A microbiota–metabolite–glial axis drives white matter repair via isorhamnetin–PSAP–GPR37 signaling after ischemic stroke

Ischemic stroke (IS) induces persistent neuroinflammation and white matter injury that limit neurological recovery, yet effective repair-oriented therapies remain lacking. Although microbiota influences stroke outcomes, how microbial activity drives central nervous system repair is unclear. Here, we integrate clinical microbiome profiling, experimental stroke models, multi-omics analyses, and mechanistic validation to define a microbiota-metabolite-glial signaling axis that promotes post-stroke recovery. Akkermansia muciniphila (Akk) is associated with favorable outcomes in patients and improves recovery in mice without altering infarct size, supporting a repair-promoting rather than neuroprotective mechanism. Mechanistically, Akk increases circulating isorhamnetin (Iso), a key systemic mediator that suppresses lipid-laden, pro-inflammatory microglia and promotes oligodendrocyte maturation and white matter repair. Iso reprograms microglia to secrete PSAP, and conditioned medium-but not direct Iso-activates GPR37-ERK signaling in oligodendrocytes. In vitro knockdown of Psap or Gpr37 markedly attenuates these effects, demonstrating a microglia-dependent mechanism. In vivo adeno-associated virus (AAV)-mediated Gpr37 knockdown abolishes the beneficial effects of Akk and Iso on functional recovery and white matter repair, establishing the necessity of PSAP-GPR37 signaling. These findings identify a microbiota-driven metabolic pathway linking gut activity to white matter repair after IS.