Microbiota-derived IPA mitigates post-stroke neuroinflammation by inhibiting TREM2-dependent pyroptosis.

Ischemic stroke remains the leading cause of long-term disability globally, underscoring the urgent need for novel therapeutic strategies. Here, we explore a microbiota-gut-brain axis that provides valuable insights for achieving this objective. Utilizing a distal middle cerebral artery occlusion (dMCAO) mouse model, we observed a marked reduction in Duncaniella muris (D. muris) post-stroke, alongside dysregulated tryptophan metabolism, characterized by elevated levels of indole-3-lactic acid (ILA) and decreased indole-3-propionic acid (IPA). D. muris supplementation restored metabolic balance by converting ILA to IPA, leading to significant improvements in neurological recovery. Mechanistically, IPA exerted neuroprotective effects by attenuating neuroinflammation through TREM2-dependent modulation of microglial activation, promoting an anti-inflammatory phenotype and inhibiting NLRP3 inflammasome-mediated pyroptosis. These findings highlight the therapeutic potential of the D. muris-IPA-TREM2-pyroptosis axis as a novel target for ischemic stroke treatment, providing a basis for future microbiome-based interventions aimed at improving stroke outcomes. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s12974-025-03660-8.