Skip to main content

Advertisement

SpringerLink
Log in

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

  • Original Article
  • Published:
GeroScience Aims and scope Submit manuscript

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.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6

Similar content being viewed by others

References

  1. Jones G, Nguyen T, Sambrook PN, Kelly PJ, Gilbert C, Eisman JA. Symptomatic fracture incidence in elderly men and women: the Dubbo Osteoporosis Epidemiology Study (DOES). Osteoporos Int. 1994;4(5):277–82.

    Article  CAS  PubMed  Google Scholar 

  2. Naik AA, Xie C, Zuscik MJ, Kingsley P, Schwarz EM, Awad H, Guldberg R, Drissi H, Puzas JE, Boyce B, Zhang X, O’Keefe RJ. Reduced COX-2 expression in aged mice is associated with impaired fracture healing. J Bone Miner Res. 2009;24(2):251–64.

    Article  CAS  PubMed  Google Scholar 

  3. Lu C, Miclau T, Hu D, Hansen E, Tsui K, Puttlitz C, Marcucio RS. Cellular basis for age-related changes in fracture repair. J Orthop Res. 2005;23(6):1300–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. He B, Zhang Z-K, Liu J, He Y-X, Tang T, Li J, Guo B-S, Lu A-P, Zhang B-T, Zhang G. Bioinformatics and microarray analysis of miRNAs in aged female mice model implied new molecular mechanisms for impaired fracture healing. Int J Mol Sci. 2016;17(8):1260.

    Article  PubMed  PubMed Central  Google Scholar 

  5. Stolzing A, Jones E, McGonagle D, Scutt A. Age-related changes in human bone marrow-derived mesenchymal stem cells: consequences for cell therapies. Mech Ageing Dev. 2008;129(3):163–73.

    Article  CAS  PubMed  Google Scholar 

  6. Einhorn TA, Gerstenfeld LC. Fracture healing: mechanisms and interventions. Nat Rev Rheumatol. 2015;11(1):45–54.

    Article  PubMed  Google Scholar 

  7. Fulop T, Larbi A, Dupuis G, Le Page A, Frost EH, Cohen AA, Witkowski JM, Franceschi C. Immunosenescence and inflamm-aging as two sides of the same coin: friends or foes? Front Immunol. 2017;8:1960.

    Article  PubMed  Google Scholar 

  8. Cohen HJ, Pieper CF, Harris T, Rao KM, Currie MS. The association of plasma IL-6 levels with functional disability in community-dwelling elderly. J Gerontol A Biol Sci Med Sci. 1997;52(4):M201–8.

    Article  CAS  PubMed  Google Scholar 

  9. Bruunsgaard H, Skinhoj P, Pedersen AN, Schroll M, Pedersen BK. Ageing, tumour necrosis factor-alpha (TNF-alpha) and atherosclerosis. Clin Exp Immunol. 2000;121(2):255–60.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Schmidt-Bleek K, Schell H, Schulz N, Hoff P, Perka C, Buttgereit F, Volk HD, Lienau J, Duda GN. Inflammatory phase of bone healing initiates the regenerative healing cascade. Cell Tissue Res. 2012;347(3):567–73.

    Article  CAS  PubMed  Google Scholar 

  11. Thomas MV, Puleo DA. Infection, inflammation, and bone regeneration: a paradoxical relationship. J Dent Res. 2011;90(9):1052–61.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Thevaranjan N, Puchta A, Schulz C, Naidoo A, Szamosi JC, Verschoor CP, Loukov D, Schenck LP, Jury J, Foley KP, Schertzer JD, Larche MJ, Davidson DJ, et al. Age-associated microbial dysbiosis promotes intestinal permeability, systemic inflammation, and macrophage dysfunction. Cell Host Microbe. 2017;21(4):455–66.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Roberts JL, Golloshi M, Harding DB, Conduah M, Liu G, Drissi H. Bifidobacterium longum supplementation improves age-related delays in fracture repair. Aging Cell. 2023;22:e13786.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Roberts JL, Liu G, Darby TM, Fernandes LM, Diaz-Hernandez ME, Jones RM, Drissi H. Bifidobacterium adolescentis supplementation attenuates fracture-induced systemic sequelae. Biomed Pharmacother. 2020;132:110831.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Vester H, Huber-Lang MS, Kida Q, Scola A, van Griensven M, Gebhard F, Nussler AK, Perl M. The immune response after fracture trauma is different in old compared to young patients. Immun Ageing. 2014;11(1):20.

    Article  PubMed  PubMed Central  Google Scholar 

  16. Emami AJ, Toupadakis CA, Telek SM, Fyhrie DP, Yellowley CE, Christiansen BA. Age dependence of systemic bone loss and recovery following femur fracture in mice. J Bone Miner Res. 2019;34(1):157–70.

    Article  CAS  PubMed  Google Scholar 

  17. Badal VD, Vaccariello ED, Murray ER, Yu KE, Knight R, Jeste DV, Nguyen TT. The Gut Microbiome, Aging, and Longevity: A Systematic Review. Nutrients. 2020;12(12):3759.

    Article  PubMed  PubMed Central  Google Scholar 

  18. Fransen F, van Beek AA, Borghuis T, Aidy SE, Hugenholtz F, van der Gaast-de Jongh C, Savelkoul HFJ, De Jonge MI, Boekschoten MV, Smidt H, Faas MM, de Vos P. Aged gut microbiota contributes to systemical inflammaging after transfer to germ-free mice. Front Immunol. 2017;8:1385.

    Article  PubMed  PubMed Central  Google Scholar 

  19. Cooney OD, Nagareddy PR, Murphy AJ, Lee MKS. Healthy gut, healthy bones: targeting the gut microbiome to promote bone health. Front Endocrinol. 2020;11:620466.

    Article  Google Scholar 

  20. Haffner-Luntzer M, Fischer V, Ignatius A. Differences in fracture healing between female and male C57BL/6J mice. Front Physiol. 2021;12:712494.

    Article  PubMed  PubMed Central  Google Scholar 

  21. Soung DY, Talebian L, Matheny CJ, Guzzo R, Speck ME, Lieberman JR, Speck NA, Drissi H. Runx1 dose-dependently regulates endochondral ossification during skeletal development and fracture healing. J Bone Miner Res. 2012;27(7):1585–97.

    Article  CAS  PubMed  Google Scholar 

  22. Roberts JL, Kinter CW, Drissi H. Generation and experimental outcomes of closed femoral fracture in mice. Methods Mol Biol. 2021;2221:205–22.

    Article  CAS  PubMed  Google Scholar 

  23. Paglia DN, Diaz-Hernandez ME, Roberts JL, Kalinowski J, Lorenzo J, Drissi H. Deletion of Runx1 in osteoclasts impairs murine fracture healing through progressive woven bone loss and delayed cartilage remodeling. J Orthop Res. 2019;38(5):1007–15.

    Article  PubMed  Google Scholar 

  24. Cauley JA, Barbour KE, Harrison SL, Cloonan YK, Danielson ME, Ensrud KE, Fink HA, Orwoll ES, Boudreau R. Inflammatory markers and the risk of hip and vertebral fractures in men: the osteoporotic fractures in men (MrOS). J Bone Miner Res. 2016;31(12):2129–38.

    Article  CAS  PubMed  Google Scholar 

  25. Kluber P, Meurer SK, Lambertz J, Schwarz R, Zechel-Gran S, Braunschweig T, Hurka S, Domann E, Weiskirchen R. Depletion of lipocalin 2 (LCN2) in mice leads to dysbiosis and persistent colonization with segmented filamentous bacteria. Int J Mol Sci. 2021;22(23):13156.

    Article  PubMed  PubMed Central  Google Scholar 

  26. Wei S, Bahl MI, Baunwall SMD, Hvas CL, Licht TR. Determining gut microbial dysbiosis: a review of applied indexes for assessment of intestinal microbiota imbalances. Appl Environ Microbiol. 2021;87(11):e00395.

    Article  PubMed  PubMed Central  Google Scholar 

  27. Zura R, Mehta S, Della Rocca GJ, Steen RG. Biological risk factors for nonunion of bone fracture. JBJS Rev. 2016;4(1):e5.

    Article  PubMed  Google Scholar 

  28. Hebb JH, Ashley JW, McDaniel L, Lopas LA, Tobias J, Hankenson KD, Ahn J. Bone healing in an aged murine fracture model is characterized by sustained callus inflammation and decreased cell proliferation. J Orthop Res. 2018;36(1):149–58.

    Article  CAS  PubMed  Google Scholar 

  29. Loffler J, Sass FA, Filter S, Rose A, Ellinghaus A, Duda GN, Dienelt A. Compromised bone healing in aged rats is associated with impaired M2 macrophage function. Front Immunol. 2019;10:2443.

    Article  PubMed  PubMed Central  Google Scholar 

  30. Roberts JL, Drissi H. Advances and promises of nutritional influences on natural bone repair. J Orthop Res. 2020;38(4):695–707.

    Article  PubMed  Google Scholar 

  31. Simsek T, Simsek HU, Canturk NZ. Response to trauma and metabolic changes: posttraumatic metabolism. Ulus Cerrahi Derg. 2014;30(3):153–9.

    PubMed  PubMed Central  Google Scholar 

  32. Cuthbertson D, Tilstone WJ. Metabolism during the postinjury period. Adv Clin Chem. 1969;12:1–55.

    Article  CAS  PubMed  Google Scholar 

  33. Slade Shantz JA, Yu YY, Andres W, Miclau T 3rd, Marcucio R. Modulation of macrophage activity during fracture repair has differential effects in young adult and elderly mice. J Orthop Trauma. 2014;28(Suppl 1):S10–4.

    Article  PubMed  PubMed Central  Google Scholar 

  34. Yukata K, Xie C, Li TF, Takahata M, Hoak D, Kondabolu S, Zhang X, Awad HA, Schwarz EM, Beck CA, Jonason JH, O'Keefe RJ. Aging periosteal progenitor cells have reduced regenerative responsiveness to bone injury and to the anabolic actions of PTH 1-34 treatment. Bone. 2014;62:79–89.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Gibon E, Lu L, Goodman SB. Aging, inflammation, stem cells, and bone healing. Stem Cell Res Ther. 2016;7:44.

    Article  PubMed  PubMed Central  Google Scholar 

  36. Hashimoto J, Yoshikawa H, Takaoka K, Shimizu N, Masuhara K, Tsuda T, Miyamoto S, Ono K. Inhibitory effects of tumor necrosis factor alpha on fracture healing in rats. Bone. 1989;10(6):453–7.

    Article  CAS  PubMed  Google Scholar 

  37. Glass GE, Chan JK, Freidin A, Feldmann M, Horwood NJ, Nanchahal J. TNF-alpha promotes fracture repair by augmenting the recruitment and differentiation of muscle-derived stromal cells. Proc Natl Acad Sci U S A. 2011;108(4):1585–90.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Yoshikawa H, Hashimoto J, Masuhara K, Takaoka K, Ono K. Inhibition by tumor necrosis factor of induction of ectopic bone formation by osteosarcoma-derived bone-inducing substance. Bone. 1988;9(6):391–6.

    Article  CAS  PubMed  Google Scholar 

  39. Fajardo LF, Kwan HH, Kowalski J, Prionas SD, Allison AC. Dual role of tumor necrosis factor-alpha in angiogenesis. Am J Pathol. 1992;140(3):539–44.

    CAS  PubMed  PubMed Central  Google Scholar 

  40. Andruszkow H, Fischer J, Sasse M, Brunnemer U, Andruszkow JH, Gansslen A, Hildebrand F, Frink M. Interleukin-6 as inflammatory marker referring to multiple organ dysfunction syndrome in severely injured children. Scand J Trauma Resusc Emerg Med. 2014;22:16.

    Article  PubMed  PubMed Central  Google Scholar 

  41. Maier B, Lefering R, Lehnert M, Laurer HL, Steudel WI, Neugebauer EA, Marzi I. Early versus late onset of multiple organ failure is associated with differing patterns of plasma cytokine biomarker expression and outcome after severe trauma. Shock. 2007;28(6):668–74.

    Article  CAS  PubMed  Google Scholar 

  42. Ono T, Okamoto K, Nakashima T, Nitta T, Hori S, Iwakura Y, Takayanagi H. IL-17-producing γδ T cells enhance bone regeneration. Nat Commun. 2016;7:10928.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Dixit M, Singh KB, Prakash R, Singh D. Functional block of IL-17 cytokine promotes bone healing by augmenting FOXO1 and ATF4 activity in cortical bone defect model. Osteoporos Int. 2017;28(7):2207–20.

    Article  CAS  PubMed  Google Scholar 

  44. Huang H, Kim HJ, Chang EJ, Lee ZH, Hwang SJ, Kim HM, Lee Y, Kim HH. IL-17 stimulates the proliferation and differentiation of human mesenchymal stem cells: implications for bone remodeling. Cell Death Differ. 2009;16(10):1332–43.

    Article  CAS  PubMed  Google Scholar 

  45. Kocic J, Santibanez JF, Krstic A, Mojsilovic S, Dordevic IO, Trivanovic D, Ilic V, Bugarski D. Interleukin 17 inhibits myogenic and promotes osteogenic differentiation of C2C12 myoblasts by activating ERK1,2. Biochim Biophys Acta. 2012;1823(4):838–49.

    Article  CAS  PubMed  Google Scholar 

  46. Jo S, Wang SE, Lee YL, Kang S, Lee B, Han J, Sung IH, Park YS, Bae SC, Kim TH. IL-17A induces osteoblast differentiation by activating JAK2/STAT3 in ankylosing spondylitis. Arthritis Res Ther. 2018;20(1):115.

    Article  PubMed  PubMed Central  Google Scholar 

  47. Noh M. Interleukin-17A increases leptin production in human bone marrow mesenchymal stem cells. Biochem Pharmacol. 2012;83(5):661–70.

    Article  CAS  PubMed  Google Scholar 

  48. Tan JY, Lei LH, Chen XT, Ding PH, Wu YM, Chen LL. AKT2 is involved in the IL17Amediated promotion of differentiation and calcification of murine preosteoblastic MC3T3E1 cells. Mol Med Rep. 2017;16(5):5833–40.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Osta B, Lavocat F, Eljaafari A, Miossec P. Effects of interleukin-17A on osteogenic differentiation of isolated human mesenchymal stem cells. Front Immunol. 2014;5:425.

    Article  PubMed  PubMed Central  Google Scholar 

  50. Uluckan O, Jimenez M, Karbach S, Jeschke A, Grana O, Keller J, Busse B, Croxford AL, Finzel S, Koenders M, van den Berg W, Schinke T, Amling M, et al. Chronic skin inflammation leads to bone loss by IL-17-mediated inhibition of Wnt signaling in osteoblasts. Sci Transl Med. 2016;8(330):330ra337.

    Article  Google Scholar 

  51. Shaw AT, Maeda Y, Gravallese EM. IL-17A deficiency promotes periosteal bone formation in a model of inflammatory arthritis. Arthritis Res Ther. 2016;18(1):104.

    Article  PubMed  PubMed Central  Google Scholar 

  52. Tyagi AM, Srivastava K, Mansoori MN, Trivedi R, Chattopadhyay N, Singh D. Estrogen deficiency induces the differentiation of IL-17 secreting Th17 cells: a new candidate in the pathogenesis of osteoporosis. PLoS One. 2012;7(9):e44552.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Wang Z, Jia Y, Du F, Chen M, Dong X, Chen Y, Huang W. IL-17A Inhibits osteogenic differentiation of bone mesenchymal stem cells via Wnt signaling pathway. Med Sci Monit. 2017;23:4095–101.

    Article  PubMed  PubMed Central  Google Scholar 

  54. Kim YG, Park JW, Lee JM, Suh JY, Lee JK, Chang BS, Um HS, Kim JY, Lee Y. IL-17 inhibits osteoblast differentiation and bone regeneration in rat. Arch Oral Biol. 2014;59(9):897–905.

    Article  CAS  PubMed  Google Scholar 

  55. Ahmadi S, Razazan A, Nagpal R, Jain S, Wang B, Mishra SP, Wang S, Justice J, Ding J, McClain DA, Kritchevsky SB, Kitzman D, Yadav H. Metformin reduces aging-related leaky gut and improves cognitive function by beneficially modulating gut microbiome/goblet cell/mucin axis. J Gerontol A Biol Sci Med Sci. 2020;75(7):e9–e21.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Hsieh H, Morin J, Filliettaz C, Varada R, LaBarre S, Radi Z. Fecal lipocalin-2 as a sensitive and noninvasive biomarker in the TNBS Crohn’s inflammatory bowel disease model. Toxicol Pathol. 2016;44(8):1084–94.

    Article  CAS  PubMed  Google Scholar 

  57. Chassaing B, Srinivasan G, Delgado MA, Young AN, Gewirtz AT, Vijay-Kumar M. Fecal lipocalin 2, a sensitive and broadly dynamic non-invasive biomarker for intestinal inflammation. PLoS One. 2012;7(9):e44328.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Asimakopoulou A, Weiskirchen S, Weiskirchen R. Lipocalin 2 (LCN2) Expression in hepatic malfunction and therapy. Front Physiol. 2016;7:430.

    Article  PubMed  PubMed Central  Google Scholar 

  59. Langille MG, Meehan CJ, Koenig JE, Dhanani AS, Rose RA, Howlett SE, Beiko RG. Microbial shifts in the aging mouse gut. Microbiome. 2014;2(1):50.

    Article  PubMed  PubMed Central  Google Scholar 

  60. Bartosch S, Fite A, Macfarlane GT, McMurdo ME. Characterization of bacterial communities in feces from healthy elderly volunteers and hospitalized elderly patients by using real-time PCR and effects of antibiotic treatment on the fecal microbiota. Appl Environ Microbiol. 2004;70(6):3575–81.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Claesson MJ, Jeffery IB, Conde S, Power SE, O’Connor EM, Cusack S, Harris HM, Coakley M, Lakshminarayanan B, O’Sullivan O, Fitzgerald GF, Deane J, O’Connor M, et al. Gut microbiota composition correlates with diet and health in the elderly. Nature. 2012;488(7410):178–84.

    Article  CAS  PubMed  Google Scholar 

  62. Claesson MJ, Cusack S, O’Sullivan O, Greene-Diniz R, de Weerd H, Flannery E, Marchesi JR, Falush D, Dinan T, Fitzgerald G, Stanton C, van Sinderen D, O’Connor M, et al. Composition, variability, and temporal stability of the intestinal microbiota of the elderly. Proc Natl Acad Sci U S A. 2011;108(Suppl 1):4586–91.

    Article  CAS  PubMed  Google Scholar 

  63. Mariat D, Firmesse O, Levenez F, Guimaraes V, Sokol H, Dore J, Corthier G, Furet JP. The Firmicutes/Bacteroidetes ratio of the human microbiota changes with age. BMC Microbiol. 2009;9:123.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Zwielehner J, Liszt K, Handschur M, Lassl C, Lapin A, Haslberger AG. Combined PCR-DGGE fingerprinting and quantitative-PCR indicates shifts in fecal population sizes and diversity of Bacteroides, bifidobacteria and Clostridium cluster IV in institutionalized elderly. Exp Gerontol. 2009;44(6-7):440–6.

    Article  CAS  PubMed  Google Scholar 

  65. Hoffman JD, Parikh I, Green SJ, Chlipala G, Mohney RP, Keaton M, Bauer B, Hartz AMS, Lin AL. Age drives distortion of brain metabolic, vascular and cognitive functions, and the gut microbiome. Front Aging Neurosci. 2017;9:298.

    Article  PubMed  PubMed Central  Google Scholar 

  66. Wu CS, Muthyala SDV, Klemashevich C, Ufondu AU, Menon R, Chen Z, Devaraj S, Jayaraman A, Sun Y. Age-dependent remodeling of gut microbiome and host serum metabolome in mice. Aging (Albany NY). 2021;13(5):6330–45.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Winter SE, Baumler AJ. Why related bacterial species bloom simultaneously in the gut: principles underlying the ‘Like will to like’ concept. Cell Microbiol. 2014;16(2):179–84.

    Article  CAS  PubMed  Google Scholar 

  68. Baldelli V, Scaldaferri F, Putignani L, Del Chierico F. The role of Enterobacteriaceae in gut microbiota dysbiosis in inflammatory bowel diseases. Microorganisms. 2021;9(4):697.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Thongaram T, Hoeflinger JL, Chow J, Miller MJ. Prebiotic galactooligosaccharide metabolism by probiotic lactobacilli and bifidobacteria. J Agric Food Chem. 2017;65(20):4184–92.

    Article  CAS  PubMed  Google Scholar 

  70. Malmir H, Ejtahed HS, Soroush AR, Mortazavian AM, Fahimfar N, Ostovar A, Esmaillzadeh A, Larijani B, Hasani-Ranjbar S. Probiotics as a new regulator for bone health: a systematic review and meta-analysis. Evid Based Complement Alternat Med. 2021;2021:3582989.

    Article  PubMed  PubMed Central  Google Scholar 

  71. Henrick BM, Rodriguez L, Lakshmikanth T, Pou C, Henckel E, Arzoomand A, Olin A, Wang J, Mikes J, Tan Z, Chen Y, Ehrlich AM, Bernhardsson AK, et al. Bifidobacteria-mediated immune system imprinting early in life. Cell. 2021;184(15):3884–98.

    Article  CAS  PubMed  Google Scholar 

  72. Miyauchi E, Ogita T, Miyamoto J, Kawamoto S, Morita H, Ohno H, Suzuki T, Tanabe S. Bifidobacterium longum alleviates dextran sulfate sodium-induced colitis by suppressing IL-17A response: involvement of intestinal epithelial costimulatory molecules. PLoS One. 2013;8(11):e79735.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Liwen Z, Yu W, Liang M, Kaihong X, Baojin C. A low abundance of Bifidobacterium but not Lactobacillius in the feces of Chinese children with wheezing diseases. Medicine (Baltimore). 2018;97(40):e12745.

    Article  PubMed  PubMed Central  Google Scholar 

  74. Shi P, Dong W, Nian D, Chen Y, Liu X, Qu H, Li Q. Bifidobacterium alleviates guillain-barré syndrome by regulating the function of T17 cells. Int J Clin Exp Med. 2018;11(5):4779–86.

    Google Scholar 

  75. Liu HX, Rocha CS, Dandekar S, Wan YJ. Functional analysis of the relationship between intestinal microbiota and the expression of hepatic genes and pathways during the course of liver regeneration. J Hepatol. 2016;64(3):641–50.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Rampelli S, Candela M, Turroni S, Biagi E, Collino S, Franceschi C, O’Toole PW, Brigidi P. Functional metagenomic profiling of intestinal microbiome in extreme ageing. Aging (Albany NY). 2013;5(12):902–12.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Funding

Funding to support this work was from the National Institutes of Health R01AG064464 (to H.D.) and R21AG065977 (to H.D.).

Author information

Authors and Affiliations

  1. Department of Orthopaedics, Emory University School of Medicine, 21 Ortho Ln, 6th Fl, Office 12, Atlanta, GA, 30329, USA

    Joseph L. Roberts & Hicham Drissi

  2. The Atlanta Department of Veterans Affairs Medical Center, Decatur, GA, USA

    Joseph L. Roberts, Brandon Chiedo & Hicham Drissi

  3. College of Health Solutions, Arizona State University, 850 N 5th St, Office 360J, Phoenix, AZ, 85004, USA

    Joseph L. Roberts

Authors
  1. Joseph L. Roberts
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Brandon Chiedo
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Hicham Drissi
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

Conceived and designed the experiments: JLR and HD. Performed the experiments: JLR and BC. Analyzed data: JLR and BC. Wrote and revised the manuscript: JLR and HD. Critical revision and final approval of the manuscript: all authors.

Corresponding authors

Correspondence to Joseph L. Roberts or Hicham Drissi.

Ethics declarations

Competing interests

The authors declare no competing interests.

Additional information

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary information

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Roberts, J.L., Chiedo, B. & Drissi, H. Systemic inflammatory and gut microbiota responses to fracture in young and middle-aged mice. GeroScience 45, 3115–3129 (2023). https://doi.org/10.1007/s11357-023-00963-7

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11357-023-00963-7

Keywords

Search

Navigation