German Center for Neurodegenerative Diseases (DZNE), Munich, Germany.
Institute for Stroke and Dementia Research (ISD), University Hospital, LMU Munich, Munich, Germany.
Elife. 2021 Apr 13;10:e59826. doi: 10.7554/eLife.59826.
Previous studies have identified a crucial role of the gut microbiome in modifying Alzheimer's disease (AD) progression. However, the mechanisms of microbiome-brain interaction in AD were so far unknown. Here, we identify microbiota-derived short chain fatty acids (SCFA) as microbial metabolites which promote Aβ deposition. Germ-free (GF) AD mice exhibit a substantially reduced Aβ plaque load and markedly reduced SCFA plasma concentrations; conversely, SCFA supplementation to GF AD mice increased the Aβ plaque load to levels of conventionally colonized (specific pathogen-free [SPF]) animals and SCFA supplementation to SPF mice even further exacerbated plaque load. This was accompanied by the pronounced alterations in microglial transcriptomic profile, including upregulation of ApoE. Despite increased microglial recruitment to Aβ plaques upon SCFA supplementation, microglia contained less intracellular Aβ. Taken together, our results demonstrate that microbiota-derived SCFA are critical mediators along the gut-brain axis which promote Aβ deposition likely via modulation of the microglial phenotype.
先前的研究已经确定了肠道微生物组在改变阿尔茨海默病（AD）进展方面的关键作用。然而，AD 中微生物组-大脑相互作用的机制目前尚不清楚。在这里，我们发现微生物衍生的短链脂肪酸（SCFA）是促进 Aβ 沉积的微生物代谢物。无菌（GF）AD 小鼠表现出明显减少的 Aβ 斑块负荷和明显降低的 SCFA 血浆浓度；相反，将 SCFA 补充到 GF AD 小鼠中会增加 Aβ 斑块负荷，达到常规定植（无特定病原体[SPF]）动物的水平，而将 SCFA 补充到 SPF 小鼠中甚至会进一步加剧斑块负荷。这伴随着小胶质细胞转录组谱的明显改变，包括 ApoE 的上调。尽管 SCFA 补充后小胶质细胞向 Aβ 斑块的募集增加，但小胶质细胞内的 Aβ 减少。总之，我们的结果表明，源自微生物组的 SCFA 是沿肠-脑轴起关键作用的介质，可能通过调节小胶质细胞表型来促进 Aβ 沉积。
