Sex-Linked Discrepancies in C57BL6/J Mouse Osteoarthritis are Associated With the Gut Microbiome and are Transferrable by Microbiome Transplantation.
Sex-Linked Discrepancies in C57BL6/J Mouse Osteoarthritis are Associated With the Gut Microbiome and are Transferrable by Microbiome Transplantation.
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C57BL6/J 小鼠骨关节炎中的性别相关差异与肠道微生物组相关，并且可通过微生物组移植转移。
DOI：
10.1002/art.42687
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发表时间：
2024
期刊：
影响因子：
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通讯作者：
Jeffries,MatlockA
中科院分区：
文献类型：
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作者：
Schlupp,Leoni;Prinz,Emmaline;Dyson,Gabriella;Barrett,Montana;Izda,Vladislav;Dunn,ChristopherM;Jeffries,MatlockA
目的在手术模型中女性减少了骨关节炎（OA）。本研究的目的是评估与性别相关的肠道微生物组在 OA 发病机制中的作用。方法我们通过对成年雄性和雌性 C57BL6/J 小鼠进行或未进行异性微生物组移植的内侧半月板不稳定手术来诱导 OA。八周后，对动物实施安乐死，并测定 OA 严重程度、滑膜炎和骨赘评分。通过显色法测量血清脂多糖，并通过多重免疫测定法对血清细胞因子进行定量。使用16S深度测序生成盲肠微生物组图谱。结果男性的OA组织学（3.5x，P= 6× 10−7）、滑膜炎（2.4x，P= 5× 10−4）和骨赘评分（3.7x，P= 3× 10−4）比女性更差。与女性相比，男性转女性移植使所有结果恶化（组织学 1.8x，P= 0.02；滑膜炎 2.0x，P= 3 × 10−5；骨赘 2.1x，P= 0.01），而女性转男性移植改善了除滑膜炎外的所有结果（组织学 0.53x，P= 2） × 10−4；骨赘 0.28x，P= 5 × 10−4) 与男性相比。在肠道微生物组分析中，44 个进化枝在至少一组比较中存在差异； 5 个分支与国际骨关节炎研究协会评分相关（乳杆菌 R = -0.40、Aldercreutzia R = -0.40、rc4_4R = -0.55、SutterellaR = -0.37 和梭菌目 R = 0.36）。在细胞因子分析中，至少有一组比较中有10个分析物存在差异； 3 在两组中存在差异（女性和女性转男性移植与男性比较，女性和女性转男性移植中均有所减少），包括白细胞介素-12（分别为 0.66x，P= 0.02；0.66x，P= 0.02）、嗜酸细胞趋化因子（0.74x，P= 5 × 10−6；0.66x，P= 10−6）。 0.57x，P= 0.03）和肿瘤坏死因子⍺（0.49x，P= 0.03；0.52x，P= 0.009）。 结论 小鼠肠道微生物组的性别相关差异与 OA 结局相关，可通过异性微生物组移植逆转，并与血清细胞因子变化相关。
ObjectiveFemales have reduced osteoarthritis (OA) in surgical models. The objective of the current study was to evaluate a sex‐linked gut microbiome in the pathogenesis of OA.MethodsWe induced OA via destabilization of the medial meniscus surgery in adult male and female C57BL6/J mice with and without opposite‐sex microbiome transplantation. Eight weeks later, animals were euthanized, and OA severity, synovitis, and osteophyte scores were determined. Serum lipopolysaccharide was measured chromogenically, and serum cytokines were quantified via multiplex immunoassay. Cecal microbiome profiles were generated using 16S deep sequencing.ResultsMales had worse OA histology (3.5x,P= 6 × 10−7), synovitis (2.4x,P= 5 × 10−4), and osteophyte scores (3.7x,P= 3 × 10−4) than females. Male‐into‐female transplantation worsened all outcomes (histology 1.8x,P= 0.02; synovitis 2.0x,P= 3 × 10−5; osteophyte 2.1x,P= 0.01) compared to females, whereas female‐into‐male transplantation improved all outcomes except for synovitis (histology 0.53x,P= 2 × 10−4; osteophyte 0.28x,P= 5 × 10−4) compared to males. In the gut microbiome analysis, 44 clades were different in at least one group comparison; 5 clades were correlated with the Osteoarthritis Research Society International score (LactobacillusR = −0.40,AldercreutziaR = −0.40,rc4_4R = −0.55,SutterellaR = −0.37, andClostridialesR = 0.36). In the cytokine analysis, 10 analytes were different in at least one group comparison; 3 were different in two groups (female and female‐into‐male transplants vs male comparisons, all reduced in female and female‐into‐male transplants), including interleukin‐12 (0.66x,P= 0.02; 0.66x,P= 0.02, respectively), eotaxin (0.74x,P= 5 × 10−6; 0.57x,P= 0.03), and tumor necrosis factor ⍺ (0.49x,P= 0.03; 0.52x,P= 0.009).ConclusionSex‐linked differences in the mouse gut microbiome are associated with OA outcomes, are reversible by opposite‐sex microbiome transplantation, and are associated with serum cytokine changes.