Increasing butyrate levels by microbiome manipulation or drug administration to delay Parkinsons disease progression.

通过微生物组控制或药物管理来提高丁酸盐水平，以延缓帕金森病的进展。

• 批准号: 9977126
• 负责人: Stephanie Michelle Garcia
• 金额: $ 3.25万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-07-31 至 2021-07-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9977126
• 关键词: 16S ribosomal RNA sequencing; Aftercare; Age-Months; Allergic; Animals; Anti-Inflammatory Agents; Attenuated; Autopsy; Behavior; Behavioral; Brain; Butyrates; Cause of Death; Clinical; Clinical Trials; DNA sequencing; Data; Diet; Diffuse Lewy Body Disease; Disease; Disease Progression; Dopamine; Dose; Enteric Nervous System; Exanthema; Feces; Fiber; Functional disorder; Gene Expression; Genes; Histones; Homeostasis; Human; Immunohistochemistry; Inflammation; Inflammatory; Intervention; Levodopa; Methods; Microbe; Midbrain structure; Motor; Movement Disorders; Mucous Membrane; Mus; Nerve Degeneration; Neurotoxins; Oral; Organism; Oxidative Stress; Parkinson Disease; Pathogenesis; Pathology; Patients; Pharmaceutical Preparations; Placebo Control; Placebos; Probiotics; Production; Reporting; Reproduction spores; Rodent; Role; Saline; Sampling; Signal Transduction; Sodium Butyrate; Sodium phenylbutyrate; Source; Testing; Therapeutic Studies; Time; Tissues; Transgenic Mice; Translating; Volatile Fatty Acids; Western Blotting; Wild Type Mouse; age related; alpha synuclein; cell motility; cognitive function; cost; cryostat; dopaminergic neuron; dysbiosis; experimental study; gastrointestinal; gastrointestinal function; gut bacteria; gut microbes; gut microbiome; gut-brain axis; improved; insight; microbial; microbiome; microbiota; misfolded protein; motor deficit; motor symptom; mouse model; mutant; neuroinflammation; neuron loss; neuropathology; neuroprotection; non-motor symptom; prebiotics; preservation; prevent; response; side effect; treatment comparison; treatment effect

Project Summary Parkinson’s disease (PD) is a movement disorder caused by the death of dopamine neurons in the midbrain. The disease also has non-motor symptoms (NMS), such as prominent gastrointestinal (GI) dysfunction prior to the motor deficit stage. Recent studies indicate a role for the gut-brain axis in PD pathogenesis. The microbiome has effects on gut-brain axis signaling, brain activity, and behavior. Recently, gut microbes were recognized as being required for α-synuclein (aSyn) neuropathology, neuroinflammation, and motor deficits. PD patients have alterations in gut microbes that support the hypothesized gut-brain axis involvement. Current therapies for PD such as L-DOPA can improve motor symptoms but do not attenuate NMS or the rate of neurodegeneration. To slow or stop the underlying pathology of Parkinson’s disease in both the gut and brain, this proposal will study the therapeutic value of butyrate (short chain fatty acid) either as an oral drug or as produced by the gut microbiome in mouse models of PD and investigate treatment-associated microbiota composition shifts. I hypothesize that oral butyrate and synbiotic treatment with pre- and pro-biotics will have similar ability to reverse microbiome dysbiosis, improve GI function, and slow PD progression. Previously, our lab showed sodium phenylbutyrate (NaPB) delaying the progression of a severe form of PD called diffuse Lewy body disease (DLB) While the clinical use of NaPB therapy appears promising, a profound financial limitation exists. NaPB for human use costs about $10,000 per kg and has several side effects including allergic skin rash in about 10% of people. Results obtained from this study will indicate whether NaB can replace NaPB therapy in clinical trials, determine if synbiotic treatment can slow DLB and PD progression, (partly by increasing neuroprotection in the brain), show if synbiotic treatment can improve GI dysfunction reported by PD patients, and finally will give insight into gut-microbial shifts that may influence brain activity and GI function.

项目摘要 帕金森氏病(PD)是一种由中脑多巴胺神经元死亡引起的运动障碍。 这种疾病也有非运动症状(NMS)，例如以前明显的胃肠道(GI)功能障碍 运动障碍阶段。最近的研究表明，肠-脑轴在帕金森病的发病机制中发挥了作用。这个 微生物组对肠道-脑轴信号、脑活动和行为有影响。最近，肠道微生物 被认为是α-突触核蛋白(ASyn)神经病理、神经炎症和运动缺陷所必需的。 帕金森病患者的肠道微生物发生了变化，这支持了假设的肠道-脑轴参与。当前 治疗帕金森病的方法，如L多巴，可以改善运动症状，但不能减轻NMS或 神经退行性变。为了减缓或阻止帕金森氏症在肠道和大脑中的潜在病理， 这项提案将研究丁酸盐(短链脂肪酸)作为口服药物或作为 在帕金森病小鼠模型中产生肠道微生物群并调查治疗相关微生物区系 构图发生了变化。我假设口服丁酸盐和合生菌治疗前和益生菌 类似的能力，逆转微生物群失调，改善胃肠道功能，并减缓帕金森病的进展。此前，我们的 实验室显示，苯丁酸钠(NaPB)延缓了一种称为弥漫性帕金森病的严重形式的帕金森病的进展 路易体病(DLB)虽然NaPB疗法的临床应用前景看好，但它带来了深远的经济影响 存在限制。人用NaPB的成本约为每公斤10,000美元，并有几个副作用，包括 大约10%的人会出现过敏性皮疹。这项研究的结果将表明NAB是否可以 在临床试验中取代NaPB疗法，确定联合生物疗法是否可以减缓DLB和PD的进展， (部分通过增加大脑中的神经保护)，表明合生体治疗是否可以改善胃肠道功能障碍 由帕金森病患者报告，并最终将深入了解可能影响大脑活动的肠道微生物变化 和胃肠功能。