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<p>Ineupatorolide B (InB), a sesquiterpene lactone with anti-inflammatory and anti-tumor properties, has not previously been evaluated for antidepressant effects. Given the central role of the gut–brain axis in stress-related mood disorders, we investigated whether InB alleviates depression-like phenotypes in mice exposed to chronic social defeat stress (CSDS) through microbiota- and vagus-dependent mechanisms. CSDS-susceptible mice received vehicle, fluoxetine, or InB and were assessed using behavioral paradigms, plasma inflammatory cytokine measurements, and analyses of synaptic-related protein expression in the medial prefrontal cortex (mPFC). CSDS induced robust depression-like behaviors, elevated interleukin-6 and tumor necrosis factor-α, caused splenomegaly, and reduced PSD-95 and BDNF expression in the mPFC. Repeated InB administration significantly reversed these behavioral, inflammatory, and synaptic abnormalities. 16S rRNA gene sequencing revealed that CSDS disrupted gut microbial α- and β-diversity, whereas InB treatment largely normalized these alterations and restored depression-associated short-chain fatty acids, including isobutyric and valeric acid, consistent with reestablishment of microbial metabolic homeostasis. Importantly, subdiaphragmatic vagotomy abolished the antidepressant-like, anti-inflammatory, and synaptic effects of InB, demonstrating that its efficacy requires intact vagus nerve–mediated gut–brain signaling. Together, these findings identify vagus-dependent modulation of the microbiota–immune–synaptic axis as a mechanistic pathway through which InB exerts antidepressant effects and highlight this compound as a potential microbiota-targeted therapeutic strategy for depression.</p>

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Vagus nerve–dependent antidepressant effects of ineupatorolide B via gut microbiota modulation in a mouse model of depression

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年6月20日

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  • Siming Wang,
  • Yuqian Zhang,
  • Ningning Wu,
  • Siqi Wang,
  • Yuhe Ma,
  • Weichen Zhang,
  • Guiying Li,
  • Kenji Hashimoto,
  • Zhiyu Ni

摘要

Ineupatorolide B (InB), a sesquiterpene lactone with anti-inflammatory and anti-tumor properties, has not previously been evaluated for antidepressant effects. Given the central role of the gut–brain axis in stress-related mood disorders, we investigated whether InB alleviates depression-like phenotypes in mice exposed to chronic social defeat stress (CSDS) through microbiota- and vagus-dependent mechanisms. CSDS-susceptible mice received vehicle, fluoxetine, or InB and were assessed using behavioral paradigms, plasma inflammatory cytokine measurements, and analyses of synaptic-related protein expression in the medial prefrontal cortex (mPFC). CSDS induced robust depression-like behaviors, elevated interleukin-6 and tumor necrosis factor-α, caused splenomegaly, and reduced PSD-95 and BDNF expression in the mPFC. Repeated InB administration significantly reversed these behavioral, inflammatory, and synaptic abnormalities. 16S rRNA gene sequencing revealed that CSDS disrupted gut microbial α- and β-diversity, whereas InB treatment largely normalized these alterations and restored depression-associated short-chain fatty acids, including isobutyric and valeric acid, consistent with reestablishment of microbial metabolic homeostasis. Importantly, subdiaphragmatic vagotomy abolished the antidepressant-like, anti-inflammatory, and synaptic effects of InB, demonstrating that its efficacy requires intact vagus nerve–mediated gut–brain signaling. Together, these findings identify vagus-dependent modulation of the microbiota–immune–synaptic axis as a mechanistic pathway through which InB exerts antidepressant effects and highlight this compound as a potential microbiota-targeted therapeutic strategy for depression.