Multiple Sclerosis Center, Department of Neurology, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China.
Department of Gastroenterology, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China.
Front Immunol. 2020 Sep 2;11:2101. doi: 10.3389/fimmu.2020.02101. eCollection 2020.
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.
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.
The results from bacterial rRNA gene sequencing showed that bacterial diversity was decreased, but and were 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 ( < 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.
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.
尽管水通道蛋白 4（AQP4）在星形胶质细胞上的抗体在视神经脊髓炎谱系疾病（NMOSD）的发病机制中起着重要作用，但 NMOSD 的病理学机制仍不清楚。我们之前的研究表明，NMOSD 患者的粪便微生物群发生了失调。在本研究中，我们进一步研究了 NMOSD 患者的肠道屏障和黏膜菌群平衡是否也受到了干扰。
通过内镜从 6 名 NMOSD 患者中采集乙状结肠黏膜活检，并与 5 名健康对照（HC）个体的样本进行比较。这些样本经过电子显微镜和免疫组织化学处理，以研究超微结构以及肠道炎症细胞的数量和大小的变化。还通过高通量 16S 核糖体 RNA 基因扩增子测序分析黏膜菌群的变化。
细菌 rRNA 基因测序结果显示，NMOSD 患者结肠黏膜标本中的细菌多样性减少，但 和 丰富。与 HC 受试者相比，NMOSD 患者的结肠黏膜上皮细胞之间的细胞间隙更宽（<0.01），并且 NMOSD 患者的紧密连接蛋白[紧密连接蛋白（occludin）、claudin-1 和 zonula occludens-1（ZO-1）]的表达明显低于 HC 受试者。我们还发现大量活化的巨噬细胞，其细胞质内有许多内含物，肥大细胞的细胞质内有许多颗粒，黏膜固有层的浆细胞体积增大，内质网发达。定量分析显示，NMOSD 患者的小 CD38+和 CD138+细胞（浆细胞）的百分比较低，但较大浆细胞的百分比较高。
本研究表明 NMOSD 患者的肠道屏障受到破坏，同时伴有肠道菌群失调和炎症激活。黏膜微生物群失衡和炎症反应可能使病原体穿过受损的肠道屏障，并参与 NMOSD 的病理过程。然而，未来仍需要进一步研究 NMOSD 肠道菌群失调的病理机制。
