Synergistic Treatment of Multiple Sclerosis by Ketogenic Diet and Vitamin D
DOI:
https://doi.org/10.54097/y38bzk12Keywords:
Multiple sclerosis (MS), Ketogenic diet, Vitamin D, Single cell RNA-sequencing, Single cell ATAC-sequencing, Oligodendrocytes.Abstract
Multiple sclerosis (MS) is a chronic autoimmune disease in which the immune system mistakenly attacks the myelin sheath, resulting in the demyelination of neurons in the central nervous system (CNS). This damage leads to symptoms such as fatigue, blurred vision, muscle weakness, and cognitive impairment. Globally, about 2.8 million people live with MS, making it a significant neurological burden. Current treatments for MS are difficult to implement because they are expensive, associated with side effects, and vary in availability across countries, which impacts their effectiveness. Nutrition has emerged as an important aspect of MS treatment. Ketogenic diets (KDs), which are low in carbohydrates and high in fats, have been shown to protect the nervous system and reduce inflammation in MS. In addition, low vitamin D levels are recognized as a risk factor for MS. Using single-nucleus and single-cell RNA sequencing analyses, together with oligodendrocyte cell line experiments, this study provides evidence that vitamin D and the KD may act synergistically to prevent MS development. These findings suggest a potential dietary approach to lowering MS risk that is simple to implement and could benefit populations across diverse social and economic conditions.
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[1] Alonso, R., Contentti, E. C., Imhoff, G., Lopez, P. A., Rubstein, A., & Tizio, S. (2019). Barriers against a successful MS treatment: The importance of effectiveness beyond efficacy. Multiple Sclerosis and Related Disorders, 30, 129–135. https://doi.org/10.1016/j.msard.2019.01.056 DOI: https://doi.org/10.1016/j.msard.2019.01.056
[2] Almsaid, H., & Khalfa, H. (2020). The effect of ketogenic diet on vitamin D3 and testosterone hormone in patients with diabetes mellitus type 2. Current Issues in Pharmacy and Medical Sciences, 33(4), 202–205. https://doi.org/10.2478/cipms-2020-0033 DOI: https://doi.org/10.2478/cipms-2020-0033
[3] Baecher-Allan, C., Kaskow, B. J., & Weiner, H. L. (2018a). Multiple sclerosis: Mechanisms and immunotherapy. Neuron, 97(4), 742–768. https://doi.org/10.1016/j.neuron.2018.01.021 DOI: https://doi.org/10.1016/j.neuron.2018.01.021
[4] Bergadà, L., Pallares, J., Arcidiacono, M. V., Cardus, A., Santacana, M., Valls, J., Cao, G., Fernàndez, E., Dolcet, X., Dusso, A. S., & Matias-Guiu, X. (2014). Role of local bioactivation of vitamin D by CYP27A1 and CYP2R1 in the control of cell growth in normal endometrium and endometrial carcinoma. Laboratory Investigation, 94(6), 608–622. https://doi.org/10.1038/labinvest.2014.57 DOI: https://doi.org/10.1038/labinvest.2014.57
[5] Buscemi, S., Buscemi, C., Corleo, D., De Pergola, G., Caldarella, R., Meli, F., Randazzo, C., Milazzo, S., Barile, A. M., Rosafio, G., Settipani, V., Gurrera, S., Borzì, A. M., & Ciaccio, M. (2021). Obesity and circulating levels of vitamin D before and after weight loss induced by a very low-calorie ketogenic diet. Nutrients, 13(6), 1829. https://doi.org/10.3390/nu13061829 DOI: https://doi.org/10.3390/nu13061829
[6] Cheng, J. B., Levine, M. A., Bell, N. H., Mangelsdorf, D. J., & Russell, D. W. (2004). Gnetic evidence that the human CYP2R1 enzyme is a key vitamin D5-hydroxylase. Proceedings of the National Academy of Sciences, 101(20), 7711–7715. https://doi.org/10.1073/pnas.0402490101 DOI: https://doi.org/10.1073/pnas.0402490101
[7] Chinese Multiple sclerosis patients Survival report. (2019, February 24). Rare Disease in China. https://www.raredisease.cn/Research/Info/17897?key=%e5%a4%9a%e5%8f%91%e6%80%a7%e7%a1%ac%e5%8c%96%e6%82%a3%e8%80%85%e7%94%9f%e5%ad%98%e6%8a%a5%e5%91%8a
[8] Deng, Y., Xie, M., Li, Q., Xu, X., & Ou, W. (2021). Targeting mitochondria-inflammation circuit by β-hydroxybutyrate mitigates HFpEF. Circulation Research, 128, 232–245. https://doi.org/10.1161/CIRCRESAHA.120.317933 DOI: https://doi.org/10.1161/CIRCRESAHA.120.317933
[9] Duan, L., Xue, Z., Ji, H., Zhang, D., & Wang, Y. (2018). Effects of CYP2R1 gene variants on Vitamin D levels and status: A systematic review and meta-analysis. Gene, 678, 361–369. https://doi.org/10.1016/j.gene.2018.08.056 DOI: https://doi.org/10.1016/j.gene.2018.08.056
[10] Eudy, B. (2021, March 2). How a ketogenic diet may change your gene expression. What Is Epigenetics? https://www.whatisepigenetics.com/how-a-ketogenic-diet-may-change-your-gene-expression/
[11] Fernandes de Abreu, D. A., Eyles, D., & Féron, F. (2009). Vitamin D, a neuro-immunomodulator: implications for neurodegenerative and autoimmune diseases. Psychoneuroendocrinology, 34(Suppl. 1), S265–S277. https://doi.org/10.1016/j.psyneuen.2009.05.023 DOI: https://doi.org/10.1016/j.psyneuen.2009.05.023
[12] Garcion, E., Nataf, S., Berod, A., Darcy, F., & Brachet, P. (1997). 1,25-Dihydroxyvitamin D3 inhibits the expression of inducible nitric oxide synthase in rat central nervous system during experimental allergic encephalomyelitis. Molecular Brain Research, 45(2), 255–267. https://doi.org/10.1016/S0169-328X(96)00260-4 DOI: https://doi.org/10.1016/S0169-328X(96)00260-4
[13] Goldberg, E. L., Asher, J. L., Molony, R. D., Shaw, A. C., Zeiss, C. J., Wang, C., Morozova-Roche, L. A., Herzog, R. I., Iwasaki, A., & Dixit, V. D. (2017). β-Hydroxybutyrate deactivates neutrophil NLRP3 inflammasome to relieve gout flares. Cell Reports, 18, 2077–2087. https://doi.org/10.1016/j.celrep.2017.02.004 DOI: https://doi.org/10.1016/j.celrep.2017.02.004
[14] Grishkan, I. V., Fairchild, A. N., Calabresi, P. A., & Gocke, A. R. (2013). 1,25-Dihydroxyvitamin D3 selectively and reversibly impairs T helper-cell CNS localization. Proceedings of the National Academy of Sciences of the United States of America, 110(52), 21101–21106. https://doi.org/10.1073/pnas.1306072110 DOI: https://doi.org/10.1073/pnas.1306072110
[15] Kashi, Z., Sadeghi, N., & Sadeghi, N. (2021). Randomized crossover trial of a modified ketogenic diet in patients with Alzheimer's disease. Alzheimer's Research & Therapy, 13(1), 1-10. https://doi.org/10.1186/s13195-021-00783-x DOI: https://doi.org/10.1186/s13195-021-00783-x
[16] Kim, D. Y., Hao, J., Liu, R., Turner, G., Shi, F. D., & Rho, J. M. (2012). Inflammation-mediated memory dysfunction and effects of a ketogenic diet in a murine model of multiple sclerosis. PLOS ONE, 7(4), e35476. https://doi.org/10.1371/journal.pone.0035476 DOI: https://doi.org/10.1371/journal.pone.0035476
[17] Kister, A., & Kister, I. (2023). Overview of myelin, major myelin lipids, and myelin-associated proteins. Frontiers in Chemistry, 10. https://doi.org/10.3389/fchem.2022.1041961 DOI: https://doi.org/10.3389/fchem.2022.1041961
[18] Kriebitzsch, C., Verlinden, L., Eelen, G., Van Schoor, N. M., Swart, K., Lips, P., Meyer, M. B., Pike, J. W., Boonen, S., Carlberg, C., Vitvitsky, V., Bouillon, R., Banerjee, R., & Verstuyf, A. (2011). 1,25-dihydroxyvitamin D3 influences cellular homocysteine levels in murine preosteoblastic MC3T3-E1 cells by direct regulation of cystathionine β-synthase. Journal of Bone and Mineral Research, 26(12), 2991–3000. https://doi.org/10.1002/jbmr.493 DOI: https://doi.org/10.1002/jbmr.493
[19] Lu, Y., Yang, Y. Y., Zhou, M. W., Liu, N., Xing, H. Y., Liu, X. X., & Li, F. (2018). Ketogenic diet attenuates oxidative stress and inflammation after spinal cord injury by activating Nrf2 and suppressing the NF-κB signaling pathways. Neuroscience Letters, 683, 13–18. https://doi.org/10.1016/j.neulet.2018.06.016 DOI: https://doi.org/10.1016/j.neulet.2018.06.016
[20] Lucas, R. M., Ponsonby, A.-L., Dear, K., Valery, P. C., Pender, M. P., Taylor, B. V., Kilpatrick, T. J., Dwyer, T., Coulthard, A., Chapman, C., van der Mei, I., Williams, D., & McMichael, A. J. (2011). Sun exposure and vitamin D are independent risk factors for CNS demyelination. Neurology, 76(6), 540–548. https://doi.org/10.1212/wnl.0b013e31820af93d DOI: https://doi.org/10.1212/WNL.0b013e31820af93d
[21] Masoumi, A., Goldenson, B., Ghirmai, S., Avagyan, H., Zaghi, J., Abel, K., et al. (2009). 1α,25-dihydroxyvitamin D3 interacts with curcuminoids to stimulate amyloid-β clearance by macrophages of alzheimer’s disease patients. Journal of Alzheimer's Disease, 17(3), 703–717. https://doi.org/10.3233/JAD-2009-1080 DOI: https://doi.org/10.3233/JAD-2009-1080
[22] Mayo Foundation for Medical Education and Research. (2022, December 24). ultiple sclerosis. Mayo Clinic. https://www.mayoclinic.org/diseases-conditions/multiple-sclerosis/symptoms-causes/syc-20350269
[23] Miclea, A., Bagnoud, M., Chan, A., & Hoepner, R. (2020). A brief review of the effects of vitamin D on multiple sclerosis. Frontiers in Immunology, 11. https://doi.org/10.3389/fimmu.2020.00781 DOI: https://doi.org/10.3389/fimmu.2020.00781
[24] Molina-Holgado, E., Vela, J. M., Arévalo-Martín, A., & Guaza, C. (2001). LPS/IFN-γ cytotoxicity in oligodendroglial cells: role of nitric oxide and protection by the anti-inflammatory cytokine IL-10. European Journal of Neuroscience, 13(3), 493–502. https://doi.org/10.1046/j.0953-816X.2000.01412.x DOI: https://doi.org/10.1046/j.0953-816x.2000.01412.x
[25] Morán-Auth, Y., Penna-Martinez, M., Shoghi, F., Ramos-Lopez, E., & Badenhoop, K. (2013). Vitamin D status and gene transcription in immune cells. The Journal of Steroid Biochemistry and Molecular Biology, 136, 83–85. v https://doi.org/10.1016/j.jsbmb.2013.02.005 DOI: https://doi.org/10.1016/j.jsbmb.2013.02.005
[26] Multiple sclerosis: What you need to know. Cleveland Clinic. (2024, January 25). https://my.clevelandclinic.org/health/diseases/17248-multiple-sclerosis
[27] Nystad, A. E., Wergeland, S., Aksnes, L., Myhr, K. M., Bø, L., & Torkildsen, Ø. (2014). Effect of high-dose 1.25 dihydroxyvitamin D3 on remyelination in the cuprizone model. APMIS, 122(12), 1178–1186. https://doi.org/10.1111/apm.12281 DOI: https://doi.org/10.1111/apm.12281
[28] Pereira, M. I., Silva, D. F., & Ribeiro, A. S. (2021). A narrative review on the effects of a ketogenic diet on patients with Alzheimer's disease. Frontiers in Nutrition, 8, 744398. https://doi.org/10.3389/fnut.2021.744398 DOI: https://doi.org/10.3389/fnut.2021.744398
[29] Prudencio, M. B., de Lima, P. A., Murakami, D. K., Sampaio, L. P., & Damasceno, N. R. (2021). Micronutrient supplementation needs more attention in patients with refractory epilepsy under ketogenic diet treatment. Nutrition, 86, 111158. https://doi.org/10.1016/j.nut.2021.111158 DOI: https://doi.org/10.1016/j.nut.2021.111158
[30] Rhead, B., Bäärnhielm, M., Gianfrancesco, M., Mok, A., Shao, X., Quach, H., et al. (2016). Mendelian randomization shows a causal effect of low Vitamin D on multiple sclerosis risk. Neurology: Genetics, 2(4), e97. https://doi.org/10.1212/NXG.0000000000000097 DOI: https://doi.org/10.1212/NXG.0000000000000097
[31] Stafford, P., Abdelwahab, M. G., Kim, D. Y., Preul, M. C., Rho, J. M., & Scheck, A. C. (2010). The ketogenic diet reverses gene expression patterns and reduces reactive oxygen species levels when used as an adjuvant therapy for glioma. Nutrition & Metabolism, 7(1). https://doi.org/10.1186/1743-7075-7-74 DOI: https://doi.org/10.1186/1743-7075-7-74
[32] Ungaro, P., Nettore, I. C., Franchini, F., Palatucci, G., Muscogiuri, G., Colao, A., & Macchia, P. E. (2022). Epigenome modulation induced by ketogenic diets. Nutrients, 14(15), 3245. https://doi.org/10.3390/nu14153245 DOI: https://doi.org/10.3390/nu14153245
[33] Walton, C., King, R., Rechtman, L., Kaye, W., Leray, E., Marrie, R. A., Robertson, N., La Rocca, N., Uitdehaag, B., van der Mei, I., Wallin, M., Helme, A., Angood Napier, C., Rijke, N., & Baneke, P. (2020). Rising prevalence of multiple sclerosis worldwide: Insights from the Atlas of MS, third edition. Multiple sclerosis (Houndmills, Basingstoke, England), 26(14), 1816–1821. https://doi.org/10.1177/1352458520970841 DOI: https://doi.org/10.1177/1352458520970841
[34] Zhang, Q., Xu, L., Xia, J., Wang, D., Qian, M., & Ding, S. (2018). Treatment of diabetic mice with a combination of ketogenic diet and aerobic exercise via modulations of PPARs gene programs. PPAR Research, 2018, 4827643. https://doi.org/10.1155/2018/4827643 DOI: https://doi.org/10.1155/2018/4827643
[35] Zheng, C., Hervé, B., Meijer, M., Rodríguez-Kirby, L. a. R., Cacais, A. O. G., Kukanja, P., Kabbe, M., Olsson, T., Agirre, E., & Castelo-Branco, G. (2023). Distinct transcriptomic and epigenomic responses of mature oligodendrocytes during disease progression in a mouse model of multiple sclerosis. bioRxiv (Cold Spring Harbor Laboratory). https://doi.org/10.1101/2023.12.18.572120 DOI: https://doi.org/10.1101/2023.12.18.572120
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