Akkermansia muciniphila Restores HPA Axis Signaling and Attenuates Post-Stroke Brain Injury under High-Fat Dietary Conditions

Ischemic stroke prognosis is influenced not only by vascular factors but also by metabolic and neuroendocrine regulation. High-fat diet (HFD), a major driver of metabolic dysfunction, may modulate gut microbiota and hypothalamic–pituitary–adrenal (HPA) axis function, yet the extent and relevance of these effects in stroke remain unclear. In particular, direct experimental evidence supporting the full physiological pathway linking HFD, gut microbiota, hormonal regulation, and stroke outcome is lacking. In this study, we show that HFD-fed mice exhibit reduced hypothalamic corticotropin-releasing hormone (CRH) expression and circulating corticosterone levels, accompanied by aggravated neurological deficits, enhanced microglial activation, and increased neuronal apoptosis following middle cerebral artery occlusion (MCAO). To probe the role of the gut microbiota in this process, we performed fecal microbiota transplantation (FMT) from normal diet-fed donors and oral administration of Akkermansia muciniphila in HFD-fed mice. Both interventions restored hormone levels, improved behavioral recovery, and attenuated neuroinflammation and cell death. Microbiota analysis revealed that the reduction of Akkermansia induced by HFD feeding was partially reversed by the intervention. These findings provide direct evidence that HFD-associated gut dysbiosis contributes to impaired HPA axis activity and worsened stroke outcomes, and that microbiota-targeted strategies may restore endogenous hormonal balance and promote neuroprotection. This study establishes a functional link along the gut microbiota–HPA axis–stroke injury axis in the context of dietary metabolic stress.