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<p>Depression is increasingly recognized as a disorder not only of the brain but also of systemic metabolic dysfunction, particularly involving the gut microbiota. Integrating multi-cohort gut microbiome data with constraint-based metabolic modeling, this study investigates how microbial metabolic fluxes mediate depressive symptoms. Significant alterations in microbial pathways, notably those related to amino acid metabolism and neurotransmitter precursors, were identified. Causal mediation analysis showed that gut microbial composition influenced depressive symptoms, significantly mediated by specific metabolites including butyrate, Cu<sup>2+</sup>, and tryptophan-derived compounds. This study, employing systems biology and mediation analysis, suggests that microbial metabolic activity mediates the gut-brain axis’s role in depression development and severity. These results enhance our understanding of microbiota-related mechanisms in mental health and highlight potential metabolic targets for depression treatment.</p>

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Gut microbial metabolic disorder in depression: insights from computational modeling and mediation analysis

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2026年4月14日

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  • Yuchen Zhang,
  • Wenkai Lai,
  • Meiling Wang,
  • Shirong Lai,
  • Qing Liu,
  • Qi Luo,
  • Zheng Chen,
  • Da Zhao,
  • Ziwei Wang,
  • Fenglong Yang

摘要

Depression is increasingly recognized as a disorder not only of the brain but also of systemic metabolic dysfunction, particularly involving the gut microbiota. Integrating multi-cohort gut microbiome data with constraint-based metabolic modeling, this study investigates how microbial metabolic fluxes mediate depressive symptoms. Significant alterations in microbial pathways, notably those related to amino acid metabolism and neurotransmitter precursors, were identified. Causal mediation analysis showed that gut microbial composition influenced depressive symptoms, significantly mediated by specific metabolites including butyrate, Cu2+, and tryptophan-derived compounds. This study, employing systems biology and mediation analysis, suggests that microbial metabolic activity mediates the gut-brain axis’s role in depression development and severity. These results enhance our understanding of microbiota-related mechanisms in mental health and highlight potential metabolic targets for depression treatment.