Integrating gene-microbiome interactions and single-cell transcriptomics reveals therapeutic strategies for aortic aneurysm.

Aortic aneurysm (AA) is a life-threatening vascular disorder lacking effective medical therapies. Gut microbiota contributes importantly to vascular homeostasis; yet, the underlying gene-microbiome interactions in AA remain unclear. Using two-sample Mendelian randomization, we identified and validated a protective causal effect of genus Intestinimonas abundance on AA risk. Genetic annotation pinpointed CCDC3 as a causal gene in the gut-aorta axis. Integration of bulk and single-cell RNA sequencing revealed that CCDC3 deficiency in vascular smooth muscle cells activates a pathogenic CXCL12-CXCR4 signaling axis, which recruits neutrophils and promotes neutrophil extracellular trap formation in aneurysmal tissue. These findings establish a mechanistic link between specific gut microbes, host genetics, and vascular inflammation at single-cell resolution, highlighting promising therapeutic targets for the treatment of aortic aneurysm.