Department of Immunology, Juntendo University School of Medicine, Bunkyo-ku, Tokyo, Japan.
Department of Neurology, Juntendo University School of Medicine, Bunkyo-ku, Tokyo, Japan.
J Neuroinflammation. 2019 Aug 9;16(1):165. doi: 10.1186/s12974-019-1552-y.
The association of gut microbiota and diseases of the central nervous system (CNS), including multiple sclerosis (MS), has attracted much attention. Although a previous analysis of MS gut microbiota revealed a reduction in species producing short-chain fatty acids (SCFAs), the influence of these metabolites on demyelination and remyelination, the critical factors of MS pathogenesis, remains unclear.
To investigate the relationship between demyelination and gut microbiota, we administered a mixture of non-absorbing antibiotics or SCFAs to mice with cuprizone-induced demyelination and evaluated demyelination and the accumulation of microglia. To analyze the direct effect of SCFAs on demyelination or remyelination, we induced demyelination in an organotypic cerebellar slice culture using lysolecithin and analyzed the demyelination and maturation of oligodendrocyte precursor cells with or without SCFA treatment.
The oral administration of antibiotics significantly enhanced cuprizone-induced demyelination. The oral administration of butyrate significantly ameliorated demyelination, even though the accumulation of microglia into demyelinated lesions was not affected. Furthermore, we showed that butyrate treatment significantly suppressed lysolecithin-induced demyelination and enhanced remyelination in an organotypic slice culture in the presence or absence of microglia, suggesting that butyrate may affect oligodendrocytes directly. Butyrate treatment facilitated the differentiation of immature oligodendrocytes.
We revealed that treatment with butyrate suppressed demyelination and enhanced remyelination in an organotypic slice culture in association with facilitating oligodendrocyte differentiation. Our findings shed light on a novel mechanism of interaction between the metabolites of gut microbiota and the CNS and may provide a strategy to control demyelination and remyelination in MS.
肠道微生物群与中枢神经系统（CNS）疾病的关联，包括多发性硬化症（MS），已引起广泛关注。虽然先前对 MS 肠道微生物群的分析显示产生短链脂肪酸（SCFA）的物种减少，但这些代谢物对脱髓鞘和髓鞘再生的影响，即 MS 发病机制的关键因素，仍不清楚。
为了研究脱髓鞘与肠道微生物群之间的关系，我们用非吸收性抗生素或 SCFAs 混合物处理杯状朊病毒诱导脱髓鞘的小鼠，并评估脱髓鞘和小胶质细胞的积累。为了分析 SCFAs 对脱髓鞘或髓鞘再生的直接影响，我们用溶血磷脂酰胆碱诱导器官型小脑切片培养中的脱髓鞘，并在有或没有 SCFA 处理的情况下分析脱髓鞘和少突胶质前体细胞的成熟。
抗生素的口服给药显著增强了杯状朊病毒诱导的脱髓鞘。丁酸盐的口服给药显著改善了脱髓鞘，尽管对脱髓鞘病变中小胶质细胞的积累没有影响。此外，我们表明丁酸盐处理显著抑制了溶酶体磷脂酰胆碱诱导的脱髓鞘，并增强了在存在或不存在小胶质细胞的器官型切片培养中的髓鞘再生，表明丁酸盐可能直接影响少突胶质细胞。丁酸盐处理促进不成熟少突胶质细胞的分化。
我们揭示了丁酸盐治疗在器官型切片培养中抑制脱髓鞘和增强髓鞘再生，同时促进少突胶质细胞分化。我们的发现揭示了肠道微生物群代谢物与 CNS 之间相互作用的新机制，并可能为控制 MS 中的脱髓鞘和髓鞘再生提供一种策略。
