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

• DOI: 10.1016/j.cmet.2024.03.010
• Publication Date: 2024-04-05T17:59:47Z
• Authors: 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
• Keywords: Gut–brain axis; Corticosterone

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, the neurotransmitter homovanillic acid (HVA) individuals with mouse models. Although R. intestinalis does not directly produce HVA, it enhances B. abundance, leading to HVA generation. This highlights a synergistic interaction among microbiota regulating intestinal production. Administering longum, or models chronic unpredictable mild stress (CUMS) corticosterone (CORT)-induced significantly improved depressive symptoms. Mechanistically, inhibited synaptic autophagic death by preventing excessive degradation of microtubule-associated protein 1 light chain 3 (LC3) SQSTM1/p62 proteins, protecting hippocampal neurons' presynaptic membrane. These findings underscore role microbial metabolism modulating integrity provide insights into potential novel treatment strategies for depression.