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

doi:10.1016/j.cmet.2024.03.010

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

Cell Metab. 2024 Apr 3:S1550-4131(24)00089-5. doi: 10.1016/j.cmet.2024.03.010. Online ahead of print.

Authors

Mingliang Zhao¹, Zhenxing Ren¹, Aihua Zhao¹, Yajun Tang¹, Junliang Kuang¹, Mengci Li¹, Tianlu Chen¹, Shouli Wang¹, Jieyi Wang¹, Huiheng Zhang¹, Jijun Wang², Tianhong Zhang², Jiahui Zeng², Xiaohua Liu², Guoxiang Xie³, Penghong Liu⁴, Ning Sun⁴, Tianhao Bao⁵, Tongtong Nie⁶, Jingchao Lin³, Ping Liu¹, Yuanyi Zheng⁶, Xiaojiao Zheng⁷, Tiemin Liu⁸, Wei Jia⁹

Affiliations

¹ Center for Translational Medicine and Shanghai Key Laboratory of Diabetes Mellitus, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, School of Biomedical Engineering, Med-X Research Institute, Shanghai Jiao Tong University, Shanghai 200030, China.
² Shanghai Mental Health Center, Shanghai Jiao Tong University School of Medicine, Shanghai Intelligent Psychological Evaluation and Engineering Technology Research Center, Shanghai Key Laboratory of Psychotic Disorders, Shanghai 200030, China.
³ Human Metabolomics Institute, Inc., Shenzhen 518109, China.
⁴ Department of Psychiatry, First Hospital of Shanxi Medical University, Taiyuan 030001, China.
⁵ The Affiliated Mental Health Center of Kunming Medical University, Kunming 650224, China.
⁶ Department of Ultrasound, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200233, China.
⁷ Center for Translational Medicine and Shanghai Key Laboratory of Diabetes Mellitus, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, School of Biomedical Engineering, Med-X Research Institute, Shanghai Jiao Tong University, Shanghai 200030, China. Electronic address: joyzheng99@sjtu.edu.cn.
⁸ State Key Laboratory of Genetic Engineering, Department of Endocrinology and Metabolism, Institute of Metabolism and Integrative Biology, Human Phenome Institute, and School of Life Sciences, Zhongshan Hospital, Fudan University, Shanghai 200438, China. Electronic address: tiemin_liu@fudan.edu.cn.
⁹ Center for Translational Medicine and Shanghai Key Laboratory of Diabetes Mellitus, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, School of Biomedical Engineering, Med-X Research Institute, Shanghai Jiao Tong University, Shanghai 200030, China; Department of Pharmacology and Pharmacy, University of Hong Kong, Hong Kong, China. Electronic address: weijia2@hku.hk.

PMID: 38582087
DOI: 10.1016/j.cmet.2024.03.010

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.

Keywords: Bifidobacterium longum; Roseburia intestinalis; autophagic death; depression; homovanillic acid; synaptic integrity.