Background/Purpose: MRL/MpJ (MRL) mice are protected from developing post-traumatic osteoarthritis (OA) histologic changes. We have previously shown the gut microbiome to play a key role in mediating this OA protection, wherein microbiome transplantation from MRL mice to B6 mice can prevent OA. The goal of the present study was to examine the effects of microbiome manipulation on OA-associated pain in MRL and wild-type C57BL/6 (B6) mice.

Methods: Young adult male B6 or MRL mice (11 weeks of age) underwent one-time microbiome transplantation via oral gavage of 200uL of diluted cecal contents from adult reciprocal-strain animals (n=6 MRL-into-B6, n=6 B6-into-MRL), or 200uL control solution (n=6 MRL, n=6 B6). One week later, unilateral destabilization of the medial meniscus (DMM) surgery was used to induce OA. Pain sensitivity thresholds were measured via small animal algometry of the operated and contralateral knees prior to intervention (10 weeks of age). Algometry data were collected every 4 weeks until euthanasia 12 weeks after DMM.

Results: There were no differences at baseline in pain sensitivity, although there was a trend towards lower pain sensitivity in MRL animals at all timepoints (P=0.073 at baseline, P=0.069 at 4 weeks, P=0.033 at 8 weeks, P=0.16 at 12 weeks). At 4 weeks after DMM, MRL-into-B6 transplanted mice had substantially reduced pain sensitivity compared to B6 controls (P=0.0090), which was lost at later timepoints (P=0.17 at 8 weeks, P=0.23 at 12 weeks, Figure 1). B6-into-MRL transplantation did not alter pain sensitivity in MRL recipient mice at any timepoint. In the contralateral (unoperated) knee, we found MRL mice to have reduced pain sensitivity at all timepoints. MRL-into-B6 transplantation reduced pain sensitivity at 4 weeks (P=0.015) and 12 weeks (P=0.032). B6-into-MRL transplantation increased pain sensitivity at 4 weeks (P=0.012). Correlation of gut microbiome changes with pain sensitivity is ongoing.

Conclusion: Knee pain sensitivity is reduced in OA-protected MRL mice compared to wild-type B6 mice and is partially mediated by the gut microbiome, although the effects of a single timepoint microbiome manipulation are lost at timepoints beyond 4 weeks post-DMM. Future studies should investigate whether sustained changes in pain sensitivity could be seen with repeated microbiome manipulation, and whether OA-associated behavioral changes are similarly mitigated with microbiome manipulation.

Figure 1: Pain sensitivity (withdrawal) thresholds by gut microbiome transplantation group

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/oa-associated-pain-sensitivity-is-reduced-in-oa-protected-mrl-mpj-mice-partially-mediated-by-the-gut-microbiome-and-transferable-via-microbiome-transplantation/