应激敏感与应激抵抗大鼠粪便代谢组学研究

Study on the fecal metabolomics of CUMS-susceptible and CUMS-resilient rats

应用核磁代谢组学技术表征应激敏感大鼠和应激抵抗大鼠的粪便代谢轮廓,明确应激敏感和应激抵抗的生物标志物及代谢通路的异同,阐释相同应激下机体不同反应的发生机制。首先,复制慢性不可预知温和刺激(chronic unpredictable mild stress,CUMS)大鼠抑郁模型;根据大鼠的粪便代谢组学轮廓将模型大鼠分为应激敏感大鼠和应激抵抗大鼠;其次,基于糖水偏爱率验证应激敏感大鼠和应激抵抗大鼠的抑郁状况;最后,应用多元统计分析明确应激敏感大鼠和应激抵抗大鼠粪便的生物标志物及相关代谢通路,阐明其机制。结果表明:与空白组相比,应激敏感大鼠的糖水偏爱率显著降低,而应激抵抗大鼠的糖水偏爱率未发生显著变化。代谢组学研究结果发现,应激敏感和应激抵抗具有相同和特异的差异代谢物和代谢途径。3条代谢途径与应激敏感显著相关,包括牛磺酸和亚牛磺酸代谢,丙氨酸、天门冬氨酸和谷氨酸代谢以及精氨酸和脯氨酸代谢。甘油酯代谢和色氨酸代谢是应激抵抗的特异性代谢通路。本研究从代谢组学角度探讨了相同刺激下,机体出现敏感和抵抗两种不同状态的机制,为抑郁症的研究提供了新视角,亦为临床个体化和精准治疗以及抗抑郁药物的研发提供了新思路。

Proton nuclear magnetic resonance(1H NMR)based metabolomics was applied to characterize the fecal metabolic profiles of chronic unpredictable mild stress(CUMS)-depression(CUMS-D)and CUMS-resilience(CUMS-R)rats.The fecal biomarkers and metabolic pathways involved in CUMS-D and CUMS-R were screened and identified,revealing the underlying mechanisms of two different responses of the body to the same stresses.Firstly,the classic depression model,i.e.CUMS,was constructed.According to the fecal metabolomics profiles,the model rats were divided into two groups,i.e.the CUMS-D group and the CUMS-R group.And then,the depression statuses of CUMS-D rats and CUMS-R rats were verified by their sucrose preference rates.Lastly,multivariate data analysis was applied to clarify the fecal biomarkers and corresponding metabolic pathways involving in CUMS-D and CUMS-R.The results show that compared with the control rats,the sucrose preference rates of CUMS-D rats were significantly reduced.By contrast,the sucrose preference rates of CUMS-R rats had no significant difference.At the same time,CUMS-D and CUMS-R showed both unique and shared biomarkers and pathways.Three pathways are significantly related to CUMS-D,including taurine and hypotaurine metabolism,alanine,aspartate and glutamate metabolism,and arginine and proline metabolism.Glycerolipid metabolism and tryptophan metabolism are specific pathways related to CUMS-R.This study explores the mechanisms of the emergence of susceptible and resilience of rats under the same stimulus from a metabolomics perspective.The current findings provide not only a new perspective for studying depression,and personalized and precision treatments in clinic,but also the research and development of antidepressants.