Article Text

Download PDFPDF
OA susceptibility in mice is partially mediated by the gut microbiome, is transferrable via microbiome transplantation and is associated with immunophenotype changes
  1. Emmaline Prinz1,2,
  2. Leoni Schlupp1,
  3. Gabby Dyson1,
  4. Montana Barrett1,
  5. Aleksander Szymczak1,
  6. Cassandra Velasco2,
  7. Vladislav Izda1,
  8. Christopher M Dunn1,2,
  9. Matlock A Jeffries1,2
  1. 1Arthritis & Clinical Immunology Program, Oklahoma Medical Research Foundation, Oklahoma City, Oklahoma, USA
  2. 2Division of Rheumatology, Immunology, and Allergy, The University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, USA
  1. Correspondence to Dr Matlock A Jeffries, Oklahoma Medical Research Foundation, Oklahoma City, Oklahoma, USA; matlock-jeffries{at}


Objectives The Murphy Roths Large (MRL)/MpJ ‘superhealer’ mouse strain is protected from post-traumatic osteoarthritis (OA), although no studies have evaluated the microbiome in the context of this protection. This study characterised microbiome differences between MRL and wild-type mice, evaluated microbiome transplantation and OA and investigated microbiome-associated immunophenotypes.

Methods Cecal material from mixed sex C57BL6/J (B6) or female MRL/MpJ (MRL) was transplanted into B6 and MRL mice, then OA was induced by disruption of the medial meniscus surgery (DMM). In other experiments, transplantation was performed after DMM and transplantation was performed into germ-free mice. Transplanted mice were bred through F2. OARSI, synovitis and osteophyte scores were determined blindly 8 weeks after DMM. 16S microbiome sequencing was performed and metagenomic function was imputed. Immunophenotypes were determined using mass cytometry.

Results MRL-into-B6 transplant prior to DMM showed reduced OA histopathology (OARSI score 70% lower transplant vs B6 control), synovitis (60% reduction) and osteophyte scores (30% reduction) 8 weeks after DMM. When performed 48 hours after DMM, MRL-into-B6 transplant improved OA outcomes but not when performed 1–2 weeks after DMM. Protection was seen in F1 (60% reduction) and F2 progeny (30% reduction). Several cecal microbiome clades were correlated with either better (eg, Lactobacillus, R=−0.32, p=0.02) or worse (eg, Rikenellaceae, R=0.43, p=0.001) OA outcomes. Baseline immunophenotypes associated with MRL-into-B6 transplants and MRL included reduced double-negative T cells and increased CD25+CD4+ T cells.

Conclusion The gut microbiome is responsible in part for OA protection in MRL mice and is transferrable by microbiome transplantation. Transplantation induces resting systemic immunophenotyping changes that correlate with OA protection.

  • Osteoarthritis
  • Osteoarthritis, Knee
  • Inflammation

Data availability statement

Data are available upon reasonable request. All raw 16S microbial sequencing data, histologic and other outcomes data are available upon reasonable request.

Statistics from

Request Permissions

If you wish to reuse any or all of this article please use the link below which will take you to the Copyright Clearance Center’s RightsLink service. You will be able to get a quick price and instant permission to reuse the content in many different ways.

Data availability statement

Data are available upon reasonable request. All raw 16S microbial sequencing data, histologic and other outcomes data are available upon reasonable request.

View Full Text


  • Handling editor Josef S Smolen

  • Twitter @matlockj

  • Contributors MAJ conceived the experiment. EP, LS, GD, MB, AS, CV, VI, CMD and MAJ planned and carried out the experiments. MAJ, CMD, AS performed data analysis. EP, LS, GD, MB, AS, CV, VI, CMD and MAJ contributed to interpretation of results. MAJ wrote the manuscript. All authors provided critical feedback and helped shape the research, analysis and manuscript. All authors approved the final manuscript.

  • Funding This work was supported by NIH grants K08AR070891, P20GM125528, R61AR078075 and R01AR076440, along with the Congressionally Directed Medical Research Program grant PR191652. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

  • Competing interests None declared.

  • Patient and public involvement Patients and/or the public were not involved in the design, or conduct, or reporting, or dissemination plans of this research.

  • Provenance and peer review Not commissioned; externally peer reviewed.

  • Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.