Department of Cell and Organism Biology, Lund University, Lund, Sweden.
PLoS One. 2010 Feb 2;5(2):e9009. doi: 10.1371/journal.pone.0009009.
Multiple 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 FINDINGS: The 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-beta1, 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/SIGNIFICANCE: Our 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.
多发性硬化症（MS）是一种中枢神经系统（CNS）的慢性炎症性自身免疫性疾病。一种治疗多发性硬化症的潜在策略是诱导调节性细胞，介导免疫耐受。益生菌，包括乳杆菌，已知具有诱导免疫调节活性的作用，在炎症性疾病中具有良好的效果。我们测试了各种乳杆菌菌株对实验性自身免疫性脑脊髓炎（EAE）的抑制作用，EAE 是多发性硬化症的动物模型。
方法/主要发现：我们在发生 EAE 的小鼠中研究了五种每日给予的乳杆菌菌株的预防作用。经过初步筛选，选择了三种减少中枢神经系统炎症和自身反应性 T 细胞反应的乳杆菌菌株：副干酪乳杆菌 DSM 13434、植物乳杆菌 DSM 15312 和 DSM 15313。副干酪乳杆菌和植物乳杆菌 DSM 15312 在肠系膜淋巴结（MLNs）中诱导 CD4+CD25+Foxp3+调节性 T 细胞（Tregs），并增强血清 TGF-β1 的产生，而植物乳杆菌 DSM 15313 增加了血清 IL-27 水平。对所选菌株的进一步筛选表明，每种单菌株益生菌在患病小鼠中均未能发挥治疗作用，而三种乳杆菌菌株的混合物可抑制疾病的进展并逆转 EAE 的临床和组织学征象。抑制活性与 MLNs、脾脏和血液中促炎 Th1 和 Th17 细胞因子的衰减以及 IL-10 的诱导相关。额外的过继转移研究表明，IL-10 产生的 CD4+CD25+Tregs 参与了乳杆菌混合物诱导的抑制作用。
结论/意义：我们的数据提供了证据，表明所选益生菌乳杆菌混合物的治疗效果与诱导 MLNs 中可转移的耐受原性 Tregs 有关，但也与外周和中枢神经系统有关，这是通过 IL-10 依赖的机制介导的。我们的发现表明口服给予益生菌组合具有治疗潜力，并提供了对有助于自身免疫性疾病有益效果的宿主共生相互作用的更全面理解。
