Xue Jiang, Chen Tianyou, Wu Shaofeng, Chen Jiarui, Feng Sitan, Huang Chengqian, Mo Sen, Zhou Zhongxian, Zhou Chenxing, Zhu Jichong, Wei Wendi, He Rongqing, Qin Boli, Qin Xiaopeng, Zhan Xinli, Liu Chong
Department of Spine Surgery and Osteopathy, The First Affiliated Hospital of Guangxi Medical University, No.6 Shuangyong Road, Qingxiu District, Nanning, Guangxi, 530021, People's Republic of China.
Clin Rheumatol. 2025 Aug 18. doi: 10.1007/s10067-025-07595-6.
Several observational studies suggest that gut microbiota (GM) may influence the onset and progression of ankylosing spondylitis (AS) through modulating host immune responses. However, the potential genetic associations between GM and AS susceptibility, as well as the immune-mediated mechanisms, remain to be elucidated.
This study initially infers the causal associations among GM, immune cell traits (ICTs), and AS using univariate two-sample Mendelian randomization (MR), and then evaluates the mediating role of ICTs in the genetic association between GM and AS through mediation MR analysis. Meanwhile, single-cell RNA sequencing is conducted on vertebral bone marrow blood samples obtained from three AS patients and three controls to characterize the differentiation status and functional alterations of relevant immune cell subsets, thereby validating their contribution to the pathogenesis of AS.
Mediation MR analysis revealed that "HLA-DR on CD14- CD16 + monocytes" acts as a protective factor for AS, attenuating the causal effect of Genus Sutterella/Sutterella Wadsworthensis on disease susceptibility. Single-cell analysis revealed distinct differences in cellular composition and transcriptional profiles between AS and the controls. Notably, monocyte subset analysis indicated a significant reduction in CD14- CD16 + monocytes in AS, concomitant with the relatively high expression of cellular activation markers.
The study indicates that CD14- CD16 + monocytes are potential protective factors for AS and exert a negative mediating effect on the causal associations between GM and AS. Boosting non-classical monocytes or modulating Sutterella abundance could help prevent or treat AS. Key Points • Novel approach integrating mediation MR and scRNA-seq offers distinct analytical strengths. • New insights into the gut-immune axis reveal its role in immune dysregulation in AS. • Mediation MR and single-cell analysis reveals CD14- CD16 + monocytes as protective factors in AS. • HLA-DR on CD14- CD16 + monocytes mitigate the genetic effect of Sutterella on AS susceptibility.
多项观察性研究表明，肠道微生物群（GM）可能通过调节宿主免疫反应影响强直性脊柱炎（AS）的发病和进展。然而，GM与AS易感性之间潜在的遗传关联以及免疫介导机制仍有待阐明。
本研究首先使用单变量双样本孟德尔随机化（MR）推断GM、免疫细胞特征（ICTs）和AS之间的因果关联，然后通过中介MR分析评估ICTs在GM与AS遗传关联中的中介作用。同时，对从三名AS患者和三名对照中获取的椎骨髓血样本进行单细胞RNA测序，以表征相关免疫细胞亚群的分化状态和功能改变，从而验证它们对AS发病机制的作用。
中介MR分析显示，“CD14-CD16+单核细胞上的HLA-DR”是AS的保护因素，减弱了萨特氏菌属/沃兹沃思萨特氏菌对疾病易感性的因果效应。单细胞分析显示AS与对照之间在细胞组成和转录谱方面存在明显差异。值得注意的是，单核细胞亚群分析表明AS中CD14-CD16+单核细胞显著减少，同时细胞活化标志物表达相对较高。
该研究表明，CD14-CD16+单核细胞是AS的潜在保护因素，对GM与AS之间的因果关联具有负向中介作用。增强非经典单核细胞或调节萨特氏菌丰度可能有助于预防或治疗AS。要点 • 整合中介MR和scRNA-seq的新方法具有独特的分析优势。 • 对肠道-免疫轴的新见解揭示了其在AS免疫失调中的作用。 • 中介MR和单细胞分析揭示CD14-CD16+单核细胞是AS的保护因素。 • CD14-CD16+单核细胞上的HLA-DR减轻了萨特氏菌对AS易感性的遗传效应。
