Objectives Emerging evidence suggests that the microbiome plays an important role in the pathogenesis of osteoarthritis (OA). We aimed to test the two-hit model of OA pathogenesis and potentiation in which one ‘hit’ is provided by an adverse gut microbiome that activates innate immunity; the other ‘hit’ is underlying joint damage.
Methods Medical history, faecal and blood samples were collected from human healthy controls (OA-METS-, n=4), knee OA without metabolic syndrome (OA+METS-, n=7) and knee OA with metabolic syndrome (OA+METS+, n=9). Each group of human faecal samples, whose microbial composition was identified by 16S rRNA sequencing, was pooled and transplanted into germ-free mice 2 weeks prior to meniscal/ligamentous injury (MLI) (n≥6 per group). Eight weeks after MLI, mice were evaluated for histological OA severity and synovitis, systemic inflammation and gut permeability.
Results Histological OA severity following MLI was minimal in germ-free mice. Compared with the other groups, transplantation with the OA+METS+ microbiome was associated with higher mean systemic concentrations of inflammatory biomarkers (interleukin-1β, interleukin-6 and macrophage inflammatory protein-1α), higher gut permeability and worse OA severity. A greater abundance of Fusobacterium and Faecalibaterium and lesser abundance of Ruminococcaceae in transplanted mice were consistently correlated with OA severity and systemic biomarkers concentrations.
Conclusion The study clearly establishes a direct gut microbiome-OA connection that sets the stage for a new means of exploring OA pathogenesis and potentially new OA therapeutics. Alterations of Fusobacterium, Faecalibaterium and Ruminococcaceae suggest a role of these particular microbes in exacerbating OA.
- knee osteoarthritis
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HW, XZ and LC are joint senior authors.
Handling editor Josef S Smolen
ZH, JC, BL and BZ contributed equally.
Presented at This work was previously presented at OARSI 2019 (Oral Presentation Contol No. 230).
Contributors ZYH, JC, BLL, WH, LC and XDZ conceived of the studies and planned the experimental design. ZYH, JC, BLL, BHZ, JWX, GC, YH, HL, FXP and BS performed the experiments and analysed the data. CHC performed the analysis on the gene expression data. ZYH wrote the manuscript, VBK assisted with data interpretation and performed critical revisions on the manuscript. ZYH, JC, BLL and LC take responsibility for the integrity of the work as a whole. All authors approved the final manuscript.
Funding This work was supported by grants from the NSFC to ZYH (NSFC: 81702185; NSFC: 81972097), LC (NSFC: 81870759), XDZ (NSFC: 81430011; NSFC: 81991501) and HW (NSFC: 81770434). This research was also supported by National Key Research and Development Program of China to HW (No. 2018YF2000504), SiChuan Science and Technology Programs to ZYH (No. 2018HH0071) and LC (No. 2017JQ0028) and a Claude D. Pepper Older Americans Independece Centers grant (5P30 AG028716 from NIA to VBK).
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.
Patient consent for publication Not required.
Provenance and peer review Not commissioned; externally peer reviewed.
Data availability statement Data are available on reasonable request.
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