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Integrated multi-omics reveals gut microbiota–metabolic mechanisms underlying the neuroprotective effects of Xijiao Dihuang Decoction against cerebral ischemia–reperfusion injury

Year: 2026

Type: article

Abstract: Background: Cerebral ischemia-reperfusion injury (CIRI) remains a major barrier to functional recovery after reperfusion therapy for ischemic stroke. Increasing evidence indicates that gut microbiota dysbiosis and metabolic disturbance are closely involved in post-stroke neuroinflammation and secondary brain injury. Xijiao Dihuang Decoction (XDD), a classical traditional Chinese medicine formula, has shown protective effects in cerebrovascular disorders; however, whether its effects against CIRI are associated with coordinated regulation of the gut microbiota and host metabolism remains unclear. Methods: Circulating XDD-derived components were characterized by ultra-high-performance liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS). Network pharmacology and molecular docking were used to predict potential targets and signaling pathways associated with CIRI. A middle cerebral artery occlusion/reperfusion (MCAO/R) rat model was established, and rats were treated with low-, medium-, or high-dose XDD for 7 days, with edaravone as a positive control. Neurological deficits, cerebral infarct volume, hemorheological parameters, histopathological changes, and serum inflammatory cytokines were assessed. Cecal microbiota composition was analyzed by 16S rDNA sequencing, and cecal metabolic profiles were investigated using untargeted LC-MS metabolomics. Multi-omics integration and Spearman correlation analysis were performed to explore associations between differentially abundant bacterial genera and characteristic metabolites. Results: A total of 54 XDD-derived circulating components were identified. Network pharmacology analysis indicated that the putative targets of XDD were mainly enriched in pathways related to inflammation, lipid and energy metabolism, and regulated cell death, with AKT1 and NLRP3 were predicted as potential hub targets. In MCAO/R rats, XDD improved neurological deficits, reduced cerebral infarct volume, alleviated hemorheological abnormalities, and attenuated neuronal injury. XDD also reduced serum IL-6 levels and lowered IL-1β levels mainly at medium and high doses. In addition, XDD partially restored gut microbial diversity and remodeled CIRI-associated microbial dysbiosis. Metabolomics analysis revealed marked metabolic disturbances after MCAO/R, and XDD reversed part of these alterations, particularly those related to lipid metabolism. Integrated analysis further linked specific bacterial genera with lipid mediators and fatty acid-related metabolites, indicating coordinated remodeling of the gut microbiota and host metabolism. Conclusion: XDD exerts neuroprotective effects against CIRI through multi-target and multi-pathway actions. Its therapeutic effects may be associated with coordinated regulation of gut microbial homeostasis, metabolic reprogramming, and inflammatory/cell death signaling. These findings provide new evidence supporting the potential application of XDD in ischemic stroke and offer insight into microbiota-related mechanisms underlying its neuroprotective effects.

Source: Frontiers in Microbiology

DOI: 10.3389/fmicb.2026.1851608