上海交通大学贾伟等研究人员合作发现，肠道细菌驱动的高香草酸通过调节突触完整性缓解抑郁症。相关论文于2024年4月5日在线发表于国际学术期刊《细胞—代谢》。

研究人员观察到，在抑郁症患者和小鼠抑郁模型中，肠道细菌物种（包括长双歧杆菌和肠道罗斯拜瑞氏菌）和神经递质高香草酸（HVA）均已减少。虽然肠道罗斯拜瑞氏菌并不直接产生 HVA，但它能提高长双歧杆菌的丰度，从而产生HVA。这凸显了肠道微生物群在调节肠道神经递质产生方面的协同作用。给慢性不可预知轻度应激（CUMS）和皮质酮（CORT）诱导的抑郁症小鼠模型注射HVA、长双歧杆菌或肠道罗斯拜瑞氏菌可显著改善抑郁症状。

从机制上讲，HVA通过防止微管相关蛋白1轻链3（LC3）和SQSTM1/p62蛋白的过度降解来抑制突触自噬死亡，从而保护海马神经元的突触前膜。这些发现强调了肠道微生物代谢在调节突触完整性中的作用，并为潜在的新型抑郁症治疗策略提供了启示。

研究人员表示，肠道-大脑轴与抑郁症的发展有关，但其潜在机制仍不清楚。

附：英文原文

Title: Gut bacteria-driven homovanillic acid alleviates depression by modulating synaptic integrity

Author: Mingliang Zhao, Zhenxing Ren, Aihua Zhao, Yajun Tang, Junliang Kuang, Mengci Li, Tianlu Chen, Shouli Wang, Jieyi Wang, Huiheng Zhang, Jijun Wang, Tianhong Zhang, Jiahui Zeng, Xiaohua Liu, Guoxiang Xie, Penghong Liu, Ning Sun, Tianhao Bao, Tongtong Nie, Jingchao Lin, Ping Liu, Yuanyi Zheng, Xiaojiao Zheng, Tiemin Liu, Wei Jia

Issue&Volume: 2024-04-05

Abstract: The gut-brain axis is implicated in depression development, yet its underlying mechanism remains unclear. We observed depleted gut bacterial species, including Bifidobacterium longum and Roseburia intestinalis, and the neurotransmitter homovanillic acid (HVA) in individuals with depression and mouse depression models. Although R. intestinalis does not directly produce HVA, it enhances B. longum abundance, leading to HVA generation. This highlights a synergistic interaction among gut microbiota in regulating intestinal neurotransmitter production. Administering HVA, B. longum, or R. intestinalis to mouse models with chronic unpredictable mild stress (CUMS) and corticosterone (CORT)-induced depression significantly improved depressive symptoms. Mechanistically, HVA inhibited synaptic autophagic death by preventing excessive degradation of microtubule-associated protein 1 light chain 3 (LC3) and SQSTM1/p62 proteins, protecting hippocampal neurons’ presynaptic membrane. These findings underscore the role of the gut microbial metabolism in modulating synaptic integrity and provide insights into potential novel treatment strategies for depression.

DOI: 10.1016/j.cmet.2024.03.010

Source: https://www.cell.com/cell-metabolism/fulltext/S1550-4131(24)00089-5