Systemic inflammatory and gut microbiota responses to fracture in young and middle-aged mice

Age is a patient-specific factor that can significantly delay fracture healing and exacerbate systemic sequelae during convalescence. The basis for this difference in healing rates is not well-understood, but heightened inflammation has been suggested to be a significant contributor. In this study, we investigated the systemic cytokine and intestinal microbiome response to closed femur fracture in 3-month-old (young adult) and 15-month-old (middle-aged) female wild-type mice. Middle-aged mice had a serum cytokine profile that was distinct from young mice at days 10, 14, and 18 post-fracture. This was characterized by increased concentrations of IL-17a, IL-10, IL-6, MCP-1, EPO, and TNFα. We also observed changes in the community structure of the gut microbiota in both young and middle-aged mice that was evident as early as day 3 post-fracture. This included an Enterobacteriaceae bloom at day 3 post-fracture in middle-aged mice and an increase in the relative abundance of the Muribaculum genus. Moreover, we observed an increase in the relative abundance of the health-promoting Bifidobacterium genus in young mice after fracture that did not occur in middle-aged mice. There were significant correlations between serum cytokines and specific genera, including a negative correlation between Bifidobacterium and the highly induced cytokine IL-17a. Our study demonstrates that aging exacerbates the inflammatory response to fracture leading to high levels of pro-inflammatory cytokines and disruption of the intestinal microbiota.