In Parkinson's patients, intestinal dysbiosis can occur years before clinical diagnosis, implicating the gut and its microbiota in the disease. Recent evidence suggests the gut microbiota may trigger body-first Parkinson Disease (PD), yet the underlying mechanisms remain unclear. This study aims to elucidate how a dysbiotic microbiome through intestinal immune alterations triggers PD-related neurodegeneration. To determine the impact of gut dysbiosis on the development and progression of PD pathology, wild-type male C57BL/6 mice were transplanted with fecal material from PD patients and age-matched healthy donors to challenge the gut-immune-brain axis. This study demonstrates that patient-derived intestinal microbiota caused midbrain tyrosine hydroxylase positive (TH +) cell loss and motor dysfunction. Ileum-associated microbiota remodeling correlates with a decrease in Th17 homeostatic cells. This event led to an increase in gut inflammation and intestinal barrier disruption. In this regard, we found a decrease in CD4 + cells and an increase in pro-inflammatory cytokines in the blood of PD transplanted mice that could contribute to an increase in the permeabilization of the blood–brain-barrier, observed by an increase in mesencephalic Ig-G-positive microvascular leaks and by an increase of mesencephalic IL-17 levels, compatible with systemic inflammation. Furthermore, alpha-synuclein aggregates can spread caudo-rostrally, causing fragmentation of neuronal mitochondria. This mitochondrial damage subsequently activates innate immune responses in neurons and triggers microglial activation. We propose that the dysbiotic gut microbiome (dysbiome) in PD can disrupt a healthy microbiome and Th17 homeostatic immunity in the ileum mucosa, leading to a cascade effect that propagates to the brain, ultimately contributing to PD pathophysiology. Our landmark study has successfully identified new peripheral biomarkers that could be used to develop highly effective strategies to prevent the progression of PD into the brain.

中文翻译：

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肠道优先帕金森病由肠道菌群失调编码


在帕金森病患者中，肠道菌群失调可能发生在临床诊断前数年，这与肠道及其微生物群有关。最近的证据表明，肠道微生物群可能会引发身体优先的帕金森病 （PD），但其潜在机制仍不清楚。本研究旨在阐明代谢失调微生物组如何通过肠道免疫改变触发 PD 相关的神经变性。为确定肠道菌群失调对 PD 病理发展的影响，将野生型雄性 C57BL/6 小鼠移植了来自 PD 患者和年龄匹配的健康供体的粪便物质，以挑战肠道免疫脑轴。这项研究表明，患者来源的肠道微生物群导致中脑酪氨酸羟化酶阳性 （TH +） 细胞丢失和运动功能障碍。回肠相关微生物群重塑与 Th17 稳态细胞的减少相关。这一事件导致肠道炎症和肠道屏障破坏增加。在这方面，我们发现 PD 移植小鼠血液中 CD4 + 细胞的减少和促炎细胞因子的增加，这可能有助于增加血液脑屏障的透化，通过中脑 Ig-G 阳性微血管渗漏的增加和中脑 IL-17 水平的增加来观察到，与全身炎症相符。此外，α-突触核蛋白聚集体可以向尾状突部扩散，导致神经元线粒体碎裂。这种线粒体损伤随后激活神经元中的先天免疫反应并触发小胶质细胞激活。 我们提出 PD 中的营养不良肠道微生物组 （dysbiome） 可以破坏回肠粘膜中健康的微生物组和 Th17 稳态免疫，导致传播到大脑的级联效应，最终导致 PD 病理生理学。我们具有里程碑意义的研究成功地确定了新的外周生物标志物，这些标志物可用于开发高效的策略来防止 PD 进展到大脑。