PROJECT SUMMARY/ABSTRACT While it is increasingly evident that gut microbiota are drivers of chronic inflammatory conditions including diabetes mellitus and obesity, the influence of host-gut microbial cross-talk on inflammation in peripheral arteries and arterial remodeling after injury is not well understood. Specifically, although it is accepted that local and systemic inflammation drive the development of restenosis after cardiovascular interventions such as bypass surgery, balloon angioplasty, and stenting, the role of gut microbes as the source or regulators of the inflammatory process is not well delineated. The PI has previously demonstrated that modulation of gut microbiota by antibiotics to permit expansion of gram-negative organisms is associated with exacerbated neointimal hyperplasia development after balloon angioplasty in a rat model of arterial injury. In addition, germ- free wildtype mice have attenuated inflammation and neointimal hyperplasia development after arterial injury. Finally, the PI observed that exchanging microbiota between rats from genetically different strains resulted in modulation of strain-related neointimal hyperplasia phenotypes and local arterial and systemic inflammation after angioplasty. We also established that the relative abundance of 8 specific gut microbial genera regardless of cage sharing status or rat strain correlated significantly with neointimal hyperplasia development. Taken together, these preliminary data support our hypothesis that specific gut microbiota have a disease-modifying effect on neointimal hyperplasia by regulating the host inflammatory response. To explore this hypothesis, we propose the following aims for this 2-year proposal: Aim 1) To investigate the direct contribution of specific microbial communities on neointimal hyperplasia and inflammation. Aim 2) To evaluate the effect of specific reference bacterial strains on neointimal hyperplasia development and inflammation. Insights on how these specific microbial communities and community members drive host intestinal, arterial, and systemic inflammation to affect arterial remodeling will potentially uncover novel microbe-related therapeutic targets that can be used to prevent and treat restenosis in patients undergoing vascular reconstruction.