C57BL6/J 小鼠骨关节炎的性连锁差异与肠道微生物组有关，并可通过微生物组移植传递。
Sex-Linked Discrepancies in C57BL6/J Mouse Osteoarthritis are Associated With the Gut Microbiome and are Transferrable by Microbiome Transplantation.
机构信息
Oklahoma Medical Research Foundation, Arthritis & Clinical Immunology Program, Oklahoma City.
Oklahoma Medical Research Foundation, Arthritis & Clinical Immunology Program and University of Oklahoma Health Sciences Center, Oklahoma City.
出版信息
Arthritis Rheumatol. 2024 Feb;76(2):231-237. doi: 10.1002/art.42687. Epub 2023 Dec 12.
OBJECTIVE
Females 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.
METHODS
We 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.
RESULTS
Males had worse OA histology (3.5x, P = 6 × 10 ), synovitis (2.4x, P = 5 × 10 ), and osteophyte scores (3.7x, P = 3 × 10 ) than females. Male-into-female transplantation worsened all outcomes (histology 1.8x, P = 0.02; synovitis 2.0x, P = 3 × 10 ; 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 ; osteophyte 0.28x, P = 5 × 10 ) 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 (Lactobacillus R = -0.40, Aldercreutzia R = -0.40, rc4_4 R = -0.55, Sutterella R = -0.37, and Clostridiales R = 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 ; 0.57x, P = 0.03), and tumor necrosis factor ⍺ (0.49x, P = 0.03; 0.52x, P = 0.009).
CONCLUSION
Sex-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.
目的
女性在手术模型中患骨关节炎（OA）的风险较低。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
我们通过内侧半月板不稳定手术诱导成年雄性和雌性 C57BL6/J 小鼠发生 OA，并进行了异性微生物组移植。8 周后，处死动物，评估 OA 严重程度、滑膜炎和骨赘评分。通过比色法测量血清脂多糖，通过多重免疫分析定量测定血清细胞因子。使用 16S 深度测序生成盲肠微生物组图谱。
结果
与雌性相比，雄性的 OA 组织学（3.5 倍，P = 6 × 10）、滑膜炎（2.4 倍，P = 5 × 10）和骨赘评分（3.7 倍，P = 3 × 10）更差。雄性到雌性的移植使所有结果都恶化（组织学 1.8 倍，P = 0.02；滑膜炎 2.0 倍，P = 3 × 10；骨赘 2.1 倍，P = 0.01），而雌性到雄性的移植除了滑膜炎（组织学 0.53 倍，P = 2 × 10；骨赘 0.28 倍，P = 5 × 10）外，所有结果均得到改善。在肠道微生物组分析中，至少有一个组比较中存在 44 个分支不同；有 5 个分支与骨关节炎研究协会国际评分相关（Lactobacillus R = -0.40，Aldercreutzia R = -0.40，rc4_4 R = -0.55，Sutterella R = -0.37，Clostridiales R = 0.36）。在细胞因子分析中，至少有一个组比较中有 10 种分析物不同；有 3 种在两组中不同（雌性和雌性到雄性移植与雄性比较，两者在雌性和雌性到雄性移植中均减少），包括白细胞介素 12（0.66 倍，P = 0.02；0.66 倍，P = 0.02）、嗜酸性粒细胞趋化因子（0.74 倍，P = 5 × 10；0.57 倍，P = 0.03）和肿瘤坏死因子 ⍺（0.49 倍，P = 0.03；0.52 倍，P = 0.009）。
结论
雄性与雌性之间肠道微生物组的差异与 OA 结局相关，通过异性微生物组移植可逆转，并与血清细胞因子变化相关。
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