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Disruption of the Gut Microbiome Increases the Risk of Periprosthetic Joint Infection in Mice

Hernandez, Christopher J. PhD; Yang, Xu MD; Ji, Gang MD; Niu, Yingzhen MD; Sethuraman, Arvinth S. BS; Koressel, Joseph MD; Shirley, Matthew MD; Fields, Michael W. BS; Chyou, Susan BS; Li, Thomas M. BS; Luna, Marysol MS; Callahan, Rowan L. BS; Ross, F. Patrick PhD; Lu, Theresa T. MD, PhD; Brito, Ilana L. PhD; Carli, Alberto V. MD; Bostrom, Mathias P. G. MD

Clinical Orthopaedics and Related Research: November 2019 - Volume 477 - Issue 11 - p 2588-2598
doi: 10.1097/CORR.0000000000000851
BASIC RESEARCH
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Background Periprosthetic joint infection (PJI) is one of the most devastating complications of total joint arthroplasty. Given the mortality and morbidity associated with PJI and the challenges in treating it, there has been increased interest in risk factors that can be modified before surgery. In this study, we used a novel mouse model to consider the role of the gut microbiome as a risk factor for PJI.

Questions/purposes (1) Does the state of the gut microbiota before surgery influence the likelihood of developing an established infection in a mouse model of PJI? (2) How does the state of the gut microbiota before surgery influence the local and systemic response to the presence of an established infection in a mouse model of PJI?

Methods Male C57Bl/6 mice were divided into two groups: those with modified microbiome ∆microbiome (n = 40) and untreated mice (n = 42). In ∆microbiome mice, the gut flora were modified using oral neomycin and ampicillin from 4 weeks to 16 weeks of age. Mice received a titanium tibial implant to mimic a joint implant and a local inoculation of Staphylococcus aureus in the synovial space (102 colony forming units [CFUs]). The proportion of animals developing an established infection in each group was determined by CFU count. The local and systemic response to established infection was determined using CFU counts in surrounding joint tissues, analysis of gait, radiographs, body weight, serum markers of inflammation, and immune cell profiles and was compared with animals that received the inoculation but resisted infection.

Results A greater proportion of animals with disrupted gut microbiota had infection (29 of 40 [73%]) than did untreated animals (21 of 42 [50%]; odds ratio, 2.63, 95% CI, 1.04–6.61; p = 0.035). The immune response to established infection in mice with altered microbiota was muted; serum amyloid A, a marker of systemic infection in mice, was greater than in mice with disrupted gut microbiota with infection (689 µg/dL; range, 68–2437 µg/dL, p < 0.05); infection associated increases in monocytes and neutrophils in the spleen and local lymph node in untreated mice but not were not observed in mice with disrupted gut microbiota.

Conclusions The findings from this in vivo mouse model suggest that the gut microbiota may influence susceptibility to PJI.

Clinical Relevance These preclinical findings support the idea that the state of the gut microbiome before surgery may influence the development of PJI and justify further preclinical and clinical studies to develop appropriate microbiome-based interventions.

C. J. Hernandez, X. Yang, G. Ji, Y. Niu, A. S. Sethuraman, J. Koressel, M. Shirley, M. W. Fields, S. Chyou, T. M. Li, F. P. Ross, T. T. Lu, A. V. Carli, M. P. G. Bostrom, Hospital for Special Surgery, New York, NY, USA

C. J. Hernandez, M. Luna, Sibley School of Mechanical and Aerospace Engineering, Cornell University, Ithaca, NY, USA

C. J. Hernandez, R. L. Callahan, I. L. Brito, Meinig School of Biomedical Engineering, Cornell University, Ithaca, NY, USA

C. J. Hernandez, Sibley School of Mechanical and Aerospace Engineering, Cornell University, 355 Upson Hall, Ithaca, NY 14853 USA, Email: cjh275@cornell.edu

This publication was supported in part by the National Institute of Arthritis and Musculoskeletal and Skin Diseases of the National Institutes of Health (US) under Award Numbers AR0671534 and AR068061 and National Institute of Allergy and Infectious Diseases under Award Number R01AI079178. The content of the work is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. The institution of one or more of the authors (CJH, XY, GJ, YN, ASS, JK, MS, MWF, SC, TML, FPR, TTL, AVC, and MPGB) has received, during the study period, funding from the National Institutes of Health (USA) and the US Department of Defense. One author (CJH) has received personal funds from the Northern California Institute for Bone Health, Inc. One author (MPGB) has received personal fees in an amount of USD 10,000 to 100,000 from Smith & Nephew (Watford, Hertfordshire, UK) and fees associated with the editorial board in an amount of USD 10,000 to 100,000 from the HSS Journal (New York, NY, USA) and fees for service on the board of the American Austrian Foundation (New York, NY, USA) in an amount of USD 10,000 to 100,000. All other authors certify that neither he or she, nor any member of his or her immediate family, have funding or commercial associations (consultancies, stock ownership, equity interest, patent/licensing arrangements, etc) that might pose a conflict of interest in connection with the submitted article.

All ICMJE Conflict of Interest Forms for authors and Clinical Orthopaedics and Related Research® editors and board members are on file with the publication and can be viewed on request.

Clinical Orthopaedics and Related Research® neither advocates nor endorses the use of any treatment, drug, or device. Readers are encouraged to always seek additional information, including FDA approval status, of any drug or device before clinical use.

Each author certifies that his or her institution approved the animal protocol for this investigation and that all investigations were conducted in conformity with ethical principles of research.

This work was performed at the Hospital for Special Surgery, New York, NY, USA.

© 2019 by the Association of Bone and Joint Surgeons
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