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Abstract
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.
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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.
Footnotes
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.
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