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<p>Asthma is frequently accompanied by anxiety disorders, yet the mechanisms linking asthma to neuropsychiatric symptoms remain poorly defined. Here, we investigated the contribution of the pulmonary microbiota and its metabolites to anxiety-like behavior in an ovalbumin-induced asthma mouse model. Behavioral testing and resting-state functional magnetic resonance imaging revealed anxiety-like phenotypes and altered hippocampal function in a subset of asthmatic mice that were susceptible to anxiety-like behavior. These mice exhibited hippocampal neuroinflammation and neuronal damage, accompanied by dysbiosis of the pulmonary microbiota. Intratracheal transplantation of lung microbiota from anxiety-susceptible donors induced similar behavioral changes in recipient mice, indicating a causal role of the pulmonary microbiota. Untargeted metabolomics identified formononetin as a candidate metabolite positively correlated with the relative abundance of <i>Acidobacteria</i>. Intratracheal administration of formononetin alleviated anxiety-like behaviors, reduced hippocampal inflammation and injury, and restored hippocampal BDNF/TrkB signaling. However, these effects were abolished by the TrkB antagonist ANA-12. Transcriptomic and immunofluorescence analyses suggested that formononetin acts through modulation of hippocampal microglia. In vitro and small RNA sequencing analyses further demonstrated that formononetin promotes BDNF production by downregulating miR-1912-3p, thereby relieving its translational repression in microglia. Together, these findings reveal a lung–brain axis in which a pulmonary microbiota–associated metabolite modulates microglial function to alleviate asthma-related anxiety.</p> Graphical Abstract <p></p>

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Pulmonary microbiota–associated formononetin modulates microglial activation in asthma-related anxiety

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年5月11日

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  • Yanbo Liu,
  • Haoyue Zhang,
  • Ying Zhou,
  • Haotian Chen,
  • Xuanyuan Pan,
  • Juan Zhi,
  • Qianyu Wang,
  • Kaixuan Zhao,
  • Weipeng Xia,
  • Dong Yang

摘要

Asthma is frequently accompanied by anxiety disorders, yet the mechanisms linking asthma to neuropsychiatric symptoms remain poorly defined. Here, we investigated the contribution of the pulmonary microbiota and its metabolites to anxiety-like behavior in an ovalbumin-induced asthma mouse model. Behavioral testing and resting-state functional magnetic resonance imaging revealed anxiety-like phenotypes and altered hippocampal function in a subset of asthmatic mice that were susceptible to anxiety-like behavior. These mice exhibited hippocampal neuroinflammation and neuronal damage, accompanied by dysbiosis of the pulmonary microbiota. Intratracheal transplantation of lung microbiota from anxiety-susceptible donors induced similar behavioral changes in recipient mice, indicating a causal role of the pulmonary microbiota. Untargeted metabolomics identified formononetin as a candidate metabolite positively correlated with the relative abundance of Acidobacteria. Intratracheal administration of formononetin alleviated anxiety-like behaviors, reduced hippocampal inflammation and injury, and restored hippocampal BDNF/TrkB signaling. However, these effects were abolished by the TrkB antagonist ANA-12. Transcriptomic and immunofluorescence analyses suggested that formononetin acts through modulation of hippocampal microglia. In vitro and small RNA sequencing analyses further demonstrated that formononetin promotes BDNF production by downregulating miR-1912-3p, thereby relieving its translational repression in microglia. Together, these findings reveal a lung–brain axis in which a pulmonary microbiota–associated metabolite modulates microglial function to alleviate asthma-related anxiety.

Graphical Abstract