Peripheral aetiopathogenic drivers and mediators of Parkinson's disease and co-morbidities: role of gastrointestinal microbiota.
Peripheral aetiopathogenic drivers and mediators of Parkinson's disease and co-morbidities: role of gastrointestinal microbiota.
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DOI：
10.1007/s13365-015-0357-8
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发表时间：
2016-02
影响因子：
3.2
通讯作者：
Bjarnason I
中科院分区：
文献类型：
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作者：
Dobbs SM;Dobbs RJ;Weller C;Charlett A;Augustin A;Taylor D;Ibrahim MA;Bjarnason I
我们寻求帕金森氏病(PD)、功能性肠病、抑郁症和认知障碍的病因模型。采用的概念是全身性免疫炎症过程介导神经炎症。该模型将基于表型、暴露组(包括胃肠道微生物组)、环境(免疫炎症和代谢组)、人类遗传学及其相互作用。它将使患者的位置能够从驱动因素、永久者和调解人的角度得到理解，并能够在有和没有干预的情况下预测未来的位置。即使是帕金森病的基本方面也可能有不同的驱动因素：拦住一个可能会让人沿着从属的小路逃脱。消化性溃疡是帕金森病的前驱症状。在我们的随机安慰剂对照试验中，在活检证实根除幽门螺杆菌后的一年中，运动不足有所改善，僵硬程度恶化。这与任何(稳定的、长时间的)抗帕金森症药物无关。有迹象表明这是一种自身免疫过程：例如，监测证实的运动减退效应是适应症特有的。在监测期间，除幽门螺杆菌外，连续的抗菌疗程与硬度的累积增加有关。尽管服用了抗帕金森病药物，但表现出的泻药似乎阻止了整体时间的增加。因此，肠道生物失调可能是旁观者神经元损伤的一个主要来源。在循环炎症标志物和白细胞亚群计数方面，PD方面的客观测量存在生物梯度。此外，乳果糖氢呼气试验对小肠细菌过度生长的阳性(存在于三分之二的PD患者中)与相同的亚群相关：较高的自然杀伤细胞和总CD4+计数以及较低的中性粒细胞。随着对病因的更多了解，相对较低的成本和现成的药物可能会产生重大影响。基于肠道微生物组的新一代动物模型被设想。
We seek an aetiopathogenic model for the spectrum of Parkinson’s disease (PD), functional bowel disease, depression and cognitive impairment. The adopted concept is that systemic immuno-inflammatory processes mediate neuro-inflammation. The model would be based on phenotype, exposome (including gastrointestinal microbiome), milieu (immuno-inflammatory and metabolome), human genetics and their interactions. It would enable a patient’s position, to be understood in terms of drivers, perpetuators and mediators, and a future position, with and without intervention, predicted. Even the cardinal facets of PD may have different drivers: halting one may allow escape down subordinate pathways. Peptic ulceration is prodromal to PD. In our randomised placebo-controlled trial, hypokinesia improved over the year following biopsy-proven Helicobacter pylori eradication and rigidity worsened. This was independent of any (stable, long t½) antiparkinsonian medication. There are pointers to an autoimmune process: for example, surveillance-confirmed hypokinesia effect was indication specific. During surveillance, successive antimicrobial courses, other than for Helicobacter, were associated with cumulative increase in rigidity. Exhibiting laxatives appeared to stem the overall temporal increase, despite antiparkinsonian medication, in rigidity. Thus, intestinal dysbiosis may be a major source of bystander neuronal damage. There are biological gradients of objective measures of PD facets on circulating inflammatory markers and leucocyte subset counts. Moreover, lactulose hydrogen breath test positivity for small-intestinal bacterial overgrowth (present in two thirds of PD patients) is associated with the same subsets: higher natural killer and total CD4+ counts and lower neutrophils. With greater aetiopathogenic understanding, relatively low cost and on-the-shelf medication could have a major impact. A new generation of animal models, based on the gut microbiome, is envisaged.