调节肠道菌群及其发酵产物SCFAs的巴戟天寡糖抗抑郁作用机制研究

Recently, accumulating studies have suggested that the gut microbiota plays a critical role in the development of depression. Short-chain fatty acids (SCFAs) are the fermentation products of gut microbiota, which might be important signal molecules for the “gut-brain axis”. Morinda officinalis oligosaccharide is an approved antidepressant chinese medicine while the mechanism has not been fully elucidated. Recently, we found that orally given morinda officinalis oligosaccharides displayed antidepressant effect in two behavioral despair models, whereas intraperitoneal injection of the same dose is ineffective. In addition, morinda officinalis oligosaccharides improved the anxiety-like behavior in mice induced by intragastric administration of mixed nonabsorbent antibiotics, and modified the relative abundance of several strains of bacteria. In this project, we will utilize in vitro intestinal model, chronic unpredictable mild stress model in SPF and germ-free mice to study the effects of morinda officinalis oligosaccharides on the gut microbiota and SCFAs and whether the regulation effects are necessary for its antidepressant efficacy. We will also try to explain how morinda officinalis oligosaccharides produce antidepressant effect through alter gut microbiota and SCFAs based on neurotransmitters, Hypothalamic–pituitary–adrenal(HPA) axis, neurotrophic and microglia-mediated immune inflammation mechanisms.Together, this study will provide useful reference for the basic and applied research on the treatment of depression through regulating mictobiota.

肠道菌群异常与抑郁症的发生密切相关，其发酵产物短链脂肪酸（Short-chain fatty acids, SCFAs）可能是连接“肠-脑轴”的重要信号分子。巴戟天寡糖是本实验室研发并已上市的抗抑郁中药，抗抑郁机制尚不明确。我们新近发现：巴戟天寡糖口服在行为绝望模型中有抗抑郁效应, 相同剂量腹腔注射则无效；可改善抗生素诱导肠道菌群紊乱小鼠的焦虑行为，并且改变肠道菌群的相对丰度。本项目拟采用体外肠道模型、SPF和无菌级小鼠平行制备慢性应激抑郁模型，研究巴戟天寡糖对肠道菌群及SCFAs的调节作用，以及该调节作用是否为其抗抑郁效应的关键，继而从神经递质、下丘脑-垂体-肾上腺（Hypothalamic–pituitary–adrenal, HPA）轴、神经营养和小胶质免疫炎症方面探究其改变肠道菌群和SCFAs发挥抗抑郁作用的机制。本项目可为调控肠道菌群治疗抑郁症的基础与应用研究提供有益借鉴。

抑郁症发病率高、病理机制复杂且药物有效率低，近年来研究表明肠道菌群异常与抑郁症的发生密切相关，但肠道菌群-肠-脑轴对抑郁症的调节机制尚不清楚。巴戟天寡糖不能被人体的消化酶代谢，难以进入血液循环，因此抗抑郁直接作用靶标不明，我们推测其抗抑郁作用可能与调节肠道菌群有关。本研究采用无菌动物、抗生素处理、慢性应激模型结合多种行为药理学以及神经生物学技术，探讨了肠道菌群对抑郁焦虑行为的影响及巴戟天寡糖抗抑郁作用的肠道菌群-肠-脑轴机制。.行为药理学和结肠内容物菌群分析研究结果显示，无菌和抗生素处理导致的菌群异常状态会导致小鼠／大鼠焦虑和抑郁行为异常，并取消巴戟天寡糖的抗抑郁作用。慢性应激导致大鼠肠道菌群发生规律性改变，巴戟天寡糖可逆转这种改变而使菌群结构趋于正常，提示肠道菌群对抑郁焦虑行为有重要的调节作用，可能是巴戟天寡糖抗抑郁作用关键。机制研究结果显示抑郁模型和抗生素处理均导致大鼠结肠短链脂肪酸（short chain fatty acid, SCFAs）的含量降低，巴戟天寡糖显著逆转。巴戟天寡糖升高抑郁模型大鼠海马脑源性神经营养因子（brain-derived neurotrophic factor，BDNF）表达和5-羟色胺（serotonin，5-HT）水平，降低海马小胶质细胞活性和组蛋白去乙酰化酶5（histone deacetylase，HDAC5）表达水平，且依赖于肠道菌群。此外，在肠道，抑郁模型大鼠和抗生素处理大鼠结肠嗜铬细胞内5-HT水平均显著降低，巨噬细胞活性显著升高，巴戟天寡糖显著逆转抑郁大鼠结肠嗜铬细胞5-HT和巨噬细胞的改变，而在抗生素处理大鼠中无效。.以上研究提示巴戟天寡糖的抗抑郁效应依赖于肠道菌群，其作用机制可能是通过调节肠道菌群，升高SCFAs水平，进而调节肠脑轴5-HT代谢、免疫炎症和表观遗传调控通路。本项目研究不仅可为巴戟天寡糖的临床应用供科学依据，而且能为调控肠道菌群治疗抑郁症的基础与应用研究供有益借鉴。