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Amelioration of experimental autoimmune encephalomyelitis by probiotic mixture is mediated by a shift in T helper cell immune response
Abstract
The immunomodulatory effect of probiotics has been shown mainly in gastro-intestinal immune disorders and little information is available on the inflammation of central nervous system. Recently we reported that IRT5 probiotics, a mixture of 5 probiotics, could suppress diverse experimental inflammatory disorders. In this study, we evaluated the prophylactic and therapeutic effects of IRT5 probiotics in experimental autoimmune encephalomyelitis (EAE), a T cell mediated inflammatory autoimmune disease of the central nervous system. Pretreatment of IRT5 probiotics before disease induction significantly suppressed EAE development. In addition, treatment with IRT5 probiotics to the ongoing EAE delayed the disease onset. Administration of IRT5 probiotics inhibited the pro-inflammatory Th1/Th17 polarization, while inducing IL10(+) producing or/and Foxp3(+) regulatory T cells, both in the peripheral immune system and at the site of inflammation. Collectively, our data suggest that IRT5 probiotics could be applicable to modulate T cell mediated neuronal autoimmune diseases, including multiple sclerosis.
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“Animal studies suggest that probiotics can modulate endogenous neuroactive molecules [17], prevent and treat neuronal autoimmune diseases [18], and ameliorate impaired spatial memory in diabetic rats [19].”
From Effect of Supplementation with Probiotics in Patients with Schizophrenia: Systematic Review and Meta-Analysis of Randomized Controlled Clinical Trials (2025) · cites this paper as [18]
In the citing paper
“The supplementation of a cocktail of five probiotics (IRT5) before or after the EAE onset in rodents is associated with the delay of the disease onset or suppression of the disease progression, respectively (154).”
From The gut-brain axis: how microbiota and host inflammasome influence brain physiology and pathology (2020) · cites this paper as [154]
In the citing paper
“The amelioration of the disease upon probiotic treatment was associated with a higher abundance of Treg cells, higher production of IL-10 by CD4+ T cells, B cells, and CD11c+ cells, together with the suppression of the pro-inflammatory Th-1/Th-17 response (154).”
From The gut-brain axis: how microbiota and host inflammasome influence brain physiology and pathology (2020) · cites this paper as [154]
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InfluentialPropionic Acid Shapes the Multiple Sclerosis Disease Course by an Immunomodulatory Mechanism
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“The results obtained in the EAE animal model support this idea, since the administration of a multistrain probiotic has been shown to result in prophylactic and therapeutic efficacy that was associated with a reduced degree of inflammation (81, 82).”
ResultThe intestinal barrier in multiple sclerosis: implications for pathophysiology and therapeutics
Camara-Lemarroy, C. R., Metz, L. M., Meddings, J. B., Sharkey, K. A., & Yong, V. W. (2018) · Brain · doi:10.1093/brain/awy131 · Cited by 188
“, 2008), inhibit the pro-inflammatory Th1/Th17 polarization (Kwon et al., 2013), induce IL10 producing Treg cells (Ochoa-Repáraz et al.”
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“Investigators found that treatment with IRT5 during induction of EAE delayed the disease onset (32).”
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Kim, D.-H., Zeng, M. Y., & Núñez, G. (2017) · Experimental & Molecular Medicine · doi:10.1038/emm.2017.24 · Cited by 191
Microbiota-gut brain axis involvement in neuropsychiatric disorders
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Yadav, S. K., Mindur, J. E., Ito, K., & Dhib-Jalbut, S. S. (2015) · Current Opinion in Neurology · doi:10.1097/wco.0000000000000205 · Cited by 173
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“Infection with Lactobacillus casei Shirota or oral Lactobacillus farciminis, Bifidobacterium bifidum, Bacteroides fragilis, and Bifidobacterium animalis in mice resulted in Treg cell induction by promoting the secretion of IL-10, which was followed by IFN-γ, TNF-α, and IL-17 reduction and inflammatory Th1/Th17 decreas…”
BackgroundProbiotics as an immune modulator
KANG, H.-J., & IM, S.-H. (2015) · Journal of Nutritional Science and Vitaminology · doi:10.3177/jnsv.61.s103 · Cited by 151
Microbiota and neurologic diseases: potential effects of probiotics
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“investigated the potential prophylactic and therapeutic effects of IRT5, a combination of Streptococcus thermophilus, Lactobacillus reuteri, Bifidobacterium bifidum, Lactobacillus acidophilus and Lactobacillus casei (1 × 108 colony forming units [CFU] for each strain) in EAE mice [87].”
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BackgroundInfluentialGut Microbiota Are Disease-Modifying Factors After Traumatic Spinal Cord Injury
Kigerl, K. A., Mostacada, K., & Popovich, P. G. (2017) · Neurotherapeutics · doi:10.1007/s13311-017-0583-2 · Cited by 126
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Clinical Effect of IRT-5 Probiotics on Immune Modulation of Autoimmunity or Alloimmunity in the Eye
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The Gut Microbiome in Multiple Sclerosis
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Combined therapies to treat complex diseases: The role of the gut microbiota in multiple sclerosis
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Boziki, M. K., Kesidou, E., Theotokis, P., Mentis, A. A., Karafoulidou, E., Melnikov, M., Sviridova, A. A., Rogovskii, V., Boyко, A., & Grigoriadis, N. (2020) · Brain Sciences · doi:10.3390/brainsci10040234 · Cited by 93
“Conversely, the administration of Lactobacilli has been repeatedly shown to protect form EAE by the induction of IL-4, IL-10, TGF-β1, and IL-27 [45,46] by mediating an increase in IL-10+ and Foxp3+ T regulatory cells [47–49].”
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Zeng, W., Shen, J., Bo, T., Peng, L., Xu, H., Nasser, M. I., Zhuang, Q., & Zhao, M. (2019) · Journal of Immunology Research · doi:10.1155/2019/1603758 · Cited by 89
“Additionally, the levels of IL-6, TNF-β, IL-1β, and IL-17 also decreased in colon tissue [48].”
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Use of Vitamins and Dietary Supplements by Patients With Multiple Sclerosis
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“Patients with multiple sclerosis (MS) showed a signi fi cantly reduced PA level, whereas PA treatment signi fi cantly enlarges gut-associated Treg cell population and subsequently reduces systemic immune reaction, leading to disease amelioration in an animal model of MS 42 – 44 .”
Probiotics in Extraintestinal Diseases: Current Trends and New Directions
Kiousi, D. E., Karapetsas, A., Karolidou, K., Panayiotidis, M. I., Pappa, A., & Galanis, Α. (2019) · Nutrients · doi:10.3390/nu11040788 · Cited by 82
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“Vitamin D regulates NO, which is believed to be an anti-bacterial molecule, produced by MCs. Finally, factors that reduce CRF stabilize activation of MCs (Larauche, 2012).”
BackgroundInfluence of the Gut Microbiome on Autoimmunity in the Central Nervous System
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“In the EAE mice model, treatment with probiotics diminished the response of Th17–Th1 cells through reduction of IL‐17 and IFN‐γ (Salehipour et al., 2017; Kwon et al., 2013).”
MethodDargahi, N., Matsoukas, J., & Apostolopoulos, V. (2020) · Brain Sciences · doi:10.3390/brainsci10020126 · Cited by 60
“An insufficient or imbalanced GIT microflora can also lead to dysfunctions in the gut–brain axis and the pathogenesis of a number of diseases inside the GIT (such as inflammatory bowel disease, IBD) and outside the GIT (such as the CNS).”
BackgroundInfluentialGut microbiota and probiotics: Novel immune system modulators in myasthenia gravis?
Rinaldi, E., Consonni, A., Guidesi, E., Elli, M., Mantegazza, R., & Baggi, F. (2018) · Annals of the New York Academy of Sciences · doi:10.1111/nyas.13567 · Cited by 57
“Disease modifying nutricals” for multiple sclerosis
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Role of the intestinal microbiome in autoimmune diseases and its use in treatments
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“14 Clearing the gut microbiota with antibiotics or altering it with probiotics alleviates EAE symptoms by inducing protective Foxp3+ Treg cells, 15,16 suggesting modulation of the gut microbiota may provide a novel management strategy for EAE and MS. Inulin is a naturally occurring polysaccharide…”
BackgroundVenkataratnamma, V., Begum, P. S., Madhavi, G., Rajagopal, S., Viswanath, B., & Razak, M. (2017) · International journal of Nutrition Pharmacology Neurological Diseases · doi:10.4103/ijnpnd.ijnpnd_90_16 · Cited by 55
“[103] One of the neurological evaluations conducted in 1-year-old children using Hammersmith infant neurological examination demonstrated a statistically noteworthy higher occurrence of suboptimal scores in the control group than in the probiotic al studies Reference Desbonnet et al.[87] , sensorimotor, Hsiao et al.[8…”
BackgroundInfluentialJiang, J., Chu, C., Wu, C., Wang, C., Zhang, C., Li, T., Zhai, Q., Yu, L., Tian, F., & Chen, W. (2021) · Food & Function · doi:10.1039/d0fo03203d · Cited by 52
Microbial modulation of the gut microbiome for treating autoimmune diseases
Balakrishnan, B., & Taneja, V. (2018) · Expert Review of Gastroenterology & Hepatology · doi:10.1080/17474124.2018.1517044 · Cited by 51
Breaking down the gut microbiome composition in multiple sclerosis
Budhram, A., Parvathy, S., Kremenchutzky, M., & Silverman, M. (2017) · Multiple Sclerosis Journal · doi:10.1177/1352458516682105 · Cited by 51
Kim, J., Chae, C.-S., Kim, G.-C., Hwang, W., Hwang, J., Hwang, S., Kim, Y., Ahn, Y., Park, S., Jun, C., et al. (2015) · Journal of Functional Foods · doi:10.1016/j.jff.2015.01.002 · Cited by 51
Ertürk-Hasdemir, D., Ochoa‐Repáraz, J., Kasper, D. L., & Kasper, L. H. (2021) · Frontiers in Immunology · doi:10.3389/fimmu.2021.662807 · Cited by 51
Calvo‐Barreiro, L., Eixarch, H., Alonso, M. P., Castillo, M., Lebrón‐Galán, R., Mestre, L., Guaza, C., Clemente, D., del Campo, R., Montalbán, X., et al. (2020) · Cells · doi:10.3390/cells9040906 · Cited by 48
Hashemi, B., Abdollahi, M., Abbaspour‐Aghdam, S., Hazrati, A., Malekpour, K., Meshgi, S., Kafil, H. S., Ghazi, F., Yousefi, M., Roshangar, L., et al. (2023) · Biomedicine & Pharmacotherapy · doi:10.1016/j.biopha.2022.114195 · Cited by 49
Feeding the gut microbiome: impact on multiple sclerosis
Bronzini, M., Maglione, A., Rosso, R., Matta, M., Masuzzo, F., Rolla, S., & Clerico, M. (2023) · Frontiers in Immunology · doi:10.3389/fimmu.2023.1176016 · Cited by 49
The Dynamics of the Gut Microbiome in Multiple Sclerosis in Relation to Disease
Mowry, E. M., & Glenn, J. D. (2017) · Neurologic Clinics · doi:10.1016/j.ncl.2017.08.008 · Cited by 48
Consonni, A., Cordiglieri, C., Rinaldi, E., Marolda, R., Ravanelli, I., Guidesi, E., Elli, M., Mantegazza, R., & Baggi, F. (2018) · Oncotarget · doi:10.18632/oncotarget.25170 · Cited by 45
“com probiotic treatments have been successfully investigated in several experimental models of autoimmune diseases, such as type 1 diabetes [43], rheumatoid arthritis [44], EAMG [45], and EAE [46, 47].”
BackgroundMicrobial treatment: the potential application for Parkinson’s disease
Fang, X. (2018) · Neurological Sciences · doi:10.1007/s10072-018-3641-6 · Cited by 45
Swartwout, B. K., & Luo, X. (2018) · Frontiers in Immunology · doi:10.3389/fimmu.2018.02840 · Cited by 48
“bifidum, Streptococcus thermophiles) by balancing Treg to the effector Th1 and Th17 cells (88).”
BackgroundGut microbiome-mediated mechanisms in aging-related diseases: are probiotics ready for prime time?
Ren, J., Li, H., Zeng, G., Pang, B., Wang, Q., & Wei, J.-P. (2023) · Frontiers in Pharmacology · doi:10.3389/fphar.2023.1178596 · Cited by 46
“Studies have reported that oral Lactobacillus casei, Lactobacillus acidophilus, and Lactobacillus reuteni delay the progression of multiple sclerosis by increasing the number of forkhead box P3 (Foxp3) and IL-10 Treg cells and reducing pro-inflammatory Th1/Th17 polarization in the peripheral immune system and inflamma…”
BackgroundBlais, L. L., Montgomery, T. L., Amiel, E., Deming, P. B., & Krementsov, D. N. (2021) · Gut Microbes · doi:10.1080/19490976.2021.1943289 · Cited by 45
“IRT5 Kwon et al.(69) Animal EAE Proph &”
BackgroundResultInfluentialAmelioration of Autoimmune Diabetes of NOD Mice by Immunomodulating Probiotics
Kim, T. K., Lee, J.-C., Im, S., & Lee, M. (2020) · Frontiers in Immunology · doi:10.3389/fimmu.2020.01832 · Cited by 43
“has been shown to be effective against several autoimmune and inflammatory disorders (20, 21), we administered 5 × 108 cfu IRT5 to female NOD mice by oral gavage six times a week for 36 weeks beginning at 4 weeks of age and monitored blood glucose level.”
BackgroundMethodInfluentialMestre, L., Carrillo-Salinas, F. J., Mecha, M., Feliú, A., & Guaza, C. (2018) · Biochemical Pharmacology · doi:10.1016/j.bcp.2018.08.037 · Cited by 43
Targeting gut microbiota: new therapeutic opportunities in multiple sclerosis
Kujawa, D., Łaczmański, Ł., Budrewicz, S. P., Pokryszko‐Dragan, A., & Podbielska, M. (2023) · Gut Microbes · doi:10.1080/19490976.2023.2274126 · Cited by 45
“53,54 There are also reports demonstrating that the combination of two probiotic strains – Bifidobacterium animalis with Lactobacillus plantarum 55 or Enterococcus faecium with Prevotella histicola 56 – ameliorated neuroinflammation in the EAE model.”
MethodGutiérrez-Franco, A., Costa, C., Eixarch, H., Castillo, M., Medina-Rodriguez, E. M., Bribián, A., de Castro, F., Montalbán, X., & Espejo, C. (2015) · Clinical Immunology · doi:10.1016/j.clim.2015.12.005 · Cited by 39
Microbiome, Immunomodulation, and the Neuronal System
Marietta, E. V., Horwath, I. E., & Taneja, V. (2018) · Neurotherapeutics · doi:10.1007/s13311-017-0601-4 · Cited by 41
Mestre, L., Carrillo-Salinas, F. J., Feliú, A., Mecha, M., Alonso, G., Espejo, C., Calvo‐Barreiro, L., Luque-Garcia, J. L., Estévez, H., Villar, L. M., et al. (2020) · Gut Microbes · doi:10.1080/19490976.2020.1813532 · Cited by 42
Jeffery, N. D., Barker, A. K., Alcott, C. J., Levine, J. M., Meren, I. L., Wengert, J. A., Jergens, A. E., & Suchodolski, J. S. (2017) · PLoS ONE · doi:10.1371/journal.pone.0170589 · Cited by 40
Libbey, J. E., Sanchez, J. M. S., Doty, D. J., Sim, J. T., Cusick, M. F., Cox, J. E., Fischer, K. F., Round, J. L., & Fujinami, R. S. (2018) · Beneficial Microbes · doi:10.3920/bm2017.0116 · Cited by 40
“Oral supplementation with Lactobacillus has been previously shown to ameliorate EAE in a strain-specific manner associated with increases in regulatory T cells (Tregs) and increased anti-inflammatory cytokines in the serum (Kwon et al., 2013; Lavasani et al., 2010).”
BackgroundResultKumar, N., Sahoo, N. K., Mehan, S., & verma, B. (2023) · Multiple Sclerosis and Related Disorders · doi:10.1016/j.msard.2023.104547 · Cited by 41
Hosseini, S. A., Nematollahi, S., Husain, D., Banaei-Jahromi, N., Majdinasab, N., & Hosseini, S. A. (2022) · Frontiers in Neuroscience · doi:10.3389/fnins.2022.901846 · Cited by 40
“In fact, probiotic supplementation has been shown to significantly increase the differentiation of native T cells to the Th2 which improve production and secretion of anti-inflammatory cytokines such as IL-10 and IL-4 (Lavasani et al., 2010; Kwon et al., 2013).”
BackgroundCalabrò, S., Kankowski, S., Cescon, M., Gambarotta, G., Raimondo, S., Haastert‐Talini, K., & Ronchi, G. (2023) · International Journal of Molecular Sciences · doi:10.3390/ijms24098061 · Cited by 40
“Meanwhile, the validity of the rationale of using microbiota-targeting interventions to restore immune homeostasis through correction of the Th17/Treg imbalance has been proven in a number of autoimmune diseases, including not only MG [172–174], but also irritable bowel syndrome [175] and autoimmune encephalomyelitis…”
BackgroundAskari, G., Ghavami, A., Shahdadian, F., & Moravejolahkami, A. R. (2021) · Clinical Nutrition · doi:10.1016/j.clnu.2021.02.015 · Cited by 36
Immunoregulatory Effects of Tolerogenic Probiotics in Multiple Sclerosis
Atabati, H., Yazdanpanah, E., Mortazavi, H., Bajestani, S. G., Raoofi, A., Esmaeili, S., Khaledi, A., Saburi, E., Afshari, J. T., Sathyapalan, T., et al. (2021) · Advances in experimental medicine and biology · doi:10.1007/978-3-030-55035-6_6 · Cited by 38
Alcohol and multiple sclerosis: an immune system-based review.
Fahim, M., Zadeh, A. R., Shoureshi, P., Ghadimi, K., Cheshmavar, M., Sheikhinia, N., & Afzali, M. (2020) · PubMed Central · Cited by 34
Papel de la microbiota intestinal en el desarrollo de la esclerosis múltiple
Castillo-Álvarez, F., & Marzo-Sola, M. E. (2015) · Neurología · doi:10.1016/j.nrl.2015.07.005 · Cited by 34
Uceda, S., Echeverry‐Alzate, V., Reiriz, M., Miguel, E. M., Pérez-Curiel, A., Gómez-Senent, S., & Beltrán-Velasco, A. I. (2023) · International Journal of Molecular Sciences · doi:10.3390/ijms241713294 · Cited by 36
Metadata
- Authors
- Kwon, H.-K., Kim, G.-C., Kim, Y., Hwang, W., Jash, A., Sahoo, A., Kim, J.-E., Nam, J. H., & Im, S.-H.
- Affiliations
- Harvard University (US)
- Gwangju Institute of Science and Technology (KR)
- Chonnam National University (KR)
- Washington University in St. Louis (US)
- Corresponding author
- Im, Sin-Hyeog
- ORCID
- Venue
- Clinical Immunology
- Publisher
- Elsevier BV
- Published
- 2013-03
- Volume
- 146
- Issue
- 3
- Pages
- 217-227
- ISSN
- 1521-6616 (ISSN-L)
- OpenAlex
- W2078792455
- Cited by
- 212
- References
- 48
- Citations by year
- 2026: 5 · 2025: 7 · 2024: 11 · 2023: 29 · 2022: 20 · 2021: 27 · 2020: 19 · 2019: 20 · 2018: 23 · 2017: 24 · 2016: 12 · 2015: 11 · 2014: 2 · 2013: 2
- FWCI
- 6.62
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Clinical Immunology (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Research Foundation (2011-0028529)
- Systems Biology Infrastructure Establishment Grant
- Topics
- Health Sciences › Medicine › Clinical Neurology › Multiple Sclerosis Research Studies
- Life Sciences › Agricultural and Biological Sciences › Food Science › Probiotics and Fermented Foods
- Life Sciences › Immunology and Microbiology › Immunology › T-cell and B-cell Immunology
- Keywords
- experimental autoimmune encephalomyelitis, probiotics, T helper cell polarization, Th1/Th17 cells, regulatory T cells, Foxp3, IL-10, immunomodulation, multiple sclerosis, neuroinflammation, T cell-mediated autoimmunity
- MeSH terms
- Animals, Encephalomyelitis, Autoimmune, Experimental, T-Lymphocytes, Helper-Inducer, Mice, Inbred C57BL, Peptide Fragments, Spinal Cord, T-Lymphocyte Subsets, Probiotics, Mice, Myelin-Oligodendrocyte Glycoprotein
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