Department of Neurobiology, The University of Chicago, Chicago, IL, 60637, USA.
The Microbiome Center, The University of Chicago, Chicago, IL, 60637, USA.
Sci Rep. 2017 Sep 5;7(1):10411. doi: 10.1038/s41598-017-11047-w.
Recent evidence suggests the commensal microbiome regulates host immunity and influences brain function; findings that have ramifications for neurodegenerative diseases. In the context of Alzheimer's disease (AD), we previously reported that perturbations in microbial diversity induced by life-long combinatorial antibiotic (ABX) selection pressure in the APP/PS1 mouse model of amyloidosis is commensurate with reductions in amyloid-β (Aβ) plaque pathology and plaque-localised gliosis. Considering microbiota-host interactions, specifically during early post-natal development, are critical for immune- and neuro-development we now examine the impact of microbial community perturbations induced by acute ABX exposure exclusively during this period in APP/PS1 mice. We show that early post-natal (P) ABX treatment (P14-P21) results in long-term alterations of gut microbial genera (predominantly Lachnospiraceae and S24-7) and reduction in brain Aβ deposition in aged APP/PS1 mice. These mice exhibit elevated levels of blood- and brain-resident Foxp3 T-regulatory cells and display an alteration in the inflammatory milieu of the serum and cerebrospinal fluid. Finally, we confirm that plaque-localised microglia and astrocytes are reduced in ABX-exposed mice. These findings suggest that ABX-induced microbial diversity perturbations during post-natal stages of development coincide with altered host immunity mechanisms and amyloidosis in a murine model of AD.
最近的证据表明，共生微生物组调节宿主免疫并影响大脑功能；这些发现对神经退行性疾病有影响。在阿尔茨海默病（AD）的背景下，我们之前报告说，淀粉样蛋白变性 APP/PS1 小鼠模型中终生组合抗生素（ABX）选择压力引起的微生物多样性的改变与淀粉样蛋白-β（Aβ）斑块病理学和斑块局部神经胶质增生的减少成正比。考虑到微生物群-宿主相互作用，特别是在出生后早期，对免疫和神经发育至关重要，我们现在检查仅在 APP/PS1 小鼠的这一时期急性 ABX 暴露引起的微生物群落扰动的影响。我们表明，早期出生后（P）ABX 治疗（P14-P21）导致肠道微生物属的长期改变（主要是 Lachnospiraceae 和 S24-7）和衰老的 APP/PS1 小鼠大脑中 Aβ沉积减少。这些小鼠表现出血液和大脑驻留 Foxp3 T 调节细胞水平升高，并显示血清和脑脊液中炎症环境发生改变。最后，我们证实 ABX 暴露小鼠中斑块定位的小胶质细胞和星形胶质细胞减少。这些发现表明，在 AD 小鼠模型中，出生后发育阶段 ABX 诱导的微生物多样性改变与宿主免疫机制改变和淀粉样蛋白变性一致。
