Fermented butyrate exhibits an anti-inflammatory response to maintain immune homeostasis within the gut. However, the effect and underlying mechanism of butyrate on myasthenia gravis (MG) remain unclear. The changes in the gut microbiota and fecal contents of SCFAs in MG patients were examined. R97-116 peptide was used to induce the experimental autoimmune myasthenia gravis (EAMG) mice and sodium butyrate (NaB) was gavaged to the EAMG mice. Gut microbiota, the frequency of Th1, Th17, Treg, Tfh, and B cells, the levels of IFN-γ, IL-17 A, IL-10, IL-21, and anti-R97-116 IgG, RNA-seq of total B cells in the spleen were explored by metagenomics, flow cytometry, ELISA, and transcriptomics. A significant reduction in SCFA-producing bacteria including Butyricimonas synergistica and functional modules including butyrate synthesis/production II was observed in MG patients and fecal SCFAs detection confirmed the increase. The EAMG mice were successfully constructed and NaB supplementation has changed the composition and function of the gut microbiota. The numbers of Th1, Th17, Tfh, and B cells were significantly increased while that of Treg cells was obviously decreased in EAMG mice compared with controls. Interestingly, NaB treatment has reduced the amounts of Th17, Tfh, and B cells but increased that of Treg cells. Accordingly, the levels of IL-17 A, IL-21, and IgG were increased while IL-10 was decreased in EAMG mice. However, NaB treatment reduced IL-17 A and IL-21 but increased that of IL-10. RNA-seq of B cells has revealed 4577 deferentially expressed genes (DEGs), in which 1218 DEGs were up-regulated while 3359 DEGs were down-regulated in NaB-treated EAMG mice. GO enrichment and KEGG pathway analysis unveiled that the function of these DEGs was mainly focused on immunoglobulin production, mitochondrial respiratory chain complex, ribosome, oxidative phosphorylation, and CNS diseases including amyotrophic lateral sclerosis. We have found that butyrate was significantly reduced in MG patients and NaB gavage could evidently improve MG symptoms in EAMG mice by changing the gut microbiota, regulating the immune response, and altering the gene expression and function of B cells, suggesting NaB might be a potential immunomodulatory supplement for MG drugs.

中文翻译：

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丁酸钠通过改善肠道微生物群和调节免疫反应减轻 R97-116 肽诱导的小鼠重症肌无力

发酵丁酸盐表现出抗炎反应，以维持肠道内的免疫稳态。然而，丁酸盐对重症肌无力（MG）的作用和潜在机制仍不清楚。检查了 MG 患者肠道微生物群和粪便 SCFA 含量的变化。使用R97-116肽诱导实验性自身免疫性重症肌无力(EAMG)小鼠，并给EAMG小鼠灌胃丁酸钠(NaB)。肠道微生物群，Th1、Th17、Treg、Tfh 和 B 细胞的频率，IFN-γ、IL-17 A、IL-10、IL-21 和抗 R97-116 IgG 的水平，RNA-seq通过宏基因组学、流式细胞术、ELISA 和转录组学研究了脾脏中的总 B 细胞。在 MG 患者中观察到产生 SCFA 的细菌（包括 Butyricimonas synergistica）和功能模块（包括丁酸合成/生产 II）显着减少，粪便 SCFA 检测证实了这种增加。EAMG 小鼠构建成功，NaB 补充剂改变了肠道微生物群的组成和功能。与对照组相比，EAMG小鼠Th1、Th17、Tfh和B细胞数量明显增加，Treg细胞数量明显减少。有趣的是，NaB 治疗减少了 Th17、Tfh 和 B 细胞的数量，但增加了 Treg 细胞的数量。因此，EAMG 小鼠中 IL-17A、IL-21 和 IgG 的水平升高，而 IL-10 的水平降低。然而，NaB 处理降低了 IL-17A 和 IL-21，但增加了 IL-10。B细胞的RNA-seq揭示了NaB处理的EAMG小鼠中有4577个差异表达基因（DEG），其中1218个DEG上调，而3359个DEG下调。GO富集和KEGG通路分析揭示这些DEG的功能主要集中在免疫球蛋白产生、线粒体呼吸链复合物、核糖体、氧化磷酸化和包括肌萎缩侧索硬化症在内的中枢神经系统疾病。我们发现 MG 患者的丁酸盐显着减少，并且 NaB 灌胃可以通过改变肠道微生物群、调节免疫反应、改变 B 细胞的基因表达和功能，明显改善 EAMG 小鼠的 MG 症状，这表明 NaB 可能是一种潜在的治疗方法。 MG 药物的免疫调节补充剂。