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

• Type of Material: Article
• Authors: Joseph Roberts, Emory University; Brandon Chiedo, The Atlanta Department of Veterans Affairs Medical Center; Hicham Drissi, Emory University
• Language: English
• Date: 2023-10-12
• Publisher: Springer
• Publication Version: Final Published Version
• Copyright Statement: © This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply 2023
• Final Published Version (URL): https://doi.org/10.1007/s11357-023-00963-7
• Title of Journal or Parent Work: GeroScience
• Volume: 45
• Issue: 6
• Start Page: 3115
• End Page: 3129
• Grant/Funding Information: Funding to support this work was from the National Institutes of Health R01AG064464 (to H.D.) and R21AG065977 (to H.D.).
• Keywords: IL-17a; Aging; Secondary bone healing; Inflammation; Microbiota
• Research Categories: Health Sciences, Immunology; Biology, Physiology

Abstract

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.