Krawczyk CM, Holowka T, Sun J, Blagih J, Amiel E, DeBerardinis RJ. Toll-like receptor-induced changes in glycolytic metabolism regulate dendritic cell activation. Blood 2010; 115(23):4742-9. doi: 10.1182/blood-2009-10-249540 [Crossref]
23. Palsson-McDermott EM, O’Neill LA. The Warburg effect then and now: from cancer to inflammatory diseases. Bioessays 2013; 35(11):965-73. doi: 10.1002/bies.201300084 [Crossref]
24. Aghamohammadi D, Ayromlou H, Dolatkhah N, Jahanjoo F, Shakouri SK. The effects of probiotic Saccharomyces boulardii on the mental health, quality of life, fatigue, pain, and indices of inflammation and oxidative stress in patients with multiple sclerosis: study protocol for a double-blind randomized controlled clinical trial. Trials 2019; 20(1):379. doi: 10.1186/s13063-019-3454-9 [Crossref]
25. Nijland PG, Molenaar RJ, van der Pol SM, van der Valk P, van Noorden CJ, de Vries HE. Differential expression of glucose-metabolizing enzymes in multiple sclerosis lesions. Acta NeuropatholCommun 2015; 3:79. doi: 10.1186/s40478-015-0261-8 [Crossref]
26. Schocke MF, Berger T, Felber SR, Wolf C, Deisenhammer F, Kremser C. Serial contrast-enhanced magnetic resonance imaging and spectroscopic imaging of acute multiple sclerosis lesions under high-dose methylprednisolone therapy. Neuroimage 2003; 20(2):1253-63. doi: 10.1016/s1053-8119(03)00409-9 [Crossref]
27. Peruzzotti-Jametti L, Pluchino S. Targeting mitochondrial metabolism in neuroinflammation: towards a therapy for progressive multiple sclerosis. Trends Mol Med 2018; 24(10):838-55. doi: 10.1016/j.molmed.2018.07.007 [Crossref]
28. Jones RG, Thompson CB. Revving the engine: signal transduction fuels T cell activation. Immunity 2007; 27(2):173-8. doi: 10.1016/j.immuni.2007.07.008 [Crossref]
29. Vander Heiden MG, Cantley LC, Thompson CB. Understanding the Warburg effect: the metabolic requirements of cell proliferation. Science 2009; 324(5930):1029-33. doi: 10.1126/science.1160809 [Crossref]
30. Brucklacher-Waldert V, Stuerner K, Kolster M, Wolthausen J, Tolosa E. Phenotypical and functional characterization of T helper 17 cells in multiple sclerosis. Brain 2009; 132(Pt 12):3329-41. doi: 10.1093/brain/awp289 [Crossref]
31. De Riccardis L, Rizzello A, Ferramosca A, Urso E, De Robertis F, Danieli A. Bioenergetics profile of CD4(+) T cells in relapsing remitting multiple sclerosis subjects. J Biotechnol 2015; 202:31-9. doi: 10.1016/j.jbiotec.2015.02.015 [Crossref]
32. Zekki H, Feinstein DL, Rivest S. The clinical course of experimental autoimmune encephalomyelitis is associated with a profound and sustained transcriptional activation of the genes encoding toll-like receptor 2 and CD14 in the mouse CNS. Brain Pathol 2002; 12(3):308-19. doi: 10.1111/j.1750-3639.2002.tb00445.x [Crossref]
33. Miranda-Hernandez S, Baxter AG. Role of toll-like receptors in multiple sclerosis. Am J Clin Exp Immunol 2013; 2(1):75-93.
34. Nagyoszi P, Wilhelm I, Farkas AE, Fazakas C, Dung NT, Haskó J. Expression and regulation of toll-like receptors in cerebral endothelial cells. Neurochem Int 2010; 57(5):556-64. doi: 10.1016/j.neuint.2010.07.002 [Crossref]
35. Comabella M, Lünemann JD, Río J, Sánchez A, López C, Julià E. A type I interferon signature in monocytes is associated with poor response to interferon-beta in multiple sclerosis. Brain 2009; 132(Pt 12):3353-65. doi: 10.1093/brain/awp228 [Crossref]
36. Vallée A, Lecarpentier Y, Guillevin R, Vallée JN. Demyelination in multiple sclerosis: reprogramming energy metabolism and potential PPARγ agonist treatment approaches. Int J Mol Sci 2018; 19(4):1212. doi: 10.3390/ijms19041212 [Crossref]
37. Lecarpentier Y, Krokidis X, Martin P, Pineau T, Hébert JL, Quillard J. Increased entropy production in diaphragm muscle of PPAR alpha knockout mice. J Theor Biol 2008; 250(1):92-102. doi: 10.1016/j.jtbi.2007.09.022 [Crossref]
38. Rone MB, Cui QL, Fang J, Wang LC, Zhang J, Khan D. Oligodendrogliopathy in multiple sclerosis: low glycolytic metabolic rate promotes oligodendrocyte survival. J Neurosci 2016; 36(17):4698-707. doi: 10.1523/jneurosci.4077-15.2016 [Crossref]
39. Thompson CB. Wnt meets Warburg: another piece in the puzzle?. EMBO J 2014; 33(13):1420-2. doi: 10.15252/embj.201488785 [Crossref]
40. Yuan S, Shi Y, Tang SJ. Wnt signaling in the pathogenesis of multiple sclerosis-associated chronic pain. J Neuroimmune Pharmacol 2012; 7(4):904-13. doi: 10.1007/s11481-012-9370-3 [Crossref]
41. Ransohoff RM, Brown MA. Innate immunity in the central nervous system. J Clin Invest 2012; 122(4):1164-71. doi: 10.1172/jci58644 [Crossref]
42. O’Shea JJ, Kontzias A, Yamaoka K, Tanaka Y, Laurence A. Janus kinase inhibitors in autoimmune diseases. Ann Rheum Dis 2013; 72 Suppl 2:ii111-5. doi: 10.1136/annrheumdis-2012-202576 [Crossref]
43. Zaheer S, Wu Y, Bassett J, Yang B, Zaheer A. Glia maturation factor regulation of STAT expression: a novel mechanism in experimental autoimmune encephalomyelitis. Neurochem Res 2007; 32(12):2123-31. doi: 10.1007/s11064-007-9383-0 [Crossref]
44. Harris TJ, Grosso JF, Yen HR, Xin H, Kortylewski M, Albesiano E. Cutting edge: an in vivo requirement for STAT3 signaling in TH17 development and TH17-dependent autoimmunity. J Immunol 2007; 179(7):4313-7. doi: 10.4049/jimmunol.179.7.4313 [Crossref]
45. Chitnis T, Najafian N, Benou C, Salama AD, Grusby MJ, Sayegh MH. Effect of targeted disruption of STAT4 and STAT6 on the induction of experimental autoimmune encephalomyelitis. J Clin Invest 2001; 108(5):739-47. doi: 10.1172/jci12563 [Crossref]
46. Kawai T, Akira S. Signaling to NF-kappaB by Toll-like receptors. Trends Mol Med 2007; 13(11):460-9. doi: 10.1016/j.molmed.2007.09.002 [Crossref]
47. Ozenci V, Kouwenhoven M, Huang YM, Kivisäkk P, Link H. Multiple sclerosis is associated with an imbalance between tumour necrosis factor-alpha (TNF-alpha)- and IL-10-secreting blood cells that is corrected by interferon-beta (IFN-beta) treatment. Clin Exp Immunol 2000; 120(1):147-53. doi: 10.1046/j.1365-2249.2000.01175.x [Crossref]
48. Arellano G, Ottum PA, Reyes LI, Burgos PI, Naves R. Stage-specific role of interferon-gamma in experimental autoimmune encephalomyelitis and multiple sclerosis. Front Immunol 2015; 6:492. doi: 10.3389/fimmu.2015.00492 [Crossref]
49. Vanderlugt CL, Rahbe SM, Elliott PJ, Dal Canto MC, Miller SD. Treatment of established relapsing experimental autoimmune encephalomyelitis with the proteasome inhibitor PS-519. J Autoimmun 2000; 14(3):205-11. doi: 10.1006/jaut.2000.0370 [Crossref]
50. Fissolo N, Kraus M, Reich M, Ayturan M, Overkleeft H, Driessen C. Dual inhibition of proteasomal and lysosomal proteolysis ameliorates autoimmune central nervous system inflammation. Eur J Immunol 2008; 38(9):2401-11. doi: 10.1002/eji.200838413 [Crossref]
51. Giacoppo S, Pollastro F, Grassi G, Bramanti P, Mazzon E. Target regulation of PI3K/Akt/mTOR pathway by cannabidiol in treatment of experimental multiple sclerosis. Fitoterapia 2017; 116:77-84. doi: 10.1016/j.fitote.2016.11.010 [Crossref]
52. Liu Y, Zhang DT, Liu XG. mTOR signaling in T cell immunity and autoimmunity. Int Rev Immunol 2015; 34(1):50-66. doi: 10.3109/08830185.2014.933957 [Crossref]
53. Goebbels S, Oltrogge JH, Kemper R, Heilmann I, Bormuth I, Wolfer S. Elevated phosphatidylinositol 3,4,5-trisphosphate in glia triggers cell-autonomous membrane wrapping and myelination. J Neurosci 2010; 30(26):8953-64. doi: 10.1523/jneurosci.0219-10.2010 [Crossref]
54. Giuliani F, Metz LM, Wilson T, Fan Y, Bar-Or A, Yong VW. Additive effect of the combination of glatiramer acetate and minocycline in a model of MS. J Neuroimmunol 2005; 158(1-2):213-21. doi: 10.1016/j.jneuroim.2004.09.006 [Crossref]
55. Mohajeri M, Sadeghizadeh M, Najafi F, Javan M. Polymerized nano-curcumin attenuates neurological symptoms in EAE model of multiple sclerosis through down regulation of inflammatory and oxidative processes and enhancing neuroprotection and myelin repair. Neuropharmacology 2015; 99:156-67. doi: 10.1016/j.neuropharm.2015.07.013 [Crossref]
56. Wade DT, Makela P, Robson P, House H, Bateman C. Do cannabis-based medicinal extracts have general or specific effects on symptoms in multiple sclerosis? A double-blind, randomized, placebo-controlled study on 160 patients. MultScler 2004; 10(4):434-41. doi: 10.1191/1352458504ms1082oa [Crossref]
57. Mähler A, Steiniger J, Bock M, Klug L, Parreidt N, Lorenz M. Metabolic response to epigallocatechin-3-gallate in relapsing-remitting multiple sclerosis: a randomized clinical trial. Am J Clin Nutr 2015; 101(3):487-95. doi: 10.3945/ajcn.113.075309 [Crossref]
58. Ghazavi A, Mosayebi G, Salehi H, Abtahi H. Effect of ethanol extract of saffron (Crocus sativus L.) on the inhibition of experimental autoimmune encephalomyelitis in C57bl/6 mice. Pak J Biol Sci 2009; 12(9):690-5. doi: 10.3923/pjbs.2009.690.695 [Crossref]
59. Jafarzadeh A, Mohammadi-Kordkhayli M, Ahangar-Parvin R, Azizi V, Khoramdel-Azad H, Shamsizadeh A. Ginger extracts influence the expression of IL-27 and IL-33 in the central nervous system in experimental autoimmune encephalomyelitis and ameliorates the clinical symptoms of disease. J Neuroimmunol 2014; 276(1-2):80-8. doi: 10.1016/j.jneuroim.2014.08.614 [Crossref]
60. Bertoglio JC, Baumgartner M, Palma R, Ciampi E, Carcamo C, Cáceres DD. Andrographis paniculata decreases fatigue in patients with relapsing-remitting multiple sclerosis: a 12-month double-blind placebo-controlled pilot study. BMC Neurol 2016; 16:77. doi: 10.1186/s12883-016-0595-2 [Crossref]
61. Kim JY, Yoon JY, Sugiura Y, Lee SK, Park JD, Song GJ. Dendropanaxmorbiferus leaf extract facilitates oligodendrocyte development. R Soc Open Sci 2019; 6(6):190266. doi: 10.1098/rsos.190266 [Crossref]
62. Sirdaarta J, Matthews B, White A, Cock IE. GC-MS and LC-MS analysis of Kakadu plum fruit extracts displaying inhibitory activity against microbial triggers of multiple sclerosis. PharmacognCommun 2015; 5(2):100-15. doi: 10.5530/pc.2015.2.2 [Crossref]
63. Sedighi B, Pardakhty A, Kamali H, Shafiee K, Naz Hasani B. Effect of Boswellia papyrifera on cognitive impairment in multiple sclerosis. Iran J Neurol 2014; 13(3):149-53.
64. Azadmehr A, Goudarzvand M, Saadat P, Ebrahimi H, Hajiaghaee R, Miri NS. Immunomodulatory and anti-inflammatory effects of Scrophulariamegalantha ethanol extract on an experimental model of multiple sclerosis. Res J Pharmacogn 2019; 6(1):43-50. doi: 10.22127/rjp.2018.80370 [Crossref]
65. Ghaffari S, Hatami H, Dehghan G. Saffron ethanolic extract attenuates oxidative stress, spatial learning, and memory impairments induced by local injection of ethidium bromide. Res Pharm Sci 2015; 10(3):222-32.
66. Ghaiad HR, Nooh MM, El-Sawalhi MM, Shaheen AA. Resveratrol promotes remyelination in cuprizone model of multiple sclerosis: biochemical and histological study. Mol Neurobiol 2017; 54(5):3219-29. doi: 10.1007/s12035-016-9891-5 [Crossref]
67. Shindler KS, Ventura E, Dutt M, Elliott P, Fitzgerald DC, Rostami A. Oral resveratrol reduces neuronal damage in a model of multiple sclerosis. J Neuroophthalmol 2010; 30(4):328-39. doi: 10.1097/WNO.0b013e3181f7f833 [Crossref]
68. Zajicek JP, Hobart JC, Slade A, Barnes D, Mattison PG. Multiple sclerosis and extract of cannabis: results of the MUSEC trial. J Neurol Neurosurg Psychiatry 2012; 83(11):1125-32. doi: 10.1136/jnnp-2012-302468 [Crossref]
69. Tegenge MA, Rajbhandari L, Shrestha S, Mithal A, Hosmane S, Venkatesan A. Curcumin protects axons from degeneration in the setting of local neuroinflammation. Exp Neurol 2014; 253:102-10. doi: 10.1016/j.expneurol.2013.12.016 [Crossref]
70. Itoh T, Fujimoto Y, Kawai Y, Toba T, Saito T. Inhibition of food-borne pathogenic bacteria by bacteriocins from Lactobacillus gasseri. Lett Appl Microbiol 1995; 21(3):137-41. doi: 10.1111/j.1472-765x.1995.tb01025.x [Crossref]
71. Berer K, Mues M, Koutrolos M, Rasbi ZA, Boziki M, Johner C. Commensal microbiota and myelin autoantigen cooperate to trigger autoimmune demyelination. Nature 2011; 479(7374):538-41. doi: 10.1038/nature10554 [Crossref]
72. Tankou SK, Regev K, Healy BC, Cox LM, Tjon E, Kivisakk P. Investigation of probiotics in multiple sclerosis. MultScler 2018; 24(1):58-63. doi: 10.1177/1352458517737390 [Crossref]
73. Chae CS, Kwon HK, Hwang JS, Kim JE, Im SH. Prophylactic effect of probiotics on the development of experimental autoimmune myasthenia gravis. PLoS One 2012; 7(12):e52119. doi: 10.1371/journal.pone.0052119 [Crossref]
74. He B, Hoang TK, Tian X, Taylor CM, Blanchard E, Luo M. Lactobacillus reuteri reduces the severity of experimental autoimmune encephalomyelitis in mice by modulating gut microbiota. Front Immunol 2019; 10:385. doi: 10.3389/fimmu.2019.00385 [Crossref]
75. Salehipour Z, Haghmorad D, Sankian M, Rastin M, Nosratabadi R, Soltan Dallal MM. Bifidobacterium animalis in combination with human origin of Lactobacillus plantarum ameliorate neuroinflammation in experimental model of multiple sclerosis by altering CD4+ T cell subset balance. Biomed Pharmacother 2017; 95:1535-48. doi: 10.1016/j.biopha.2017.08.117 [Crossref]
76. Tamtaji OR, Kouchaki E, Salami M, Aghadavod E, Akbari E, Tajabadi-Ebrahimi M. The effects of probiotic supplementation on gene expression related to inflammation, insulin, and lipids in patients with multiple sclerosis: a randomized, double-blind, placebo-controlled trial. J Am Coll Nutr 2017; 36(8):660-5. doi: 10.1080/07315724.2017.1347074 [Crossref]
77. Kwon HK, Kim GC, Kim Y, Hwang W, Jash A, Sahoo A. Amelioration of experimental autoimmune encephalomyelitis by probiotic mixture is mediated by a shift in T helper cell immune response. Clin Immunol 2013; 146(3):217-27. doi: 10.1016/j.clim.2013.01.001 [Crossref]
78. Goudarzvand M, Rasouli Koohi S, Khodaii Z, Soleymanzadeh Moghadam S. Probiotics Lactobacillus plantarum and bifidobacterium B94: cognitive function in demyelinated model. Med J Islam Repub Iran 2016; 30:391.
79. Kouchaki E, Tamtaji OR, Salami M, Bahmani F, Daneshvar Kakhaki R, Akbari E. Clinical and metabolic response to probiotic supplementation in patients with multiple sclerosis: a randomized, double-blind, placebo-controlled trial. Clin Nutr 2017; 36(5):1245-9. doi: 10.1016/j.clnu.2016.08.015 [Crossref]
80. Salami M, Kouchaki E, Asemi Z, Tamtaji OR. How probiotic bacteria influence the motor and mental behaviors as well as immunological and oxidative biomarkers in multiple sclerosis? A double blind clinical trial. J Funct Foods 2019; 52:8-13. doi: 10.1016/j.jff.2018.10.023 [Crossref]
81. Dargahi N, Matsoukas J, Apostolopoulos V. Streptococcus thermophilus ST285 alters pro-inflammatory to anti-inflammatory cytokine secretion against multiple sclerosis peptide in mice. Brain Sci 2020; 10(2):126. doi: 10.3390/brainsci10020126 [Crossref]
82. Farber R, Xia Z. Prebiotic vs Probiotic in Multiple Sclerosis (MS). ClinicalTrials.gov. https://clinicaltrials.gov/ct2/show/NCT04038541. Published July 31, 2019.
83. New High-Risk Pilot Projects Explore Probiotics, Virtual Reality, Repairing MS Damage, And Other Novel Solutions for People Affected by MS. National multiple sclerosis society. https://www.nationalmssociety.org/About-the-Society/News/New-High-Risk-Pilot-Projects-Explore-Probiotics-Vi. Published April 19, 2019. Accessed March 15, 2021.