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01-10-2018 | Original Article

Antibiotics protect against EAE by increasing regulatory and anti-inflammatory cells

Authors: Hilary A. Seifert, Gil Benedek, Ha Nguyen, Grant Gerstner, Ying Zhang, Gail Kent, Arthur A. Vandenbark, Jürgen Bernhagen, Halina Offner

Published in: Metabolic Brain Disease | Issue 5/2018

Abstract

A seven day pretreatment course of an oral antibiotic cocktail (Ampicillin, Metronidazole, Neomycin Sulfate, and Vancomycin) was shown to induce changes in peripheral immune regulation and protect mice from signs of experimental autoimmune encephalomyelitis (EAE). To determine if a shorter course of antibiotic pretreatment could also protect the mice from EAE and induce regulatory immune cells, studies were conducted using the same oral antibiotic cocktail for three days. In addition, the CNS was examined to determine the effects of antibiotic pretreatment on EAE disease course and immune modulation within the affected tissue. The shorter three day pretreatment course was also significantly protective against severe EAE in C57BL/6 mice. Moreover, our study found increased frequencies of regulatory cells and a decrease in the frequency of anti-inflammatory macrophages in the spleen of EAE protected mice. Additionally, a chemokine and chemokine receptor array run on mRNA from spinal cords revealed that genes associated with regulatory T cells and macrophage recruitment were strongly upregulated in the antibiotic pretreated mice. Additional RT-PCR data showed genes associated with anti-inflammatory microglia/macrophages were upregulated and pro-inflammatory genes were downregulated. This suggests the macrophages recruited to the spinal cord by chemokines are subsequently polarized toward an anti-inflammatory phenotype. These results lend strong support to the conclusion that a three day course of antibiotic treatment given prior to the induction of severe EAE profoundly protected the mice by inducing regulatory lymphocytes in the periphery and an anti-inflammatory milieu in the affected spinal cord tissue.

Berer K et al (2011) Commensal microbiota and myelin autoantigen cooperate to trigger autoimmune demyelination. Nature 479:538–541. https://doi.org/10.1038/nature10554 CrossRefPubMed

Bodhankar S, Chen Y, Lapato A, Vandenbark AA, Murphy SJ, Saugstad JA, Offner H (2015) Regulatory CD8(+)CD122 (+) T-cells predominate in CNS after treatment of experimental stroke in male mice with IL-10-secreting B-cells. Metab Brain Dis 30:911–924. https://doi.org/10.1007/s11011-014-9639-8 CrossRefPubMed

Dziembowska M, Tham TN, Lau P, Vitry S, Lazarini F, Dubois-Dalcq M (2005) A role for CXCR4 signaling in survival and migration of neural and oligodendrocyte precursors. Glia 50:258–269. https://doi.org/10.1002/glia.20170 CrossRefPubMed

Erny D et al (2015) Host microbiota constantly control maturation and function of microglia in the CNS. Nat Neurosci 18:965–977. https://doi.org/10.1038/nn.4030 CrossRefPubMedPubMedCentral

Fararjeh M, Mohammad MK, Bustanji Y, Alkhatib H, Abdalla S (2008) Evaluation of immunosuppression induced by metronidazole in Balb/c mice and human peripheral blood lymphocytes. Int Immunopharmacol 8:341–350. https://doi.org/10.1016/j.intimp.2007.10.018 CrossRefPubMed

Freedman SN, Shahi SK, Mangalam AK (2018) The "gut feeling": breaking down the role of gut microbiome in multiple sclerosis. Neurotherapeutics 15:109–125. https://doi.org/10.1007/s13311-017-0588-x CrossRefPubMed

Ivanov II et al (2008) Specific microbiota direct the differentiation of IL-17-producing T-helper cells in the mucosa of the small intestine. Cell Host Microbe 4:337–349. https://doi.org/10.1016/j.chom.2008.09.009 CrossRefPubMedPubMedCentral

Iwata Y et al (2011) Characterization of a rare IL-10-competent B-cell subset in humans that parallels mouse regulatory B10 cells. Blood 117:530–541. https://doi.org/10.1182/blood-2010-07-294249 CrossRefPubMedPubMedCentral

Kowarik MC et al (2012) CXCL13 is the major determinant for B cell recruitment to the CSF during neuroinflammation. J Neuroinflammation 9:93. https://doi.org/10.1186/1742-2094-9-93 CrossRefPubMedPubMedCentral

Lee YK, Menezes JS, Umesaki Y, Mazmanian SK (2011) Proinflammatory T-cell responses to gut microbiota promote experimental autoimmune encephalomyelitis. Proc Natl Acad Sci U S A 108(Suppl 1):4615–4622. https://doi.org/10.1073/pnas.1000082107 CrossRefPubMed

Lim HW, Lee J, Hillsamer P, Kim CH (2008) Human Th17 cells share major trafficking receptors with both polarized effector T cells and FOXP3+ regulatory T cells. J Immunol 180:122–129CrossRefPubMed

Liu J et al (2008) IFN-gamma and IL-17 production in experimental autoimmune encephalomyelitis depends on local APC-T cell complement production. J Immunol 180:5882–5889CrossRefPubMed

Livak KJ, Schmittgen TD (2001) Analysis of relative gene expression data using real-time quantitative PCR and the 2(−Delta Delta C(T)) Method. Methods 25:402–408. https://doi.org/10.1006/meth.2001.1262 CrossRefPubMed

Matsumoto M et al (2014) Interleukin-10-producing plasmablasts exert regulatory function in autoimmune inflammation. Immunity 41:1040–1051. https://doi.org/10.1016/j.immuni.2014.10.016 CrossRefPubMed

Meiron M, Zohar Y, Anunu R, Wildbaum G, Karin N (2008) CXCL12 (SDF-1alpha) suppresses ongoing experimental autoimmune encephalomyelitis by selecting antigen-specific regulatory T cells. J Exp Med 205:2643–2655. https://doi.org/10.1084/jem.20080730 CrossRefPubMedPubMedCentral

Mielcarz DW, Kasper LH (2015) The gut microbiome in multiple sclerosis. Curr Treat Options Neurol 17:344. https://doi.org/10.1007/s11940-015-0344-7 CrossRefPubMed

Niess JH, Leithauser F, Adler G, Reimann J (2008) Commensal gut flora drives the expansion of proinflammatory CD4 T cells in the colonic lamina propria under normal and inflammatory conditions. J Immunol 180:559–568CrossRefPubMed

Ochoa-Reparaz J, Kasper LH (2014) Gut microbiome and the risk factors in central nervous system autoimmunity. FEBS Lett 588:4214–4222. https://doi.org/10.1016/j.febslet.2014.09.024 CrossRefPubMedPubMedCentral

Ochoa-Reparaz J, Mielcarz DW, Ditrio LE, Burroughs AR, Foureau DM, Haque-Begum S, Kasper LH (2009) Role of gut commensal microflora in the development of experimental autoimmune encephalomyelitis. J Immunol 183:6041–6050. https://doi.org/10.4049/jimmunol.0900747 CrossRefPubMed

Ochoa-Reparaz J, Mielcarz DW, Haque-Begum S, Kasper LH (2010) Induction of a regulatory B cell population in experimental allergic encephalomyelitis by alteration of the gut commensal microflora. Gut Microbes 1:103–108. https://doi.org/10.4161/gmic.1.2.11515 CrossRefPubMedPubMedCentral

Palm NW, de Zoete MR, Flavell RA (2015) Immune-microbiota interactions in health and disease. Clin Immunol 159:122–127. https://doi.org/10.1016/j.clim.2015.05.014 CrossRefPubMedPubMedCentral

Rupprecht TA et al (2009) The chemokine CXCL13 is a key regulator of B cell recruitment to the cerebrospinal fluid in acute Lyme neuroborreliosis. J Neuroinflammation 6:42. https://doi.org/10.1186/1742-2094-6-42 CrossRefPubMedPubMedCentral

Shi Z, Rifa'i M, Lee YH, Shiku H, Isobe K, Suzuki H (2008) Importance of CD80/CD86-CD28 interactions in the recognition of target cells by CD8+CD122+ regulatory T cells. Immunology 124:121–128. https://doi.org/10.1111/j.1365-2567.2007.02747.x CrossRefPubMedPubMedCentral

Wang Y et al (2014) A commensal bacterial product elicits and modulates migratory capacity of CD39(+) CD4 T regulatory subsets in the suppression of neuroinflammation. Gut Microbes 5:552–561. https://doi.org/10.4161/gmic.29797 CrossRefPubMed

Zhang J, Lapato A, Bodhankar S, Vandenbark AA, Offner H (2015) Treatment with IL-10 producing B cells in combination with E2 ameliorates EAE severity and decreases CNS inflammation in B cell-deficient mice. Metab Brain Dis 30:1117–1127. https://doi.org/10.1007/s11011-015-9661-5 CrossRefPubMedPubMedCentral

Title: Antibiotics protect against EAE by increasing regulatory and anti-inflammatory cells
Authors: Hilary A. Seifert
Gil Benedek
Ha Nguyen
Grant Gerstner
Ying Zhang
Gail Kent
Arthur A. Vandenbark
Jürgen Bernhagen
Halina Offner
Publication date: 01-10-2018
Publisher: Springer US
Published in: Metabolic Brain Disease / Issue 5/2018
Print ISSN: 0885-7490
Electronic ISSN: 1573-7365
DOI: https://doi.org/10.1007/s11011-018-0266-7

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Antibiotics protect against EAE by increasing regulatory and anti-inflammatory cells

Abstract

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Springer Medicine

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