Morais Livia H, Boktor Joseph C, MahmoudianDehkordi Siamak, Kaddurah-Daouk Rima, Mazmanian Sarkis K
Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, CA, USA.
Aligning Science Across Parkinson's (ASAP) Collaborative Research Network, Chevy Chase, MD, 20815, USA.
NPJ Parkinsons Dis. 2024 Oct 30;10(1):208. doi: 10.1038/s41531-024-00816-w.
Pathological forms of α-synuclein contribute to synucleinopathies, including Parkinson's disease (PD). Most cases of PD arise from gene-environment interactions. Microbiome composition is altered in PD, and gut bacteria are causal to symptoms in animal models. We quantitatively profiled nearly 630 metabolites in the gut, plasma, and brain of α-synuclein-overexpressing (ASO) mice, compared to wild-type (WT) animals, and comparing germ-free (GF) to specific pathogen-free (SPF) animals (n = 5 WT-SPF; n = 6 ASO-SPF; n = 6 WT-GF; n = 6 ASO-GF). Many differentially expressed metabolites in ASO mice are also dysregulated in human PD patients, including amine oxides, bile acids and indoles. The microbial metabolite trimethylamine N-oxide (TMAO) strongly correlates from the gut to the plasma to the brain in mice, notable since TMAO is elevated in the blood and cerebrospinal fluid of PD patients. These findings uncover broad metabolomic changes that are influenced by the intersection of host genetics and microbiome in a mouse model of PD.
α-突触核蛋白的病理形式会导致突触核蛋白病，包括帕金森病（PD）。大多数帕金森病病例是由基因-环境相互作用引起的。帕金森病患者的微生物群组成会发生改变，并且肠道细菌在动物模型中会导致症状出现。与野生型（WT）动物相比，我们对过表达α-突触核蛋白（ASO）的小鼠的肠道、血浆和大脑中的近630种代谢物进行了定量分析，并比较了无菌（GF）小鼠和无特定病原体（SPF）小鼠（n = 5只WT-SPF；n = 6只ASO-SPF；n = 6只WT-GF；n = 6只ASO-GF）。ASO小鼠中许多差异表达的代谢物在人类帕金森病患者中也失调，包括氧化胺、胆汁酸和吲哚。微生物代谢产物氧化三甲胺（TMAO）在小鼠体内从肠道到血浆再到大脑呈现出强烈的相关性，值得注意的是，帕金森病患者的血液和脑脊液中TMAO水平升高。这些发现揭示了在帕金森病小鼠模型中，宿主遗传学和微生物群相互作用所影响的广泛代谢组学变化。
