Institute of Neuroscience and the Collaborative Innovation Center for Brain Science, Chongqing Medical University, Chongqing 400016, China; Chongqing Key Laboratory of Neurobiology, Chongqing Medical University, Chongqing 400016, China; Department of Neurology, The First Affiliated Hospital, Chongqing Medical University, Chongqing 400016, China.
Department of Laboratory Animal Science, College of Basic Medical Sciences, Third Military Medical University, Chongqing, China.
J Proteomics. 2019 Mar 1;194:132-147. doi: 10.1016/j.jprot.2018.11.023. Epub 2018 Dec 4.
Major depressive disorders impact approximately 17% of the population worldwide, whose high morbidity and considerable adversity have resulted in enormous social and economic burden. In addition, clinically depressed patients often show reduced volume of olfactory bulb (OB) and decreased olfactory sensitivity. Although mounting evidence conveyed that the gut microbiota may implicate the pathophysiology of major depressive disorder (MDD) via the microbe-gut-brain axis, knowledge about its distinctive molecular mechanism is rudimentary. Herein, iTRAQ coupled with LC-MS/MS was applied to compare the OB proteome between "pathological microbiota" and "healthy microbiota" germ-free mice. A set of 367 proteins were differentially identified in the OB, including 119 up-regulated and 248 down-regulated proteins compared with the levels in controls. A combined analysis with significantly changed OB proteins from CUMS depression model supported the role of CREB signaling, whose dysregulation is likely to disrupt the axonogenesis of OB under microbiota condition. With that, the down-regulated CACNA1E and its downstream proteins (CALM/ CaMKII/ CREB/ BDNF) in CREB pathway were validated by Western blot. Meanwhile, the canonical pathways involved Nuclear Receptor Signaling highlighted the fecal microbiota transplantation (FMT) model, which would be a new breakthrough for depressive research. These findings enrich the previous research achievements about the gut microbiota in psychiatric disorders, providing a creative insight into the intricate mechanisms of OB dysfunction in depression. SIGNIFICANCE: Emerging evidence has shown that gut microbiota can greatly influence brain functions and even behaviors. As one of the post-developmental neurogenesis areas for the adult brain, the OB is becoming increasingly important in the study of the pathogenesis of depression. Using an iTRAQ-based proteomics, we identified 367 altered proteins in the OB of fecal microbiota transplanted mouse, which provide a novel insight for further research of the "microbiota-gut-brain axis". In addition, combined analyses with the CUMS depression model and the validation of key proteins by Western blot may assist in the investigation of OB dysfunction in mental sickness.
重度抑郁症影响全球约 17%的人口，其高发病率和相当大的逆境给社会和经济带来了巨大的负担。此外，临床抑郁患者通常表现出嗅球（OB）体积减小和嗅觉敏感性降低。尽管越来越多的证据表明，肠道微生物群可能通过微生物-肠道-大脑轴参与重度抑郁症（MDD）的病理生理学，但对其独特的分子机制知之甚少。在此，我们应用 iTRAQ 联合 LC-MS/MS 比较了“病理性微生物群”和“健康微生物群”无菌小鼠的 OB 蛋白质组。在 OB 中鉴定出一组 367 种差异表达的蛋白质，与对照组相比，其中 119 种上调，248 种下调。与 CUMS 抑郁模型中 OB 明显变化的蛋白质进行综合分析支持了 CREB 信号的作用，其失调可能破坏微生物条件下 OB 的轴突发生。通过下调 CACNA1E 及其下游蛋白（CALM/CaMKII/CREB/BDNF）在 CREB 通路中的作用，通过 Western blot 进行验证。同时，涉及核受体信号的经典途径突出了粪便微生物群移植（FMT）模型，这将为抑郁研究提供新的突破。这些发现丰富了先前关于精神疾病中肠道微生物群的研究成果，为 OB 功能障碍在抑郁症中的复杂机制提供了新的见解。意义：越来越多的证据表明，肠道微生物群可以极大地影响大脑功能甚至行为。作为成人大脑的后发育神经发生区域之一，OB 在抑郁症发病机制的研究中变得越来越重要。我们使用基于 iTRAQ 的蛋白质组学方法，鉴定出粪便微生物群移植小鼠 OB 中 367 种改变的蛋白质，为进一步研究“微生物群-肠道-大脑轴”提供了新的见解。此外，与 CUMS 抑郁模型的综合分析和 Western blot 验证关键蛋白可能有助于研究精神疾病中的 OB 功能障碍。
