Abstract Body: Abdominal aortic aneurysm (AAA) is a cardiovascular disease characterized by accumulation of immune cells, inflammation, and degradation of medial layer of the abdominal aorta. While the link between altered microbiota composition and atherosclerosis had been established, only a few studies suggested that altered gut microbiota composition may contribute to AAA, but mechanisms remain unknown. Cytokines are crucial regulators of inflammation in AAA, however, whether cytokines control microbial homeostasis in the intestine to regulate AAA has not been examined. Interleukin (IL)-27 is known to regulate various immune and inflammatory diseases in context-dependent manner. Here, we found that Apoe^-/-Il27ra^-/- mice were protected from gut dysbiosis and contain less pro-inflammatory bacterial genera in their colons. Unexpectedly, microbiota depletion by broad-spectrum antibiotics (Abx) accelerated AAA development in Apoe^-/-Il27ra^-/- mice while Apoe^-/- controls were protected from the disease. Our bulk RNAseq data on suprarenal aortas revealed that multiple pro-inflammatory and collagen/ECM degradation pathways were upregulated, while extracellular matrix and cell junction organization pathways were downregulated in Ang II-infused Apoe^-/-Il27ra^-/- mice with depleted microbiota. We found that numbers of circulating mature myeloid cells, and the level of pro-inflammatory serum metabolites were microbiota-dependent and correlated with AAA development. Moreover, fecal microbiota transplant (FMT) from Apoe^-/-Il27ra^-/- mice which contain less pro-inflammatory bacterial genera in their colon, but not from Apoe^-/- mice, attenuated AAA incidence in Ang II-infused Apoe^-/- recipients, indicating that protection from the disease can be transferred with microbiota. Collectively, our findings provide novel insight into the mechanisms of how IL27R signaling regulates AAA development by controlling intestinal microbiota and microbiota-derived metabolites, which in turn modulate pathogenic myeloid cell production and activation driving AAA.