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

• Published in: Cell metabolism Vol. 36; no. 5; pp. 1000 - 1012.e6
• Main Authors: Zhao, Mingliang, Ren, Zhenxing, Zhao, Aihua, Tang, Yajun, Kuang, Junliang, Li, Mengci, Chen, Tianlu, Wang, Shouli, Wang, Jieyi, Zhang, Huiheng, Wang, Jijun, Zhang, Tianhong, Zeng, Jiahui, Liu, Xiaohua, Xie, Guoxiang, Liu, Penghong, Sun, Ning, Bao, Tianhao, Nie, Tongtong, Lin, Jingchao, Liu, Ping, Zheng, Yuanyi, Zheng, Xiaojiao, Liu, Tiemin, Jia, Wei
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 07.05.2024
• Subjects: autophagic death; Bifidobacterium longum; depression; homovanillic acid; Roseburia intestinalis; synaptic integrity; Roseburia intestinalis; homovanillic acid; Bifidobacterium longum; synaptic integrity; autophagic death; depression
• ISSN: 1550-4131; 1932-7420
• DOI: 10.1016/j.cmet.2024.03.010

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. [Display omitted] •HVA levels are depleted along with altered gut bacteria in people with depression•R. intestinalis promotes the abundance of B. longum for HVA production•Treatment with HVA, B. longum, or R. intestinalis alleviates depression in mice•HVA restores synaptic function by inhibiting autophagic death The study by Zhao et al. shows that administering intestinal B. longum, R. intestinalis, or the neurotransmitter, homovanillic acid, improved depressive symptoms in mice. This highlights the role of gut microbial metabolism in maintaining synaptic integrity and suggests potential treatment strategies for depression.