Microbiota-derived short chain fatty acids modulate microglia and promote Aβ plaque deposition.
Microbiota-derived short chain fatty acids modulate microglia and promote Aβ plaque deposition.
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微生物区系衍生的短链脂肪酸调节小胶质细胞并促进Aβ斑块沉积。
DOI：
10.7554/elife.59826
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发表时间：
2021-04-13
期刊：
影响因子：
7.7
通讯作者：
Liesz A
中科院分区：
文献类型：
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作者：
Colombo AV;Sadler RK;Llovera G;Singh V;Roth S;Heindl S;Sebastian Monasor L;Verhoeven A;Peters F;Parhizkar S;Kamp F;Gomez de Aguero M;MacPherson AJ;Winkler E;Herms J;Benakis C;Dichgans M;Steiner H;Giera M;Haass C;Tahirovic S;Liesz A
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）进展中起着至关重要的作用。然而，到目前为止，阿尔茨海默病中微生物组 - 大脑相互作用的机制尚不清楚。在此，我们确定微生物群衍生的短链脂肪酸（SCFA）是促进Aβ沉积的微生物代谢产物。无菌（GF）阿尔茨海默病小鼠表现出Aβ斑块负荷大幅降低以及短链脂肪酸血浆浓度显著降低；相反，给无菌阿尔茨海默病小鼠补充短链脂肪酸会使Aβ斑块负荷增加到常规定植（无特定病原体[SPF]）动物的水平，并且给无特定病原体小鼠补充短链脂肪酸甚至会进一步加剧斑块负荷。这伴随着小胶质细胞转录组图谱的显著改变，包括载脂蛋白E（ApoE）的上调。尽管补充短链脂肪酸后小胶质细胞向Aβ斑块的募集增加，但小胶质细胞内所含的Aβ减少。综上所述，我们的研究结果表明，微生物群衍生的短链脂肪酸是肠 - 脑轴上的关键介质，可能通过调节小胶质细胞表型来促进Aβ沉积。
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.