Epsilon toxin-producing Clostridium perfringens colonize the multiple sclerosis gut microbiome overcoming CNS immune privilege.
Epsilon toxin-producing Clostridium perfringens colonize the multiple sclerosis gut microbiome overcoming CNS immune privilege.
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DOI：
10.1172/jci163239
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发表时间：
2023-05-01
影响因子：
15.9
通讯作者：
Vartanian, Timothy
中科院分区：
文献类型：
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作者：
Ma, Yinghua;Sannino, David;Linden, Jennifer R.;Haigh, Sylvia;Zhao, Baohua;Grigg, John B.;Zumbo, Paul;Duendar, Friederike;Butler, Daniel;Profaci, Caterina P.;Telesford, Kiel;Winokur, Paige N.;Rumah, Kareem R.;Gauthier, Susan A.;Fischetti, Vincent A.;McClane, Bruce A.;Uzal, Francisco A.;Zexter, Lily;Mazzucco, Michael;Rudick, Richard;Danko, David;Balmuth, Evan;Nealon, Nancy;Perumal, Jai;Kaunzner, Ulrike;Brito, Ilana L.;Chen, Zhengming;Xiang, Jenny Z.;Betel, Doron;Daneman, Richard;Sonnenberg, Gregory F.;Mason, Christopher E.;Vartanian, Timothy
多发性硬化症 (MS) 是一种复杂的中枢神经系统疾病，被认为需要环境触发。肠道菌群失调在多发性硬化症中很常见，但具体致病菌种尚不清楚。为了解决这一知识差距，我们使用灵敏的定量 PCR 检测来表明，与健康对照 (HC) 个体相比，多发性硬化症患者的肠道微生物组中更有可能藏匿并显示出更丰富的产气荚膜梭菌产生 epsilon 毒素（ETX）菌株。来自多发性硬化症患者的分离株产生功能性 ETX，并具有高度接合质粒的典型遗传结构。在实验性自身免疫性脑脊髓炎（EAE）的主动免疫模型中，使用百日咳毒素（PTX）克服中枢神经系统免疫特权，ETX可以替代PTX。与 PTX 诱导的 EAE 相比，炎症性脱髓鞘主要局限于脊髓，而 ETX 诱导的 EAE 引起胼胝体、丘脑、小脑、脑干和脊髓脱髓鞘，更类似于 MS 中看到的神经解剖学病变分布。 CNS 内皮细胞转录谱揭示了 ETX 诱导的基因，这些基因已知在克服 CNS 免疫特权中发挥作用。总之，这些发现表明，产生 ETX 的产气荚膜梭菌菌株是多发性硬化症中生物学上合理的病原体，可在循环髓磷脂自身反应性淋巴细胞的背景下引发炎症脱髓鞘。
Multiple sclerosis (MS) is a complex disease of the CNS thought to require an environmental trigger. Gut dysbiosis is common in MS, but specific causative species are unknown. To address this knowledge gap, we used sensitive and quantitative PCR detection to show that people with MS were more likely to harbor and show a greater abundance of epsilon toxin–producing (ETX-producing) strains of C. perfringens within their gut microbiomes compared with individuals who are healthy controls (HCs). Isolates derived from patients with MS produced functional ETX and had a genetic architecture typical of highly conjugative plasmids. In the active immunization model of experimental autoimmune encephalomyelitis (EAE), where pertussis toxin (PTX) is used to overcome CNS immune privilege, ETX can substitute for PTX. In contrast to PTX-induced EAE, where inflammatory demyelination is largely restricted to the spinal cord, ETX-induced EAE caused demyelination in the corpus callosum, thalamus, cerebellum, brainstem, and spinal cord, more akin to the neuroanatomical lesion distribution seen in MS. CNS endothelial cell transcriptional profiles revealed ETX-induced genes that are known to play a role in overcoming CNS immune privilege. Together, these findings suggest that ETX-producing C. perfringens strains are biologically plausible pathogens in MS that trigger inflammatory demyelination in the context of circulating myelin autoreactive lymphocytes.