Wonderful descriptions; but complete failure at producing anything for stroke recovery!
Targeting the microbiota-gut-brain axis in post-stroke insomnia: a phase-dependent therapeutic framework
Abstract
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.
1 Introduction
1.1 The silent epidemic: beyond symptomology
Stroke remains a formidable global health challenge, consistently ranking among the leading causes of mortality and long-term adult disability worldwide (GBD 2019 Stroke Collaborators, 2021; Feigin et al., 2025). While the advent of hyper-acute recanalization therapies—such as mechanical thrombectomy and intravenous thrombolysis—has improved acute outcomes, these advances have coincided with a growing population of survivors living with chronic sequelae (GBD 2019 Stroke Collaborators, 2021; Feigin et al., 2025). Among these, sleep–wake disturbances are pervasive yet frequently underestimated in routine clinical practice, often overshadowed by more visible motor deficits (Khot and Morgenstern, 2019). Epidemiological evidence suggests that sleep problems affect roughly half of stroke survivors, consistent with pooled estimates of poor sleep quality after stroke and broader post-stroke sleep-disorder burden (Khot and Morgenstern, 2019; Luo et al., 2023). Of these disorders, post-stroke insomnia (PSI) is commonly reported and can persist, presenting a barrier to effective neurorehabilitation (Wang et al., 2024; Sun et al., 2026). PSI is characterized not merely by difficulties in sleep initiation, but also by fragmentation of sleep continuity and non-restorative rest (Wang et al., 2024). The clinical ramifications of untreated PSI extend beyond subjective fatigue or daytime somnolence; disrupted sleep after stroke has been associated with poorer functional outcomes and increased risk of adverse vascular events in observational and review evidence (Khot and Morgenstern, 2019). Sleep is a fundamental physiological pillar for neuroplasticity and memory consolidation, and sleep disruption may therefore hinder recovery processes after stroke (Khot and Morgenstern, 2019). Indeed, disrupted sleep in the post-stroke period has been linked to worse functional recovery and mood and cognitive outcomes, supporting proactive recognition and targeted management rather than passive observation.
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