Pang Shimin, Ren Zhili, Ding Hui, Chan Piu
Department of Neurobiology and Neurology, Xuanwu Hospital of Capital Medical University, Beijing, China.
National Clinical Research Center for Geriatric Disorders, Xuanwu Hospital of Capital Medical University, Beijing, China.
Neural Regen Res. 2026 Mar 1;21(3):938-956. doi: 10.4103/NRR.NRR-D-24-01265. Epub 2025 Apr 29.
Short-chain fatty acids, metabolites produced by the fermentation of dietary fiber by gut microbiota, have garnered significant attention due to their correlation with neurodegenerative diseases, particularly Parkinson's disease. In this review, we summarize the changes in short-chain fatty acid levels and the abundance of short-chain fatty acid-producing bacteria in various samples from patients with Parkinson's disease, highlighting the critical role of gut homeostasis imbalance in the pathogenesis and progression of the disease. Focusing on the nervous system, we discuss the molecular mechanisms by which short-chain fatty acids influence the homeostasis of both the enteric nervous system and the central nervous system. We identify key processes, including the activation of G protein-coupled receptors and the inhibition of histone deacetylases by short-chain fatty acids. Importantly, structural or functional disruptions in the enteric nervous system mediated by these fatty acids may lead to abnormal α-synuclein expression and gastrointestinal dysmotility, which could serve as an initiating event in Parkinson's disease. Furthermore, we propose that short-chain fatty acids help establish communication between the enteric nervous system and the central nervous system via the vagal nerve, immune circulation, and endocrine signaling. This communication may shed light on their potential role in the transmission of α-synuclein from the gut to the brain. Finally, we elucidate novel treatment strategies for Parkinson's disease that target short-chain fatty acids and examine the challenges associated with translating short-chain fatty acid-based therapies into clinical practice. In conclusion, this review emphasizes the pivotal role of short-chain fatty acids in regulating gut-brain axis integrity and their significance in the pathogenesis of Parkinson's disease from the perspective of the nervous system. Moreover, it highlights the potential value of short-chain fatty acids in early intervention for Parkinson's disease. Future research into the molecular mechanisms of short-chain fatty acids and their synergistic interactions with other gut metabolites is likely to advance the clinical translation of innovative short-chain fatty acid-based therapies for Parkinson's disease.
短链脂肪酸是肠道微生物群对膳食纤维进行发酵产生的代谢产物，因其与神经退行性疾病尤其是帕金森病的相关性而备受关注。在本综述中，我们总结了帕金森病患者各种样本中短链脂肪酸水平的变化以及产生短链脂肪酸的细菌的丰度，强调了肠道稳态失衡在该疾病发病机制和进展中的关键作用。聚焦于神经系统，我们讨论了短链脂肪酸影响肠神经系统和中枢神经系统稳态的分子机制。我们确定了关键过程，包括短链脂肪酸对G蛋白偶联受体的激活和组蛋白脱乙酰酶的抑制。重要的是，这些脂肪酸介导的肠神经系统结构或功能破坏可能导致α-突触核蛋白表达异常和胃肠动力障碍，这可能是帕金森病的起始事件。此外，我们提出短链脂肪酸通过迷走神经、免疫循环和内分泌信号通路帮助建立肠神经系统与中枢神经系统之间的通信。这种通信可能揭示它们在α-突触核蛋白从肠道向大脑传播中的潜在作用。最后，我们阐明了针对短链脂肪酸的帕金森病新治疗策略，并审视了将基于短链脂肪酸的疗法转化为临床实践所面临的挑战。总之，本综述强调了短链脂肪酸在调节肠-脑轴完整性中的关键作用及其从神经系统角度在帕金森病发病机制中的重要性。此外，它突出了短链脂肪酸在帕金森病早期干预中的潜在价值。未来对短链脂肪酸分子机制及其与其他肠道代谢产物协同相互作用的研究可能会推动基于短链脂肪酸的帕金森病创新疗法的临床转化。
