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

项目摘要 帕金森病（PD）是一种运动障碍，由中脑多巴胺神经元死亡引起。 该疾病还具有非运动症状（NMS），例如在治疗之前的显著的胃肠道（GI）功能障碍。 运动缺陷阶段最近的研究表明，肠-脑轴在PD发病机制中的作用。的 微生物组对肠-脑轴信号传导、大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）神经病理学、神经炎症和运动缺陷所需的。 PD患者的肠道微生物发生了改变，这支持了假设的肠-脑轴参与。电流 用于PD的治疗如L-DOPA可改善运动症状，但不减弱NMS或 神经变性为了减缓或阻止帕金森病在肠道和大脑中的潜在病理， 该建议将研究丁酸盐（短链脂肪酸）作为口服药物或作为 在PD小鼠模型中由肠道微生物组产生，并研究治疗相关的微生物群 成分变化。我假设，口服丁酸盐和合生素治疗与前和益生菌将有 逆转微生物群失调、改善GI功能和减缓PD进展的能力相似。此前，我们 实验室显示苯丁酸钠（NaPB）可延缓一种称为弥漫性PD的严重形式的进展 路易体病（DLB）虽然NaPB治疗的临床应用似乎很有希望，但一个深刻的经济问题是， 存在局限性。人类使用的NaPB成本约为每公斤10，000美元，并有几种副作用，包括 过敏性皮疹约10%的人。从这项研究中获得的结果将表明NaB是否可以 在临床试验中取代NaPB疗法，确定合生素治疗是否可以减缓DLB和PD进展， （部分通过增加大脑中的神经保护作用），显示合生元治疗是否可以改善GI功能障碍 报告的PD患者，并最终将深入了解肠道微生物的变化，可能会影响大脑活动 GI功能。

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.