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.

Abstract

Abstract Background: Stroke remains a leading cause of death globally, with post-stroke infections (PSIs) representing its main life-threatening complication. While traditionally attributed to nosocomial infections or medical procedures, emerging research has revealed that PSIs primarily originate from bacterial translocation following gut barrier disruption. Yet, the phenomenon of bacterial translocation remains poorly characterized. Critical knowledge gaps persist regarding the exact spatiotemporal dynamics of this event, and whether bacterial dissemination actively drives stroke pathogenesis and worsens neurological outcomes. Consequently, the development of targeted therapies remains severely limited. In this context, short-chain fatty acids (SCFAs) have emerged as key regulators of the brain-gut-immune axis, exerting neuroprotective and anti-inflammatory properties. However, their potential therapeutic modulation of bacterial translocation has remained unexplored. Methods and Results: Using a middle cerebral artery occlusion model in mice, we confirmed that stroke induces systemic bacterial dissemination to the liver, lungs, and spleen, and provided novel evidence of the presence of bacteria in the heart, brainstem, and ischemic lesion core. Interestingly, systemic bacterial load correlated with worse neurological outcomes but not with ischemic volume. Furthermore, we described for the first time the spatiotemporal kinetics of this process, demonstrating that translocation initiated as early as 6 hours post-stroke, peaked between 24 hours and 4 days, and had almost completely resolved systemically by 7 days, while strikingly persisting in the central nervous system. Importantly, SCFA treatment reduced both systemic and cerebral bacterial translocation, preserved gut barrier integrity, and reversed post-stroke immunosuppression. SCFAs also reduced infarct volume and blood-brain barrier leakage, ultimately improving survival rates. Conclusion: These findings provide crucial insights into the complex process of bacterial translocation and highlight SCFAs as a promising therapeutic strategy for both the ischemic event and its most lethal, yet least understood, complications.