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

Cell Metab. 2024 May 7;36(5):1000-1012.e6. doi: 10.1016/j.cmet.2024.03.010. Epub 2024 Apr 5.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Depression* / drug therapy
  • Depression* / metabolism
  • Female
  • Gastrointestinal Microbiome* / drug effects
  • Hippocampus / drug effects
  • Hippocampus / metabolism
  • Homovanillic Acid* / metabolism
  • Humans
  • Male
  • Mice
  • Mice, Inbred C57BL*
  • Neurons / drug effects
  • Neurons / metabolism
  • Synapses / drug effects
  • Synapses / metabolism

Substances

  • Homovanillic Acid