From the Department of Neurology (S.-J.C., C.-H.L.) and Division of Gastroenterology and Hepatology, Department of Internal Medicine (C.-C.C., J-.M.L., M.-S.W.), College of Medicine, and Department of Pharmacy (C.-H.K.), National Taiwan University Hospital, and Graduate Institute of Clinical Medicine (S.-J.C., C.-C.C.), School of Pharmacy (H.-Y.L., Y.-T.L., C.-H.K.), College of Medicine, and The Metabolomics Core Laboratory, NTU Centers of Genomic and Precision Medicine (C.-H.K.), National Taiwan University, Taipei; Department of Neurology (S.-J.C.), National Taiwan University Hospital Bei-Hu Branch; and Graduate Institute of Biomedical Informatics, College of Medical Science and Technology (Y.-W.W.), Taipei Medical University, Taiwan.
Neurology. 2022 Feb 22;98(8):e848-e858. doi: 10.1212/WNL.0000000000013225. Epub 2022 Jan 7.
BACKGROUND AND OBJECTIVES: Short-chain fatty acids (SCFAs) are gut microbial metabolites that promote the disease process in a rodent model of Parkinson disease (PD), but fecal levels of SCFAs in patients with PD are reduced. Simultaneous assessments of fecal and plasma SCFA levels, and their interrelationships with the PD disease process, are scarce. We aimed to compare fecal and plasma levels of different SCFA subtypes in patients with PD and healthy controls to delineate their interrelations and link to gut microbiota changes and clinical severity of PD. METHODS: A cohort of 96 patients with PD and 85 controls were recruited from National Taiwan University Hospital. Fecal and plasma concentrations of SCFAs were measured using chromatography and mass spectrometry. Gut microbiota was analyzed using metagenomic shotgun sequencing. Body mass index and medical comorbidities were evaluated and dietary information was obtained using a food frequency questionnaire. To assess motor and cognitive impairment, we used the Movement Disorder Society-Unified Parkinson's Disease Rating Scale (MDS-UPDRS) and the Mini-Mental Status Examination (MMSE). RESULTS: Compared with controls, patients with PD had lower fecal but higher plasma concentrations of acetate, propionate, and butyrate. After adjustment for age, sex, disease duration, and anti-PD medication dosage, MDS-UPDRS part III motor scores correlated with reduced fecal levels of acetate (ρ = -0.37, = 0.012), propionate (ρ = -0.32, = 0.036), and butyrate (ρ = -0.40, = 0.004) and with increased plasma propionate concentrations (ρ = 0.26, = 0.042) in patients with PD. MMSE scores negatively correlated with plasma levels of butyrate (ρ = -0.09, = 0.027) and valerate (ρ = -0.032, = 0.033) after adjustment for confounders. SCFAs-producing gut bacteria correlated positively with fecal levels of SCFAs in healthy controls but revealed no association in patients with PD. In the PD patient group, the abundance of proinflammatory microbes, such as and , significantly correlated with decreased fecal levels and increased plasma levels of SCFAs, especially propionic acid. DISCUSSION: Reductions in fecal SCFAs but increased plasma SCFAs were observed in patients with PD and corelated to specific gut microbiota changes and the clinical severity of PD. CLASSIFICATION OF EVIDENCE: This study provides Class III evidence that gut metabolite SCFAs distinguish between patients with PD and controls and are associated with disease severity in patients with PD.
背景与目的：短链脂肪酸（SCFAs）是肠道微生物代谢物，可促进帕金森病（PD）的啮齿动物模型中的疾病进程，但 PD 患者的粪便 SCFA 水平降低。粪便和血浆 SCFA 水平的同时评估及其与 PD 疾病进程的相互关系很少见。我们旨在比较 PD 患者和健康对照者的粪便和血浆中不同 SCFA 亚型的水平，以描绘它们之间的关系，并与肠道微生物群的变化和 PD 的临床严重程度相关联。 方法：我们从国立台湾大学医院招募了 96 名 PD 患者和 85 名对照者。使用色谱法和质谱法测量粪便和血浆中的 SCFA 浓度。使用宏基因组鸟枪法测序分析肠道微生物群。评估体重指数和合并症，并使用食物频率问卷获得饮食信息。使用运动障碍协会统一帕金森病评定量表（MDS-UPDRS）和简易精神状态检查（MMSE）评估运动和认知障碍。 结果：与对照组相比，PD 患者的粪便中乙酸盐、丙酸盐和丁酸盐的浓度较低，但血浆中的浓度较高。在调整年龄、性别、疾病持续时间和抗 PD 药物剂量后，MDS-UPDRS 第 III 部分运动评分与 PD 患者粪便中乙酸盐（ρ=-0.37， = 0.012）、丙酸盐（ρ=-0.32， = 0.036）和丁酸盐（ρ=-0.40， = 0.004）水平降低以及血浆中丙酸盐浓度升高（ρ=0.26， = 0.042）相关。在调整混杂因素后，MMSE 评分与血浆中丁酸盐（ρ=-0.09， = 0.027）和戊酸盐（ρ=-0.032， = 0.033）水平呈负相关。在健康对照组中，产生 SCFA 的肠道细菌与 SCFA 的粪便水平呈正相关，但在 PD 患者中没有相关性。在 PD 患者组中，促炎微生物（如 和 ）的丰度与粪便中 SCFA 水平降低和血浆中 SCFA 水平升高（特别是丙酸）显著相关。 讨论：PD 患者的粪便 SCFA 减少，但血浆 SCFA 增加，与特定的肠道微生物群变化和 PD 的临床严重程度相关。 证据分类：本研究提供了 III 级证据，表明肠道代谢物 SCFAs 可区分 PD 患者和对照组，并与 PD 患者的疾病严重程度相关。
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