Lamei Pill Against Ischemic Stroke: Mechanistic Insights from CXCL8 upregulation and Gut-Brain Axis Modulation

Background: Ischemic Stroke (IS) is a major cause of global mortality and disability with limited effective therapies. Lamei Pill (LMP), a traditional Tibetan medicine, has demonstrated efficacy against cerebrovascular diseases, but its mechanisms of action remain incompletely understood. To elucidate the bioactive components, targets, and mechanisms of LMP against IS using an integrated methodology. Methods: A multi-methodological approach was employed: (1) UHPLC-QE-MS-based untargeted metabolomics to identify LMP-derived components in rat brain and serum; (2) Network pharmacology to predict potential targets and construct component-target-pathway networks; (3) Mendelian Randomization (MR) to assess causal relationships between prioritized targets and IS susceptibility using large-scale GWAS data; (4) 16S rRNA sequencing and H&E staining to evaluate LMP-induced changes in gut microbiota and intestinal histoarchitecture in a Middle Cerebral Artery Occlusion (MCAO) rat model. Results: Integrated analysis identified 31 active components and 214 shared targets of LMP related to IS. Linderagalactone C was pinpointed as the primary bioactive compound, with CXCL8 as its core target. MR analysis revealed a causal relationship between genetically predicted lower CXCL8 levels and increased stroke risk (IVW OR=0.94, 95% CI: 0.89-0.99, P=0.046). In vivo, LMP attenuated cerebral ischemia-induced colonic damage, restored the Bacillota/Bacteroidota ratio, suppressed Enterobacteriaceae, and increased Bifidobacterium abundance. Conclusion: This study suggests that Lamei pill ameliorates ischemic stroke likely by upregulating CXCL8 and restoring Microbiota-Gut-Brain Axis (MGBA) homeostasis, with Linderagalactone C identified as a key mediating component.