Sodium oligomannate therapeutically remodels gut microbiota and suppresses gut bacterial amino acids-shaped neuroinflammation to inhibit Alzheimer's disease progression
Sodium oligomannate therapeutically remodels gut microbiota and suppresses gut bacterial amino acids-shaped neuroinflammation to inhibit Alzheimer's disease progression
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DOI：
10.1038/s41422-019-0216-x
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发表时间：
2019-10-01
期刊：
影响因子：
44.1
通讯作者：
Geng, Meiyu
中科院分区：
文献类型：
--
作者：
Wang, Xinyi;Sun, Guangqiang;Geng, Meiyu
近年来，越来越多的证据表明肠道菌群失调与阿尔茨海默病（AD）进展之间存在关联，但肠道菌群在AD发病机制中的作用仍不清楚。在此，我们提供了AD进展中肠道微生物群生态失调和神经炎症之间的潜在机制联系。使用AD小鼠模型，我们发现，在AD进展期间，肠道微生物群组成的改变导致苯丙氨酸和异亮氨酸的外周积累，这刺激促炎性T辅助1（Th 1）细胞的分化和增殖。脑内浸润的外周血Th 1免疫细胞与M1小胶质细胞活化相关，导致AD相关的神经炎症。重要的是，苯丙氨酸和异亮氨酸浓度的升高以及血液中Th 1细胞频率的增加也在两个小型独立队列的AD所致轻度认知障碍（MCI）患者中观察到。此外，GV-971是一种低聚甘露酸钠，在中国的3期临床试验中显示出稳定和一致的认知改善，抑制肠道生态失调和相关的苯丙氨酸/异亮氨酸积累，利用神经炎症并逆转认知障碍。总之，我们的研究结果强调了肠道生态失调促进的神经炎症在AD进展中的作用，并提出了通过重塑肠道微生物群来治疗AD的新策略。
Recently, increasing evidence has suggested the association between gut dysbiosis and Alzheimer's disease (AD) progression, yet the role of gut microbiota in AD pathogenesis remains obscure. Herein, we provide a potential mechanistic link between gut microbiota dysbiosis and neuroinflammation in AD progression. Using AD mouse models, we discovered that, during AD progression, the alteration of gut microbiota composition leads to the peripheral accumulation of phenylalanine and isoleucine, which stimulates the differentiation and proliferation of pro-inflammatory T helper 1 (Th1) cells. The brain-infiltrated peripheral Th1 immune cells are associated with the M1 microglia activation, contributing to AD-associated neuroinflammation. Importantly, the elevation of phenylalanine and isoleucine concentrations and the increase of Th1 cell frequency in the blood were also observed in two small independent cohorts of patients with mild cognitive impairment (MCI) due to AD. Furthermore, GV-971, a sodium oligomannate that has demonstrated solid and consistent cognition improvement in a phase 3 clinical trial in China, suppresses gut dysbiosis and the associated phenylalanine/isoleucine accumulation, harnesses neuroinflammation and reverses the cognition impairment. Together, our findings highlight the role of gut dysbiosis-promoted neuroinflammation in AD progression and suggest a novel strategy for AD therapy by remodelling the gut microbiota.