D-甘露糖调控PPARγ-TPH2轴促进5-HT合成发挥抗抑郁作用及机制

抑郁症是高发性严重危害人类和社会健康的精神障碍性疾病。大脑合成神经递质五羟色胺的限速酶TPH2可调控抑郁行为，是治疗抑郁症的靶点。据报道D-甘露糖具有抑制肿瘤、调控肠道菌群等重要的生理功能，但其是否改善抑郁行为目前还没有报道。我们前期发现D-甘露糖可提升海马脑区肠道菌群发酵产物短链脂肪酸的含量，上调TPH2转录水平，逆转五羟色胺的降低进而改善抑郁小鼠抑郁及焦虑样行为。但D-甘露糖如何调控TPH2还不清楚。经生物信息学预测, 受短链脂肪酸激活的转录因子PPARγ可以结合TPH2启动子。本课题拟在前期研究的基础上，利用慢性应激诱导的抑郁小鼠模型，通过动物行为学及多种细胞和分子生物学方法，确定D-甘露糖上调TPH2转录而发挥抗抑郁的机制。通过论证我们的假说：“D-甘露糖调控PPARγ-TPH2轴促进5-HT合成发挥抗抑郁作用”，以期揭示D-甘露糖抗抑郁机制，为其安全有效治疗抑郁症奠定基础。

Major depressive disorder is a prevalent, severe, life-threatening and psychiatric disorder. TPH2 is the rate-limiting enzyme for generating brain serotonin and thus involved as a promising therapeutic target for depression. D-mannose has been reported to suppress tumor and prevent obesity by maintaining the gut microflora homeostasis. However, whether D-mannose has an antidepressant-like effect is largely unknown. Surprisingly, we have found that D-mannose increases gut microbiota derived short chain fatty acid levels in hippocampus and TPH2 transcription, reverses the decline of serotonin and resist to stress-induced depression and anxiety. While how D-mannose controls TPH2 is still unclear. It is predicted that transcription activator PPARγ, which can be activated by short chain fatty acid, can bind the TPH2 promoter by bioinformatics analysis. In this study, we will use chronic stress-induced depression and anxiety-like mouse, animal behavior detection, cellular and molecular biological methods to confirm the role of D-mannose in depression through TPH2 and explore the underling mechanism by proving our hypothesis "D-mannose promotes PPARγ mediated TPH2 transcription to resist depression by reversing the reduction of 5-HT ". Our research will clarify the molecular mechanism of anti-depressive effect of D-mannose and lay the ground for its therapeutic application as a safe, promising and efficient anti-depressive method in clinical setups.