Leaky intestine and impaired microbiome in an amyotrophic lateral sclerosis mouse model.
Leaky intestine and impaired microbiome in an amyotrophic lateral sclerosis mouse model.
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DOI：
10.14814/phy2.12356
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发表时间：
2015-04
影响因子：
2.5
通讯作者：
Sun J
中科院分区：
文献类型：
--
作者：
Wu S;Yi J;Zhang YG;Zhou J;Sun J
新出现的证据表明，肠道内稳态和微生物组在帕金森病等神经系统疾病中起着重要作用。肌萎缩性侧索硬化症（ALS）是一种致命的神经退行性疾病，其特征是运动神经元的进行性丧失和肌肉萎缩。目前尚无有效的治疗方法。大多数患者因呼吸麻痹在3-5年内死亡。虽然运动神经元的死亡是ALS的一个标志，但其他器官也可能导致疾病的进展。我们检测了表达突变型超氧化物歧化酶（SOD1G93A）的ALS小鼠模型G93A的肠道，发现紧密连接结构受损，通透性增加，紧密连接蛋白ZO-1和粘附连接蛋白E-cadherin的表达水平显著降低。此外，我们的数据显示G93A小鼠肠道中异常Paneth细胞数量增加。Paneth细胞是一种特殊的肠上皮细胞，可以感知微生物并分泌抗菌肽，因此在宿主先天免疫反应和塑造肠道微生物群中发挥关键作用。在ALS患者的肠道中确实发现了抗微生物肽防御素5 α水平的降低。这些变化与肠道微生物群的变化有关，包括G93A小鼠中溶纤维丁酸弧菌、大肠杆菌和费米氏菌的水平降低。与野生型小鼠相比，G93A小鼠的细菌相对丰度发生了变化。主坐标分析表明，ALS与野生型小鼠粪便微生物群落存在差异。综上所述，我们的研究提示肠上皮和微生物组在ALS进展中的潜在新作用。
Emerging evidence has demonstrated that intestinal homeostasis and the microbiome play essential roles in neurological diseases, such as Parkinson's disease. Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by a progressive loss of motor neurons and muscle atrophy. Currently, there is no effective treatment. Most patients die within 3–5 years due to respiratory paralysis. Although the death of motor neurons is a hallmark of ALS, other organs may also contribute to the disease progression. We examined the gut of an ALS mouse model, G93A, which expresses mutant superoxide dismutase (SOD1G93A), and discovered a damaged tight junction structure and increased permeability with a significant reduction in the expression levels of tight junction protein ZO-1 and the adherens junction protein E-cadherin. Furthermore, our data demonstrated increased numbers of abnormal Paneth cells in the intestine of G93A mice. Paneth cells are specialized intestinal epithelial cells that can sense microbes and secrete antimicrobial peptides, thus playing key roles in host innate immune responses and shaping the gut microbiome. A decreased level of the antimicrobial peptides defensin 5 alpha was indeed found in the ALS intestine. These changes were associated with a shifted profile of the intestinal microbiome, including reduced levels of Butyrivibrio Fibrisolvens, Escherichia coli, and Fermicus, in G93A mice. The relative abundance of bacteria was shifted in G93A mice compared to wild-type mice. Principal coordinate analysis indicated a difference in fecal microbial communities between ALS and wild-type mice. Taken together, our study suggests a potential novel role of the intestinal epithelium and microbiome in the progression of ALS.