Integrated multi-omics reveals gut microbiota–metabolic mechanisms underlying the neuroprotective effects of Xijiao Dihuang Decoction against cerebral ischemia–reperfusion injury
4 affiliations
- 1Key Laboratory of TCM Diagnostics of Hunan Province, Hunan University of Chinese Medicine
- 2Hunan Engineering Technology Research Center for Medicinal and Functional Food
- 3Key Laboratory of TCM Heart and Lung Syndrome Differentiation & Medicated Diet and Dietotherapy
- 4Laboratory Animal Center, Hunan University of Chinese Medicine
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.
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BibTeX
@article{long2026integrated,
title = {{Integrated multi-omics reveals gut microbiota–metabolic mechanisms underlying the neuroprotective effects of Xijiao Dihuang Decoction against cerebral ischemia–reperfusion injury}},
author = {Yu-yan Long and Yu-jing Feng and Kai-ni Mao and Zhi-guang Song and Yu-chen Liu and Si-yuan Chen and Cai-xing Zheng and Yi-di Zeng and Shu-ting Yin and Si-si Dai and Hua Li and Wang-hua Liu},
journal = {Frontiers in Microbiology},
year = {2026},
month = oct,
doi = {10.3389/fmicb.2026.1851608},
url = {https://www.frontiersin.org/articles/10.3389/fmicb.2026.1851608/full},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Integrated multi-omics reveals gut microbiota–metabolic mechanisms underlying the neuroprotective effects of Xijiao Dihuang Decoction against cerebral ischemia–reperfusion injury
AU - Yu-yan Long
AU - Yu-jing Feng
AU - Kai-ni Mao
AU - Zhi-guang Song
AU - Yu-chen Liu
AU - Si-yuan Chen
AU - Cai-xing Zheng
AU - Yi-di Zeng
AU - Shu-ting Yin
AU - Si-si Dai
AU - Hua Li
AU - Wang-hua Liu
PY - 2026
DA - 2026/10/15
JO - Frontiers in Microbiology
DO - 10.3389/fmicb.2026.1851608
UR - https://www.frontiersin.org/articles/10.3389/fmicb.2026.1851608/full
AB - 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.
SN - 1664-302X
ER -