[论文解读] Microbiome-derived bile acids contribute to elevated antigenic response and bone erosion in rheumatoid arthritis

Xiuli Su, Xiaona Li+16 more|arXiv (Cornell University)|Jul 14, 2023

Mycobacterium research and diagnosisMedicine被引用 3

一句话总结

本研究识别出肠道菌群-胆汁酸轴是类风湿性关节炎（RA）中自身免疫反应和骨破坏的关键驱动因素。通过在RA患者中进行多组学分析，研究发现以拟杆菌属为主导的菌群失调通过胆盐水解酶（BSH）和7α-羟基类固醇脱氢酶（7α-HSDH）酶促进次级胆汁酸的生成，该过程与抗环瓜氨酸蛋白抗体（ACPA）水平及影像学骨侵蚀程度显著相关，提示微生物源性胆汁酸可能是RA发病机制的潜在介导因子，并可作为治疗新靶点。

ABSTRACT

Rheumatoid arthritis (RA) is a chronic, disabling and incurable autoimmune disease. It has been widely recognized that gut microbial dysbiosis is an important contributor to the pathogenesis of RA, although distinct alterations in microbiota have been associated with this disease. Yet, the metabolites that mediate the impacts of the gut microbiome on RA are less well understood. Here, with microbial profiling and non-targeted metabolomics, we revealed profound yet diverse perturbation of the gut microbiome and metabolome in RA patients in a discovery set. In the Bacteroides-dominated RA patients, differentiation of gut microbiome resulted in distinct bile acid profiles compared to healthy subjects. Predominated Bacteroides species expressing BSH and 7a-HSDH increased, leading to elevated secondary bile acid production in this subgroup of RA patients. Reduced serum fibroblast growth factor-19 and dysregulated bile acids were evidence of impaired farnesoid X receptor-mediated signaling in the patients. This gut microbiota-bile acid axis was correlated to ACPA. The patients from the validation sets demonstrated that ACPA-positive patients have more abundant bacteria expressing BSH and 7a-HSDH but less Clostridium scindens expressing 7a-dehydroxylation enzymes, together with dysregulated microbial bile acid metabolism and more severe bone erosion than ACPA-negative ones. Mediation analyses revealed putative causal relationships between the gut microbiome, bile acids, and ACPA-positive RA, supporting a potential causal effect of Bacteroides species in increasing levels of ACPA and bone erosion mediated via disturbing bile acid metabolism. These results provide insights into the role of gut dysbiosis in RA in a manifestation-specific manner, as well as the functions of bile acids in this gut-joint axis, which may be a potential intervention target for precisely controlling RA conditions.

研究动机与目标

• 探讨肠道菌群衍生代谢物在类风湿性关节炎（RA）发病机制中的作用。
• 确定RA患者中胆汁酸代谢是否发生改变，并与自身免疫反应和关节损伤相关联。
• 识别在RA中参与胆汁酸转化的特定微生物类群和酶。
• 评估肠道菌群、胆汁酸与ACPA阳性RA之间的因果关系。
• 探讨通过胆汁酸代谢靶向肠-关节轴以干预RA的潜在可能性。

提出的方法

• 采用非靶向代谢组学和16S rRNA基因测序对RA患者和健康对照者的肠道菌群及代谢组进行分析。
• 通过检测编码胆盐水解酶（BSH）和7α-羟基类固醇脱氢酶（7α-HSDH）的基因，评估微生物的功能潜力。
• 检测血清成纤维细胞生长因子-19（FGF-19）水平，作为法尼醇X受体（FXR）信号活性的标志物。
• 应用统计中介分析，检验从菌群经胆汁酸代谢到ACPA和骨侵蚀的潜在因果路径。
• 在独立患者队列中验证结果，以确认与ACPA状态和影像学损伤的关联性。
• 亚组分析聚焦于以拟杆菌属为主导的菌群，以识别驱动胆汁酸失调的特定微生物。

实验结果

研究问题

• RQ1 RA患者的肠道微生物失调如何改变胆汁酸代谢？
• RQ2 哪些微生物酶（如BSH、7α-HSDH）在RA患者中富集，并与次级胆汁酸生成相关？
• RQ3 RA患者中血清FGF-19水平与胆汁酸信号传导之间是否存在相关性？
• RQ4 肠道菌群来源的胆汁酸在多大程度上介导RA中的ACPA产生和骨侵蚀？
• RQ5 能否建立从肠道菌群经胆汁酸代谢到ACPA阳性RA的因果路径？

主要发现

• ACPA阳性RA患者中，以拟杆菌属为主导的菌群表现出显著升高的次级胆汁酸水平，这与胆盐水解酶（BSH）和7α-羟基类固醇脱氢酶（7α-HSDH）表达增加有关。
• RA患者血清成纤维细胞生长因子-19（FGF-19）水平降低，提示法尼醇X受体（FXR）介导的胆汁酸信号转导功能受损。
• ACPA阳性RA患者中，表达BSH和7α-HSDH的细菌丰度更高，而可产生7α-去氢化酶的梭菌属（Clostridium scindens）水平更低。
• 菌群源性胆汁酸代谢紊乱与ACPA阳性患者影像学骨侵蚀程度显著相关。
• 中介分析揭示了一条从拟杆菌属物种经胆汁酸代谢异常导致ACPA水平升高和骨侵蚀的潜在因果路径。
• 肠道菌群-胆汁酸轴与ACPA阳性RA特异性相关，提示RA发病机制中存在表现特异性的作用机制。