Intestinal Barrier Breakdown and Mucosal Microbiota Disturbance in Neuromyelitis Optical Spectrum Disorders
Intestinal Barrier Breakdown and Mucosal Microbiota Disturbance in Neuromyelitis Optical Spectrum Disorders
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神经脊髓炎光谱疾病中的肠道屏障破坏和粘膜微生物群紊乱
DOI：
10.3389/fimmu.2020.02101
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发表时间：
2020-09-02
影响因子：
7.3
通讯作者：
Qiu, Wei
中科院分区：
文献类型：
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作者：
Cui, Chunping;Tan, Sha;Qiu, Wei
背景与目的尽管星形胶质细胞水通道蛋白水通道蛋白AQP4的抗体发挥了重要作用，但视神经脊髓炎光谱障碍(NMOSD)的发病机制仍不清楚。我们先前的研究表明，NMOSD患者的粪便微生物区系发生了生态失调。在这项研究中，我们进一步调查了NMOSD患者的肠道屏障和粘膜菌群平衡是否也被破坏。方法收集6例NMOSD患者乙状结肠黏膜活检标本，并与5例健康对照(HC)标本进行比较。对这些样本进行电子显微镜和免疫组织化学处理，以研究超微结构以及肠炎性细胞的数量和大小的变化。用高通量16S核糖体RNA基因扩增序列分析粘膜菌群的变化。结果细菌rRNA基因测序结果显示，NMOSD患者结肠组织中细菌多样性降低，但链球菌属和颗粒菌较多。NMOSD组结肠黏膜上皮细胞间隙较HC组明显增宽(p<；0.01)，紧密连接蛋白[occludin、claudin-1和zonula occludens-1(ZO-1)]的表达明显低于HC组。NMOSD患者黏膜固有层内可见大量活化的巨噬细胞，胞质内有大量包涵体，肥大细胞胞浆内颗粒较多，胞浆细胞增大，粗面内质网发达。定量分析显示，NMOSD患者小CD38+、CD138+细胞(浆细胞)比例较低，较大浆细胞比例较高。结论NMOSD患者存在肠道屏障功能障碍，并伴有肠道生物失调和炎性激活。粘膜微生物区系失衡和炎症反应可能使病原体穿过受损的肠道屏障，参与NMOSD的病理过程。然而，NMOSD肠道生物失调的病理机制有待于进一步研究。
Background and Purpose The mechanism underlying the pathology of neuromyelitis optica spectrum disorders (NMOSD) remains unclear even though antibodies to the water channel protein aquaporin-4 (AQP4) on astrocytes play important roles. Our previous study showed that dysbiosis occurred in the fecal microbiota of NMOSD patients. In this study, we further investigated whether the intestinal barrier and mucosal flora balance are also interrupted in NMOSD patients. Methods Sigmoid mucosal biopsies were collected by endoscopy from six patients with NMOSD and compared with samples from five healthy control (HC) individuals. These samples were processed for electron microscopy and immunohistochemistry to investigate changes in ultrastructure and in the number and size of intestinal inflammatory cells. Changes in mucosal flora were also analyzed by high-throughput 16S ribosomal RNA gene amplicon sequencing. Results The results from bacterial rRNA gene sequencing showed that bacterial diversity was decreased, butStreptococcusandGranulicatellawere abundant in the colonic mucosa specimens of NMOSD patients compared to the HC individuals. The intercellular space between epithelia of the colonic mucosa was wider in NMOSD patients compared to the HC subjects (p< 0.01), and the expression of tight junction proteins [occludin, claudin-1 and zonula occludens-1 (ZO-1)] in NMOSD patients significantly decreased compared to that in the HC subjects. We also found numerous activated macrophages with many inclusions within the cytoplasm, mast cells with many particles in their cytoplasm, and enlarged plasma cells with rich developed rough endoplasmic reticulum in the lamina propria of the mucosa of the patients with NMOSD. Quantitative analysis showed that the percentages of small CD38+ and CD138+ cells (plasma cells) were lower, but the percentage of larger plasma cells was higher in NMOSD patients. Conclusion The present study demonstrated that the intestinal barrier was disrupted in the patients with NMOSD, accompanied by dysbiosis and inflammatory activation of the gut. The mucosal microbiota imbalance and inflammatory responses might allow pathogens to cross the damaged intestinal barrier and participate in pathological process in NMOSD. However, further study on the pathological mechanism of NMOSD underlying gut dysbiosis is warranted in the future.