Department of Neurological Sciences, The University of Vermont, Burlington, VT, USA.
Department of Pharmacology, The University of Vermont, Burlington, VT, USA.
Neurogastroenterol Motil. 2018 Sep;30(9):e13349. doi: 10.1111/nmo.13349. Epub 2018 Apr 11.
Multiple sclerosis (MS) is an autoimmune disease of the central nervous system that, in addition to motor, sensory, and cognitive symptoms, also causes constipation, which is poorly understood. Here, we characterize gastrointestinal (GI) dysmotility in the experimental autoimmune encephalomyelitis (EAE) mouse model of MS and evaluate whether autoantibodies target the enteric nervous system (ENS) and cause dysmotility.
EAE was induced in male SJL and B6 mice. GI motility was assessed in vivo and ex vivo in wild type (WT) and B cell-deficient mice. MS and EAE serum was used to survey potential targets in the ENS and changes in the ENS structure were characterized using immunohistochemistry.
EAE mice developed accelerated gastric emptying and delayed whole GI transit with reduced colonic motility. Fecal water content was reduced, and colonic migrating myoelectrical complexes (CMMC) and slow waves were less frequent. Colons from EAE mice exhibited decreased GFAP levels in glia. Sera from MS patients and from EAE mice targeted ENS neurons and glia. B-cell deficiency in EAE protected against colonic dysmotility.
CONCLUSIONS & INFERENCES: Consistent with symptoms experienced in MS, we demonstrate that EAE mice widely exhibit features of GI dysmotility that persisted in the absence of extrinsic innervation, suggesting direct involvement of ENS neurocircuitry. The absence of GI dysmotility in B cell-deficient mice with EAE together with EAE and MS serum immunoreactivity against ENS targets suggests that MS could be classified among other diseases known to induce autoimmune GI dysmotility.
多发性硬化症（MS）是一种中枢神经系统自身免疫性疾病，除了运动、感觉和认知症状外，还会导致便秘，但其发病机制尚不清楚。在这里，我们描述了实验性自身免疫性脑脊髓炎（EAE）MS 小鼠模型中的胃肠道（GI）动力障碍，并评估了自身抗体是否靶向肠神经系统（ENS）并导致动力障碍。
在雄性 SJL 和 B6 小鼠中诱导 EAE。在野生型（WT）和 B 细胞缺陷小鼠中体内和离体评估 GI 动力。使用 MS 和 EAE 血清来调查 ENS 中的潜在靶点，并使用免疫组织化学方法来描述 ENS 结构的变化。
EAE 小鼠表现出加速的胃排空和整个 GI 转运延迟，结肠运动减少。粪便含水量减少，结肠移行性肌电复合波（CMMC）和慢波减少。EAE 小鼠的结肠中胶质细胞的 GFAP 水平降低。MS 患者和 EAE 小鼠的血清靶向 ENS 神经元和胶质细胞。EAE 中的 B 细胞缺陷可预防结肠动力障碍。
与 MS 患者的症状一致，我们证明 EAE 小鼠广泛表现出 GI 动力障碍的特征，即使在没有外在神经支配的情况下，也提示 ENS 神经回路的直接参与。EAE 中缺乏 B 细胞的小鼠没有 GI 动力障碍，以及 EAE 和 MS 血清对 ENS 靶标的免疫反应性提示 MS 可归类于其他已知可引起自身免疫性 GI 动力障碍的疾病。
