肠道细菌代谢物咪唑丙酸增强阿尔茨海默病病理
Gut bacterial metabolite imidazole propionate potentiates Alzheimer's disease pathology.
摘要(中文译文)
肠道微生物组调节与阿尔茨海默病及相关痴呆症（ADRD）有关的代谢和神经血管过程，但其潜在机制仍不清楚。在此，我们鉴定出细菌代谢物咪唑丙酸（ImP）是ADRD病理的修饰因子。在一个由1196名认知功能未受损成年人组成的队列中，较高的血浆ImP水平与较低的临床前认知评分及ADRD生物标志物相关，这一关联在横断面和纵向分析中均成立。粪便宏基因组分析将推定的ImP产生菌与ADRD表型联系起来。全基因组整合分析揭示，人类12号染色体上的一个位点与血浆ImP水平和AD风险均相关，支持宿主遗传因素对ImP调控的贡献以及该代谢物在AD中的因果作用。在小鼠中，长期给予ImP加重了AD样病理。ImP损害脑内皮屏障，并促进原代神经元中tau蛋白过度磷酸化，而抑制糖原合成酶激酶-3β可阻断这一效应。总之，本研究将ImP与神经退行性变的标志性特征联系起来，并提示靶向ImP可能代表一种改变ADRD风险的潜在策略。
Abstract
The gut microbiome modulates metabolic and neurovascular processes implicated in Alzheimer's disease and related dementias (ADRD), but the underlying mechanisms remain unclear. Here, we identify the bacterial metabolite imidazole propionate (ImP) as a modifier of ADRD pathology. In a cohort of 1196 cognitively unimpaired adults, higher plasma ImP levels were associated with lower preclinical cognitive scores and biomarkers of ADRD, both cross-sectionally and longitudinally. Fecal metagenomic analysis linked putative ImP producers to ADRD phenotypes. Genome-wide integrative analysis revealed a locus on chromosome 12 associated with both plasma ImP levels and AD risk in humans, supporting a host genetic contribution to ImP regulation and a causal role of this metabolite in AD. In mice, chronic ImP administration exacerbated AD-like pathology. ImP impaired brain endothelial barrier and promoted tau hyperphosphorylation in primary neurons, an effect blocked by glycogen synthase kinase-3β inhibition. Together, this study links ImP to hallmarks of neurodegeneration and suggests that targeting ImP may represent a potential strategy to modify ADRD risk.
如何引用
AMA
Vaibhav Vemuganti, Jea Woo Kang, Qijun Zhang, Eric R McGregor, James R Hilser, Ruben Aquino-Martinez, et al. Gut bacterial metabolite imidazole propionate potentiates Alzheimer's disease pathology.. Nature communications. 2026; doi:10.1038/s41467-026-74744-z.
APA
Vaibhav Vemuganti, Jea Woo Kang, Qijun Zhang, Eric R McGregor, James R Hilser, Ruben Aquino-Martinez, et al (2026). Gut bacterial metabolite imidazole propionate potentiates Alzheimer's disease pathology.. Nature communications. https://doi.org/10.1038/s41467-026-74744-z
GB/T 7714
Vaibhav Vemuganti, Jea Woo Kang, Qijun Zhang, Eric R McGregor, James R Hilser, Ruben Aquino-Martinez, et al. Gut bacterial metabolite imidazole propionate potentiates Alzheimer's disease pathology.[J]. Nature communications, 2026 doi:10.1038/s41467-026-74744-z.
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