Manipulation of Gut Microbiota Influences Immune Responses, Axon Preservation, and Motor Disability in a Model of Progressive Multiple Sclerosis
Manipulation of Gut Microbiota Influences Immune Responses, Axon Preservation, and Motor Disability in a Model of Progressive Multiple Sclerosis
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DOI：
10.3389/fimmu.2019.01374
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发表时间：
2019-06-14
影响因子：
7.3
通讯作者：
Guaza, Carmen
中科院分区：
文献类型：
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作者：
Mestre, Leyre;Javier Carrillo-Salinas, Francisco;Guaza, Carmen
肠道菌群失调与多发性硬化症和其他免疫性疾病有关，尽管目前尚不清楚如何操纵肠道菌群可能影响病程。通过建立由颅内感染Theiler's小鼠脑脊髓炎病毒（TMEV）引发的进展性MS模型，我们试图确定在疾病症状前和症状期口服抗生素（ABX）诱导的生态失调是否会影响其病程。我们还讨论了在益生菌存在或不存在的情况下停用ABX后微生物群再定殖的影响。评估中枢和外周免疫、血浆乙酸和丁酸水平、轴突损伤和运动障碍。ABX鸡尾酒可预防小鼠运动功能障碍并限制轴突损伤，小鼠中枢神经系统中CD4（+）和CD8(+) T细胞减少，而肠道微生物群再定殖使运动功能和轴突完整性恶化。ABX保护作用的潜在机制似乎与进入中枢神经系统的CD4(+)CD39(+) T细胞和CD5(+)CD1d(+) B细胞有关。此外，在给予ABX的TMEV小鼠脊髓中，小胶质细胞采用与抗炎基因谱相关的圆形变形虫形态。脾脏和肠系膜淋巴结的免疫变化不大，但ABX治疗小鼠体内限制了IL-17的产生。总的来说，我们的研究结果提供了证据，证明肠道微生物群操纵与进展性MS模型中神经退行性状态和疾病严重程度的功能相关性，并强化了肠道微生物群作为MS治疗靶点的作用。
Gut microbiota dysbiosis has been implicated in MS and other immune diseases, although it remains unclear how manipulating the gut microbiota may affect the disease course. Using a well-established model of progressive MS triggered by intracranial infection with Theiler's murine encephalomyelitis virus (TMEV), we sought to determine whether dysbiosis induced by oral antibiotics (ABX) administered on pre-symptomatic and symptomatic phases of the disease influences its course. We also addressed the effects of microbiota recolonization after ABX withdrawn in the presence or absence of probiotics. Central and peripheral immunity, plasma acetate and butyrate levels, axon damage and motor disability were evaluated. The cocktail of ABX prevented motor dysfunction and limited axon damage in mice, which had fewer CD4(+) and CD8(+) T cells in the CNS, while gut microbiota recolonization worsened motor function and axonal integrity. The underlying mechanisms of ABX protective effects seem to involve CD4(+)CD39(+) T cells and CD5(+)CD1d(+) B cells into the CNS. In addition, microglia adopted a round amoeboid morphology associated to an anti-inflammatory gene profile in the spinal cord of TMEV mice administered ABX. The immune changes in the spleen and mesenteric lymph nodes were modest, yet ABX treatment of mice limited IL-17 production ex vivo. Collectively, our results provide evidence of the functional relevance of gut microbiota manipulation on the neurodegenerative state and disease severity in a model of progressive MS and reinforce the role of gut microbiota as target for MS treatment.