Multi-omics profiling of gut microbiota and host transcriptome identifies diagnostic signatures and mechanistic links in moyamoya disease.

BACKGROUND: Moyamoya disease (MMD) features progressive intracranial artery stenosis and collateralization. Growing evidence implicates a dysregulated gut–brain axis in cerebrovascular pathology. We aimed to identify MMD-associated gut microbes and delineate the molecular mechanisms linking intestinal signals to vascular inflammation in MMD. RESULTS: We profiled fecal microbiota using full-length 16S rRNA sequencing from 24 MMD patients and 20 matched controls, prioritizing taxa with LEfSe, LASSO, and random forest algorithms. A species-level diagnostic model showed robust discrimination in our cohort (ROC AUC = 0.9146), and DCA supported its clinical utility. To connect gut signals to host vascular responses, we integrated peripheral and vascular transcriptomes from GEO and a cross-disease cerebrovascular cohort. Differential expression, WGCNA, and LASSO analyses identified key MMD genes and their immune modules. We then intersected these with microbiome-derived, gut-related genes to nominate candidate mediators of gut–immune–vessel crosstalk. This multi-omics pipeline identified Fusobacterium nucleatum, Lachnoanaerobaculum cf. saburreum C27KA, and NK4A214_group as MMD-specific microbial markers. Crucially, these markers were associated with immune infiltration signatures and inflammatory pathway activation in diseased vessels. Further integration pinpointed QRFPR and HCAR2 as key mediators of gut-derived cerebrovascular inflammation, suggesting a potential microbiota–immune–vascular pathway along the gut–brain axis. CONCLUSION: We characterized an MMD-associated microbiota profile and proposed QRFPR and HCAR2 as candidate genes linking intestinal microbes to vascular immune activation. By mapping the gut–brain axis from microbial taxa to host receptors and vessel-wall transcriptional programs, this study uncovers potential disease mechanisms and highlights new avenues for microbiome-informed biomarkers and therapeutic targeting in MMD.