Targeting the microbiota-gut-brain axis in post-stroke insomnia: a phase-dependent therapeutic framework

Post-stroke insomnia (PSI) is a critical biological barrier to neurorehabilitation afflicting over half of all stroke survivors. Traditional sedatives often force clinicians into a therapeutic dilemma between sleep efficacy and cognitive suppression. The microbiota-gut-brain (MGB) axis has recently emerged as a transformative target to resolve this impasse. Acute stroke triggers profound autonomic dysfunction, causing immediate intestinal barrier collapse. This "leaky gut" facilitates the systemic translocation of lipopolysaccharides (LPS) and activates the NLRP3 inflammasome. The resulting inflammatory storm hijacks central tryptophan metabolism via the indoleamine 2,3-dioxygenase (IDO) enzyme. This "tryptophan steal" diverts serotonin precursors toward neurotoxic kynurenine pathways, driving severe cortical hyperarousal. Sleep fragmentation then prevents the glymphatic system from clearing metabolic waste, further exacerbating neuroinflammation. To break this vicious cycle of neurotoxicity, we propose a phase-dependent therapeutic framework. During the highly vulnerable acute phase, interventions must prioritize gut barrier protection using postbiotics to mitigate infection risks under CNS injury-induced immunodepression (CIDS), often discussed as stroke-induced immunosuppression. As patients enter the chronic phase, therapy shifts toward metabolic restoration using live therapeutics, such as washed microbiota transplantation (WMT) and next-generation psychobiotics like Akkermansia muciniphila. Targeting the MGB axis offers a mechanism-based strategy to achieve precision sleep medicine, restoring the biological foundation necessary for optimal neuroplasticity and recovery.