The main cause of total joint replacement failure is aseptic loosening due to particle-induced peri-implant osteolysis. The annual cost of failure is more than $10B/year in the U.S. and by 2030 more than 350,000 patients per year will need revision surgery. The current thinking is that peri-implant osteolysis is caused by particle-induced inflammation, leading to release of osteoclast-stimulating cytokines. We propose to begin testing the novel hypothesis that there is bi-directional cross-talk between the gut microbiome and the implant microenvironment that is integral to the progression of particle-induced osteolysis. The gut microbiome is the collective genetic material of the bacteria, fungi and viruses in the intestinal track. Gut ecology can be altered by diet, drugs, environment, host genetics and early-life microbial exposure. The symbiotic relationship between gut microorganisms and the host is essential to overall health. The scientific premise for the project is the growing recognition that manipulating the gut microbiome affects musculoskeletal tissues and our new data that the gut microbiome is altered in a rat model of particle-induced peri-implant osteolysis and that aseptic loosening is accelerated in total hip replacement patients who have irritable bowel disease. Given these observations we believe there is sufficient evidence to study the possibility of cross-talk between the digestive and musculoskeletal systems, which could lead to a vicious cycle whereby an initial inflammatory response in the musculoskeletal system contributes to gut dysbiosis, which, in turn, exacerbates the musculoskeletal inflammatory process. We propose testing the hypothesis through two specific aims: (1) Determining if altering the gut microbiome through use of a prebiotic dietary supplement affects the progression of particle-induced peri-implant osteolysis in our rat model and (2) Characterizing how particle-induced peri-implant osteolysis alters the gut microbiome. If this new hypothesis is correct, then there are two novel therapeutic opportunities for preventing or treating peri-implant osteolysis: (1) using dietary supplements to alter the gut microbiome, thus altering the gut-joint feedback loop and (2) interfering with the joint-gut feedback loop. Mechanisms of action for manipulation of the gut microbiome profile to affect remote site tissues include mucosal-mediated immunity, nutrition or release of bacterial products. We will investigate release of bacterial products from the gut as a mechanism of action. How the ?challenge? in the musculoskeletal system influences the gut is currently not known and we will begin to study this. Finally, it is also possible that there is a gut bacterial profile unique to particle-induced osteolysis, which would provide a potential novel biomarker for this condition.