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