Mendelian Randomization Unlocks Stroke Therapeutics: Dioscin Inhibits CD27-Driven Neuroinflammation via Gut...

Research on the gut-brain-immune axis shows it plays a critical role in ischemic stroke, but the exact causal links between gut bacteria imbalance, immune system problems, and brain blood vessel damage remain unclear. To investigate this, we combined multiple types of biological data using a statistical method called Bayesian weighted Mendelian randomization (BWMR). We analyzed large genetic datasets covering 731 immune cell traits, 91 inflammatory proteins, 412 gut microbes and their pathways, and ischemic stroke cases. Shared genetic variants were confirmed using colocalization, and we used computer simulations to explore potential treatments. The analysis found that genetically predicted higher levels of the protein CD27 on specific memory B cells (CD24⁺ CD27⁺ and IgD^- CD38^dim) directly increased the risk of stroke caused by large-artery atherosclerosis. Computer modeling indicated that a compound called Dioscin could potentially block CD27 effectively. Conversely, bacteria from the order Burkholderiales (specifically at the family, genus, and species level Burkholderiales_bacterium_1_1_47) showed strong protective effects against small-vessel stroke. Further analysis revealed that about 12.6% of the protective effect of the gut bacterium g_Odoribacter worked through the signaling protein FGF19. This study identifies CD27-positive B cells as key drivers of brain inflammation in stroke and suggests Dioscin as a promising treatment candidate. It also demonstrates a protective mechanism where specific gut microbes communicate with blood vessels in the brain via FGF19, providing a foundation for new stroke therapies targeting the microbiome and immune system.