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.

血清素能功能障碍与帕金森病 (PD) 的运动和非运动症状有关。5-HT4受体（5-HT4R）作为5-HT受体，已被充分研究并已用于便秘的临床治疗，便秘是PD的典型非运动症状。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剂的作用。MPTP 治疗前 3 天每日腹膜内注射 GR 125487（5-HT4R 拮抗剂）直至处死。MPTP治疗后7天，收集粪便并测量胃肠道通过时间（GITT），MPTP治疗后8天，进行行为测试，然后处死动物用于进一步分析。我们发现 GR 125487 预处理不仅会增加 GITT，还会加剧 MPTP 引起的运动迟缓。此外，GR 125487 预处理可能通过抑制 JAK2/PKA/CREB ​​信号通路以及增加纹状体中的反应性胶质细胞和神经炎症来加剧多巴胺能神经元的损失。粪便微生物群的16S rRNA测序显示，GR 125487预处理改变了肠道微生物群的组成，其中Akkermansia muciniphila和Clostridium clostridioforme的丰度增加，而Parabacteroides distasonis和Bacteroides fragilis的丰度减少，这与炎症状况密切相关。综上所述，我们证明 GR 125487 预处理可能通过 JAK2/PKA/CREB ​​通路和改变肠道微生物群组成的神经炎症加剧 MPTP 诱导的纹状体神经退行性过程。在PD的微生物群-肠-脑轴中，5-HT4R值得进一步探索，并可能作为PD诊断和治疗的靶点。