Abstract：
Serotonergic dysfunction is related to both motor and nonmotor symptoms in Parkinson\'s disease (PD). As a 5-HT receptor, 5-HT4 receptor (5-HT4R) is well-studied and already-used in clinical therapy of constipation, which is a typical non-motor symptom in PD. In this study, we investigated the role of 5-HT4R as a regulator of gut function in MPTP-induced acute PD mice model. Daily intraperitoneal injection of GR 125487 (5-HT4R antagonist) was administered 3 days before MPTP treatment until sacrifice. Seven days post-MPTP treatment, feces were collected and gastrointestinal transit time (GITT) was measured, 8 days post-MPTP treatment, behavioral tests were performed, and then animals were sacrificed for the further analysis. We found GR 125487 pretreatment not only increased GITT, but also aggravated MPTP-induced motor bradykinesia. In addition, GR 125487 pretreatment exacerbated the loss of dopaminergic neurons probably by suppressing JAK2/PKA/CREB signaling pathway and increased reactive glia and neuroinflammation in the striatum. 16 S rRNA sequencing of fecal microbiota showed that GR 125487 pretreatment altered the composition of gut microbiota, in which the abundance of Akkermansia muciniphila and Clostridium clostridioforme was increased, whereas that of Parabacteroides distasonis and Bacteroides fragilis was decreased, which are closely associated with inflammation condition. Taken together, we demonstrated that GR 125487 pretreatment exacerbates MPTP-induced striatal neurodegenerative processes possibly via the JAK2/PKA/CREB pathway and neuroinflammation by altering gut microbiota composition. In the microbiota-gut-brain axis of PD, 5-HT4R should be further explored and might serve as a target for PD diagnosis and treatment.
摘要：
5-羟色胺能功能障碍与帕金森病（PD）的运动和非运动症状有关。作为5-HT受体,5-HT4受体（5-HT4R）已被充分研究并已用于便秘的临床治疗，这是PD中典型的非运动症状。在这项研究中,我们研究了5-HT4R在MPTP诱导的急性PD小鼠模型中作为肠道功能调节因子的作用。在MPTP治疗前3天每天腹膜内注射GR125487(5-HT4R拮抗剂)直至处死。MPTP治疗后7天，收集粪便并测量胃肠运输时间（GITT），MPTP治疗后8天，进行了行为测试，然后处死动物用于进一步分析。我们发现GR125487预处理不仅增加了GITT，但也加重了MPTP引起的运动迟缓。此外,GR125487预处理可能通过抑制JAK2/PKA/CREB信号通路和增加纹状体反应性胶质细胞和神经炎症而加剧多巴胺能神经元的丢失。16SrRNA测序显示，GR125487预处理改变了肠道菌群的组成，其中粘虫和梭状芽孢杆菌的丰度增加，而偏端副杆菌和脆弱拟杆菌的数量减少了，与炎症密切相关。一起来看,我们证明,GR125487预处理可能通过JAK2/PKA/CREB通路加剧MPTP诱导的纹状体神经退行性过程,并通过改变肠道微生物群组成加剧神经炎症.在PD的微生物群-肠-脑轴中，5-HT4R应进一步探索，并可能作为PD诊断和治疗的目标。
