BACKGROUND: Ischemic stroke (IS), the predominant clinical stroke subtype, is increasingly linked to dysregulation of the gut-brain axis (GBA)-a bidirectional neuroendocrine-immune interface connecting intestinal homeostasis with cerebrovascular pathophysiology. Xinqingning Tablet (XQNT) demonstrates neuroprotective potential in IS complicated by gut dysbiosis (GD), yet its mechanisms of GBA modulation remain unclear.
METHODS: A dual-hit IS-GD mouse model was established via fecal slurry transplantation and permanent middle cerebral artery occlusion (pMCAO) surgery. Gut function was evaluated by constipation indices and histopathological changes, while the neuroprotective efficacy of XQNT (0.36, 0.48, and 0.61 g kg⁻¹) was assessed via TTC staining, neurological deficit scores, cerebral water content, and Evans blue (EB) extravasation assays. Additionally, Western blot was employed to quantify blood-brain barrier (BBB) and inflammation-associated proteins. microRNA sequencing was used to screen the differentially expressed miRNAs. miR-126 expression levels were measured by RT-qPCR, while concentrations of LPS, IL-6 and IL-10 were determined by ELISA. Finally, mechanistic validation employed intravenous miR-126 agonism/antagonism coupled with phenotypic rescue experiments.
RESULTS: XQNT conferred robust survival benefits, while concurrently ameliorating intestinal dysfunction and neurovascular injury. Mechanistically, XQNT elevated miR-126 expression, suppressing NF-κB-driven neuroinflammation. Additionally, miR-126 agonism phenocopied XQNT efficacy, whereas miR-126 inhibition abrogated therapeutic benefits.
CONCLUSIONS: This study provides early evidence that XQNT functions as a dual-target GBA modulator that alleviates IS with GD via regulation of the miR-126/NF-κB axis. By simultaneously promoting barrier restoration and inflammatory resolution, XQNT offers a promising therapeutic approach that links regulation of the gastrointestinal system with cerebrovascular protection.
