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 PD 病例源于基因-环境相互作用。PD 中的微生物组组成发生改变，肠道细菌是动物模型中症状的因果关系。与野生型 （WT） 动物相比，我们定量分析了 α-突触核蛋白过表达 （ASO） 小鼠肠道、血浆和大脑中的近 630 种代谢物，并将无菌 （GF） 与特定病原体 （SPF） 动物 （n = 5 WT-SPF;n = 6 ASO-SPF;n = 6 WT-GF;n = 6 ASO-GF）。ASO 小鼠中许多差异表达的代谢物在人 PD 患者中也失调，包括氧化胺、胆汁酸和吲哚。微生物代谢物三甲胺 N-氧化物 （TMAO） 在小鼠的肠道、血浆和大脑之间具有很强的相关性，值得注意的是，因为 TMAO 在 PD 患者的血液和脑脊液中升高。这些发现揭示了 PD 小鼠模型中受宿主遗传学和微生物组交叉影响的广泛代谢组学变化。