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

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.