Department of Neurobiology, The University of Chicago, Chicago, IL.
Department of Pediatrics and Scripps Institution of Oceanography, University of California, San Diego, San Diego, CA.
J Exp Med. 2022 Jan 3;219(1). doi: 10.1084/jem.20200895. Epub 2021 Dec 2.
We previously demonstrated that lifelong antibiotic (ABX) perturbations of the gut microbiome in male APPPS1-21 mice lead to reductions in amyloid β (Aβ) plaque pathology and altered phenotypes of plaque-associated microglia. Here, we show that a short, 7-d treatment of preweaned male mice with high-dose ABX is associated with reductions of Aβ amyloidosis, plaque-localized microglia morphologies, and Aβ-associated degenerative changes at 9 wk of age in male mice only. More importantly, fecal microbiota transplantation (FMT) from transgenic (Tg) or WT male donors into ABX-treated male mice completely restored Aβ amyloidosis, plaque-localized microglia morphologies, and Aβ-associated degenerative changes. Transcriptomic studies revealed significant differences between vehicle versus ABX-treated male mice and FMT from Tg mice into ABX-treated mice largely restored the transcriptome profiles to that of the Tg donor animals. Finally, colony-stimulating factor 1 receptor (CSF1R) inhibitor-mediated depletion of microglia in ABX-treated male mice failed to reduce cerebral Aβ amyloidosis. Thus, microglia play a critical role in driving gut microbiome-mediated alterations of cerebral Aβ deposition.
我们之前的研究表明，在雄性 APPPS1-21 小鼠中，终生抗生素（ABX）对肠道微生物组的干扰会导致淀粉样蛋白β（Aβ）斑块病理学减少和斑块相关小胶质细胞表型改变。在这里，我们表明，在雄性小鼠中，对未成熟雄性小鼠进行为期 7 天的高剂量 ABX 短期治疗与 Aβ 淀粉样变性、斑块定位小胶质细胞形态以及 Aβ 相关退行性变化的减少有关，仅在 9 周龄时出现。更重要的是，来自转基因（Tg）或 WT 雄性供体的粪便微生物群移植（FMT）到 ABX 处理的雄性小鼠中完全恢复了 Aβ 淀粉样变性、斑块定位小胶质细胞形态和 Aβ 相关退行性变化。转录组研究表明，与 ABX 处理的雄性小鼠相比，载体处理的雄性小鼠之间存在显著差异，而 Tg 小鼠的 FMT 将转录组谱在很大程度上恢复到 Tg 供体动物的状态。最后，ABX 处理的雄性小鼠中集落刺激因子 1 受体（CSF1R）抑制剂介导的小胶质细胞耗竭未能减少大脑中的 Aβ 淀粉样变性。因此，小胶质细胞在驱动肠道微生物组介导的大脑 Aβ 沉积改变中起着关键作用。
