The American Heart Association supports an association between periodontal diseases and atherosclerosis but not a causal association. This study explores the use of the integrin β6(-/-) mouse to study the causality. We investigated the ability of a polymicrobial consortium of Porphyromonas gingivalis, Treponema denticola, Tannerella forsythia and Fusobacterium nucleatum to colonize the periodontium and induce local and systemic inflammatory responses. Polymicrobial-infected Itgβ6(-/-) mice demonstrate higher susceptibility to gingival colonization/infection with severe gingival inflammation, apical migration of junctional epithelium, periodontal pocket formation, alveolar bone resorption, osteoclast activation, bacterial invasion of gingiva, a greater propensity for the bacteria to disseminate hematogenously, and a strong splenic T cell cytokine response. Atherosclerosis risk factors including serum nitric oxide, oxidized low-density lipoprotein, serum amyloid A, and lipid peroxidation were significantly altered by polybacterial infection, demonstrating enhanced potential for atherosclerotic plaque progression. Aortic gene expression revealed significant alterations in specific toll-like receptor (TLR) and nucleotide-binding domain, leucine rich repeat containing receptor (NLR) pathway genes in response to periodontal bacterial infection. Histomorphometry of aorta demonstrated larger atherosclerotic plaques in Itgβ6(-/-) mice than WT mice but no significant difference in atherosclerotic plaque size between polybacterial-infected and sham-infected mice. Fluorescent in situ hybridization demonstrated active invasion of aortic adventitial layer by P. gingivalis. Our observations suggest that polybacterial infection elicits distinct aortic TLR and inflammasome signaling and significantly elevates local aortic oxidative stress. These results are the first to demonstrate the mechanism of host aortic inflammatory response induced by polymicrobial infection with well-characterized periodontal pathogens.