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.
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Funding
This work was supported by Deutsche Forschungsgemeinschaft (DFG) EXC1010 SyNergy (JB), NIH, National Institute Of Neurological Disorders And Stroke of the National Institutes R01NS080890 (HO) and the Department of Veterans Affairs IO1 BX000226-09 and 1 IK6 BX004209 (AAV). This material is also the result of work supported with resources and the use of facilities at the VA Portland Health Care Center in Portland, Oregon. The contents do not represent the views of the U.S. Department of Veterans Affairs, the United States Government or the official views of the National Institutes of Health.
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All applicable international, national and/or institutional guidelines for the care and use of animals were followed. All procedures performed in studies involving animals were in accordance with the ethical standards of the institution or practice at which the studies were conducted. This article does not contain any studies with human participants performed by any of the authors.
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Seifert, H.A., Benedek, G., Nguyen, H. et al. Antibiotics protect against EAE by increasing regulatory and anti-inflammatory cells. Metab Brain Dis 33, 1599–1607 (2018). https://doi.org/10.1007/s11011-018-0266-7
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DOI: https://doi.org/10.1007/s11011-018-0266-7