Lactobacillus acidophilus promotes cognitive function recovery via regulating microglial peroxisomal function in...

Cerebral ischemia causes significant mortality and is accompanied by inflammatory reactions that exacerbate damage. While the gut microbiota is linked to clinical outcomes, specific treatments and mechanisms remain unclear. Our metagenomics linked low Lactobacillus abundance to cognitive decline in patients with cerebral ischemia. L. acidophilus supplementation alleviated post-ischemic deficits in murine middle cerebral artery occlusion and bilateral carotid artery stenosis models. The neuroprotective effects of L. acidophilus were driven by enhanced gut absorption of linoleic acid (LinA). L. acidophilus-induced LinA activates peroxisomes in microglia, triggering microglial reprogramming to an anti-inflammatory state via reactive oxygen species (ROS) scavenging and β-oxidation-mediated epigenetic changes. These L. acidophilus-driven effects are lost upon dietary deficits in LinA, microglia depletion, or peroxisome disruption. A randomized clinical trial showed that L. acidophilus improved cognition and cerebral blood flow in ischemic patients. This study was registered at ClinicalTrials.gov (NCT05845983). Collectively, these findings reveal a therapeutic axis whereby L. acidophilus drives microglial reprogramming, providing a basis for microbiome-targeted neurotherapies.