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<p>The gut–brain axis plays a critical role in anxiety disorders, yet the underlying mechanisms remain incompletely understood. Using a mouse model of radiofrequency radiation (RFR)-induced anxiety-like behaviors, we employed gut microbiota intervention, regulation of tryptophan metabolites, and other methods to investigate the impact of the gut–brain axis on brain function changes. It was found that gut microbiota dysbiosis disrupts tryptophan metabolism, leading to reduced serotonin (5-HT) levels and NLRP3 inflammasome-mediated neuronal pyroptosis in the medial prefrontal cortex (mPFC). Probiotic intervention restored microbial homeostasis, normalized central 5-HT metabolism, suppressed neuronal pyroptosis, and partially alleviated anxiety-like behaviors. Similarly, treatment with the selective serotonin reuptake inhibitor (SSRI) paroxetine increased brain 5-HT, attenuated NLRP3 activation and pyroptosis, and improved behavioral outcomes. These findings reveal that perturbations in gut–brain tryptophan metabolism are strongly correlated with anxiety-like behaviors via neuroinflammatory pyroptotic pathways, offering new mechanistic insights and potential therapeutic targets for anxiety disorders.</p> Graphical abstract <p></p>

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Gut microbiota-tryptophan-serotonin axis drives anxiety-like behavior via NLRP3-mediated neuronal pyroptosis in the medial prefrontal cortex

  • 期刊论文

  • 发表日期：

    2026年5月9日

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  • Guiqiang Zhou,
  • Xing Wang,
  • Tongzhou Qin,
  • Ling Guo,
  • Jiajin Lin,
  • Zhaowen Zhang,
  • Peng Gao,
  • Yan Zhou,
  • Wei He,
  • Jing Li,
  • Guirong Ding

摘要

The gut–brain axis plays a critical role in anxiety disorders, yet the underlying mechanisms remain incompletely understood. Using a mouse model of radiofrequency radiation (RFR)-induced anxiety-like behaviors, we employed gut microbiota intervention, regulation of tryptophan metabolites, and other methods to investigate the impact of the gut–brain axis on brain function changes. It was found that gut microbiota dysbiosis disrupts tryptophan metabolism, leading to reduced serotonin (5-HT) levels and NLRP3 inflammasome-mediated neuronal pyroptosis in the medial prefrontal cortex (mPFC). Probiotic intervention restored microbial homeostasis, normalized central 5-HT metabolism, suppressed neuronal pyroptosis, and partially alleviated anxiety-like behaviors. Similarly, treatment with the selective serotonin reuptake inhibitor (SSRI) paroxetine increased brain 5-HT, attenuated NLRP3 activation and pyroptosis, and improved behavioral outcomes. These findings reveal that perturbations in gut–brain tryptophan metabolism are strongly correlated with anxiety-like behaviors via neuroinflammatory pyroptotic pathways, offering new mechanistic insights and potential therapeutic targets for anxiety disorders.

Graphical abstract