Gut dysbiosis impairs HPA axis function and exacerbates post-stroke inflammation in high-fat diet-fed male mice.

UNLABELLED: High-fat diet (HFD)-induced metabolic stress is associated with impaired hypothalamic-pituitary-adrenal (HPA) axis function, but its impact on stroke outcomes and the role of the gut microbiota remain unclear. In a mouse middle cerebral artery occlusion (MCAO) model, we found that HFD induced gut dysbiosis, suppressed hypothalamic CRH expression, and reduced circulating corticosterone, which in turn exacerbated neuroinflammation and neuronal apoptosis, and worsened neurological recovery. Interventions with fecal microbiota transplantation or supplementation of Akkermansia muciniphila partially restored HPA axis activity, mitigated inflammatory injury, and improved behavioral outcomes post-stroke. These findings suggest that a gut microbiota-HPA axis may be relevant under metabolic stress conditions and open a possible microbiota-based adjunctive strategy for improving stroke prognosis in metabolically vulnerable populations. IMPORTANCE: Metabolic disorders such as obesity and high-fat diet exposure are known to worsen stroke outcomes, but the mechanisms connecting metabolic stress, gut microbiota alterations, and neuroendocrine dysfunction have not been well defined. Our data indicate that gut dysbiosis under HFD conditions is associated with HPA axis suppression and worse neuroinflammatory injury after stroke and that microbiota-targeted intervention can restore hormonal regulation and functional recovery. This highlights the gut microbiota-neuroendocrine interface as a promising area for therapeutic exploration in metabolically at-risk stroke patients.