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bioRxiv · 10.1101/2025.11.03.686233

Administration of short-chain fatty acids reduces bacterial translocation to peripheral organs and the brain, preserves gut barrier integrity, and mitigates brain injury following stroke

Castillo Gonzalez, J.·Mousavi, M.·Buscemi, L.·Price, M.·Hirt, L.
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Abstract

Ischemic stroke leads to neuronal death, neuroinflammation, blood-brain barrier breakdown, and disruption of the brain-immune-gut (BIG) axis. Despite improvements in recanalization treatments, stroke remains the second leading cause of death globally. Post-stroke infections (PSIs) are the main life-threatening complication (30-45% of all patients and 20% of mortality) after stroke. Traditionally attributed to nosocomial infections /associated medical procedures, ground-breaking research has revealed that PSIs primarily originate from bacterial translocation (BT) following gut barrier disruption after stroke. Despite the high mortality associated with PSIs, current treatments, including antibiotic prophylaxis, are largely ineffective, underscoring the urgent need for a better understanding of their aetiology. Short-chain fatty acids (SCFAs), microbiota-derived metabolites produced by bacterial fermentation of fibres, are key regulators of the BIG axis. SCFAs exert neuroprotective, anti-inflammatory, and antimicrobial effects across models of neurodegenerative and infectious diseases. Using a preclinical stroke model (transient middle cerebral artery occlusion, MCAO) in 12-week-old male mice, we evaluated the effects of SCFA administration starting 24 h after stroke until sacrifice at day 4 on BT, gut integrity, and brain injury. Our findings confirmed that stroke induces BT to several organs (e.g., liver, heart, spleen) and, for the first time, demonstrated bacterial presence in the brainstem and the ischemic core of the injured brain. Importantly, we also showed that SCFA treatment significantly reduced BT to several organs. In addition, SCFAs modulated gut barrier integrity, reduced brain lesion size, and improved functional recovery. These findings highlight the crucial role of SCFAs in the BIG axis following stroke and their potential to mitigate not only gut barrier disruption and brain injury, but also infection-related complications, offering a promising therapeutic strategy for one of the least understood yet most lethal complications of stroke.

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Castillo Gonzalez, J., Mousavi, M., Buscemi, L., Price, M., Hirt, L.. 2025-11-04. Administration of short-chain fatty acids reduces bacterial translocation to peripheral organs and the brain, preserves gut barrier integrity, and mitigates brain injury following stroke. https://doi.org/10.1101/2025.11.03.686233

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