Oral microbiome link to neurodegeneration in glaucoma.
Oral microbiome link to neurodegeneration in glaucoma.
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DOI：
10.1371/journal.pone.0104416
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发表时间：
2014
期刊：
影响因子：
3.7
通讯作者：
Danias J
中科院分区：
文献类型：
--
作者：
Astafurov K;Elhawy E;Ren L;Dong CQ;Igboin C;Hyman L;Griffen A;Mittag T;Danias J
青光眼是一种进行性视神经退行性疾病，常导致失明。局部炎症反应与青光眼的病理学有关。虽然CNS外的炎症发作，如急性全身性感染，与中枢神经变性有关，但它们似乎与青光眼无关。基于临床观察，我们假设慢性亚临床外周炎症有助于青光眼的神经变性。分析了青光眼患者和对照组的漱口水样本中的细菌数量。为了确定可能的致病机制，在两种不同的青光眼动物模型中给予低剂量皮下脂多糖（LPS）。两个月后评估视网膜和视神经的青光眼性神经变性。在视网膜和视神经中分析Toll样受体4（TLR 4）信号通路和补体的基因表达的变化以及小胶质细胞数量和形态的变化。测定纳洛酮对TLR 4的药理学阻断作用。青光眼患者的口腔细菌计数高于对照组（p<0.017）。在青光眼动物模型中给予低剂量LPS导致轴突变性和神经元丢失的增强。观察到视神经和视网膜中的小胶质细胞活化以及TLR 4信号传导和补体系统的上调。药物阻断TLR 4部分改善了增强的损伤。上述发现表明，口腔微生物组有助于青光眼病理生理学。在该疾病的动物模型中进行的实验提供了一种合理的机制，通过该机制增加的细菌负荷可以导致神经变性，并且该机制涉及视网膜和视神经中的小胶质细胞的激活，通过TLR 4信号传导和补体上调介导。肠道细菌可能在神经胶质瘤病理学的发展和/或进展中发挥作用的发现也可能与其他慢性神经退行性疾病有关。
Glaucoma is a progressive optic nerve degenerative disease that often leads to blindness. Local inflammatory responses are implicated in the pathology of glaucoma. Although inflammatory episodes outside the CNS, such as those due to acute systemic infections, have been linked to central neurodegeneration, they do not appear to be relevant to glaucoma. Based on clinical observations, we hypothesized that chronic subclinical peripheral inflammation contributes to neurodegeneration in glaucoma. Mouthwash specimens from patients with glaucoma and control subjects were analyzed for the amount of bacteria. To determine a possible pathogenic mechanism, low-dose subcutaneous lipopolysaccharide (LPS) was administered in two separate animal models of glaucoma. Glaucomatous neurodegeneration was assessed in the retina and optic nerve two months later. Changes in gene expression of toll-like receptor 4 (TLR4) signaling pathway and complement as well as changes in microglial numbers and morphology were analyzed in the retina and optic nerve. The effect of pharmacologic blockade of TLR4 with naloxone was determined. Patients with glaucoma had higher bacterial oral counts compared to control subjects (p<0.017). Low-dose LPS administration in glaucoma animal models resulted in enhancement of axonal degeneration and neuronal loss. Microglial activation in the optic nerve and retina as well as upregulation of TLR4 signaling and complement system were observed. Pharmacologic blockade of TLR4 partially ameliorated the enhanced damage. The above findings suggest that the oral microbiome contributes to glaucoma pathophysiology. A plausible mechanism by which increased bacterial loads can lead to neurodegeneration is provided by experiments in animal models of the disease and involves activation of microglia in the retina and optic nerve, mediated through TLR4 signaling and complement upregulation. The finding that commensal bacteria may play a role in the development and/or progression of glaucomatous pathology may also be relevant to other chronic neurodegenerative disorders.
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