A Novel Probiotic Mixture Exerts a Therapeutic Effect on Experimental Autoimmune Encephalomyelitis Mediated by IL-10 Producing Regulatory T Cells

Shahram Lavasani,Sophia Buske,Björn Weström,Bengt Jeppsson,Mehrnaz Nouri,Henrik Thorlacius,Frida Fåk,Balik Dzhambazov,Jan Alenfall,Göran Molin,Derya Unutmaz

doi:10.1371/journal.pone.0009009

Abstract

BackgroundMultiple sclerosis (MS) is a chronic inflammatory autoimmune disease of the central nervous system (CNS). One potential therapeutic strategy for MS is to induce regulatory cells that mediate immunological tolerance. Probiotics, including lactobacilli, are known to induce immunomodulatory activity with promising effects in inflammatory diseases. We tested the potential of various strains of lactobacilli for suppression of experimental autoimmune encephalomyelitis (EAE), an animal model of MS.Methodology/Principal FindingsThe preventive effects of five daily-administered strains of lactobacilli were investigated in mice developing EAE. After a primary screening, three Lactobacillus strains, L. paracasei DSM 13434, L. plantarum DSM 15312 and DSM 15313 that reduced inflammation in CNS and autoreactive T cell responses were chosen. L. paracasei and L. plantarum DSM 15312 induced CD4+CD25+Foxp3+ regulatory T cells (Tregs) in mesenteric lymph nodes (MLNs) and enhanced production of serum TGF-β1, while L. plantarum DSM 15313 increased serum IL-27 levels. Further screening of the chosen strains showed that each monostrain probiotic failed to be therapeutic in diseased mice, while a mixture of the three lactobacilli strains suppressed the progression and reversed the clinical and histological signs of EAE. The suppressive activity correlated with attenuation of pro-inflammatory Th1 and Th17 cytokines followed by IL-10 induction in MLNs, spleen and blood. Additional adoptive transfer studies demonstrated that IL-10 producing CD4+CD25+ Tregs are involved in the suppressive effect induced by the lactobacilli mixture.Conclusions/SignificanceOur data provide evidence showing that the therapeutic effect of the chosen mixture of probiotic lactobacilli was associated with induction of transferable tolerogenic Tregs in MLNs, but also in the periphery and the CNS, mediated through an IL-10-dependent mechanism. Our findings indicate a therapeutic potential of oral administration of a combination of probiotics and provide a more complete understanding of the host-commensal interactions that contribute to beneficial effects in autoimmune diseases.

Highlights

Multiple sclerosis (MS) is believed to be a T cell-mediated inflammatory autoimmune disease directed against myelin or oligodendrocytes in the central nervous system (CNS) and considered as one of the most common neurological diseases of young adults in Europe and North America [1]
We found that the immunosuppressive potential of these probiotic strains was associated with induction of Tregs and production of IL-4, IL-10 and transforming growth factor (TGF)-b1 in mesenteric lymph nodes (MLNs) and spleen
In order to examine the ability of probiotic lactobacilli to affect systemic immune responses by suppressing the T cell-mediated chronic inflammation in the CNS, five different strains, L. paracasei DSM 13434, L. plantarum DSM 15312, L. plantarum DSM 15313 L. paracasei PCC 101, L. delbrueckii DSM 20081 or vehicle as control, were orally administered daily to groups of C57BL/6 mice, starting 12 days prior to immunization for EAE

Summary

Introduction

Multiple sclerosis (MS) is believed to be a T cell-mediated inflammatory autoimmune disease directed against myelin or oligodendrocytes in the central nervous system (CNS) and considered as one of the most common neurological diseases of young adults in Europe and North America [1]. Experimental autoimmune encephalomyelitis (EAE) in mice is an established animal model for MS sharing a number of clinical, genetic and immunological features with the human disease, which makes it suitable to elucidate the pathogenesis and devise therapy [3]. One potential therapeutic strategy for MS is to induce regulatory cells that mediate immunological tolerance. We tested the potential of various strains of lactobacilli for suppression of experimental autoimmune encephalomyelitis (EAE), an animal model of MS

Methods

Results

Conclusion