Arthritis & Clinical Immunology Program, Oklahoma Medical Research Foundation, Oklahoma City, Oklahoma, USA.
Division of Rheumatology, Immunology, and Allergy, The University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, USA.
Ann Rheum Dis. 2024 Feb 15;83(3):382-393. doi: 10.1136/ard-2023-224907.
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.
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.
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, R=-0.32, p=0.02) or worse (eg, , 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.
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.
Murphy Roths Large（MRL）/MpJ“超级治愈者”小鼠品系对创伤后骨关节炎（OA）具有保护作用，尽管尚无研究评估该保护作用背景下的微生物组。本研究对 MRL 和野生型小鼠的微生物组差异进行了特征描述，评估了微生物组移植和 OA，并研究了微生物组相关的免疫表型。
混合性别 C57BL6/J（B6）或雌性 MRL/MpJ（MRL）的盲肠材料被移植到 B6 和 MRL 小鼠中，然后通过内侧半月板手术（DMM）破坏诱导 OA。在其他实验中，DMM 后进行移植，并将移植进行到无菌小鼠中。通过 F2 繁殖移植小鼠。DMM 后 8 周，盲法评估 OARSI、滑膜炎和骨赘评分。进行 16S 微生物组测序并推断宏基因组功能。使用质谱细胞术测定免疫表型。
MRL 移植到 B6 之前进行 DMM 显示出减少的 OA 组织病理学（移植的 OARSI 评分比 B6 对照低 70%）、滑膜炎（减少 60%）和骨赘评分（减少 30%）8 周后 DMM。当在 DMM 后 48 小时进行时，MRL 移植到 B6 可改善 OA 结局，但在 DMM 后 1-2 周进行时则无效。在 F1（减少 60%）和 F2 后代（减少 30%）中都观察到了保护作用。几个盲肠微生物组分支与更好（例如，R=-0.32，p=0.02）或更差（例如，R=0.43，p=0.001）的 OA 结局相关。与 MRL 移植和 MRL 相关的基线免疫表型包括减少的双阴性 T 细胞和增加的 CD25+CD4+T 细胞。
肠道微生物组部分负责 MRL 小鼠的 OA 保护，并且可以通过微生物组移植进行传递。移植诱导与 OA 保护相关的静止系统性免疫表型变化。
