难治性类风湿性关节炎患者肠道菌群粪便Gram染色形态学特征及其疾病活动度的 相关性分析综述

Review of the Correlation between Morphological Characteristics of Fecal Gram Staining of Gut Microbiota and Disease Activity in Patients with Refractory Rheumatoid Arthritis

摘要: 类风湿关节炎(Rheumatoid Arthritis, RA)是一种慢性的自身免疫病，会累及全球大约百分之一的人口，它的主要特征有滑膜炎症、骨侵蚀、免疫激活以及自身抗体产生。虽然现在的治疗手段已经取得了不小的进步，难治性RA (Difficult-to-treat RA, D2T RA)的治疗却依然是临床管理中一个相当棘手的问题。近些年，“肠–关节轴”假说指出，肠道菌群失调能够通过破坏肠黏膜屏障、推动细菌代谢产物的易位，进而把全身免疫反应激活，最终参与到RA的发生和病情进展当中。已有的高通量测序研究已经证实，RA患者存在菌群多样性下降、产丁酸盐菌减少等特点，但是D2T RA是否会表现出更极端的菌群结构偏移，仍还不明确。另一方面，现阶段肠道菌群研究对高通量测序技术的依赖程度很高，这项技术本身有成本高昂、周期偏长等局限，很难在基层临床得到推广。粪便直接涂片革兰染色属于一种快速且廉价的形态学评估手段，已在多个疾病领域被证明能够有效捕捉到菌群结构的偏移，不过，它在风湿免疫病里的应用还非常少见。这篇综述将围绕D2T RA面对的临床挑战、它的定义与机制研究、肠–关节轴的研究进展以及肠道菌群研究技术的现状和局限来展开，同时探讨粪便革兰染色技术向D2T RA转化的潜力，以期为D2T RA的快速筛查和基层管理提供一些新的思路。

Abstract: Rheumatoid arthritis (RA) is a chronic autoimmune disease affecting approximately 1% of the global population, characterized primarily by synovial inflammation, bone erosion, immune activation, and autoantibody production. Although current treatments have made significant progress, difficult-to-treat RA (D2T RA) remains a challenging issue in clinical management. In recent years, the “gut-joint axis” hypothesis has suggested that gut microbiota dysbiosis can activate systemic immune responses by disrupting the intestinal mucosal barrier and promoting the translocation of bacterial metabolites, thereby contributing to the onset and progression of RA. High-throughput sequencing studies have confirmed that RA patients exhibit reduced microbial diversity and decreased abundance of butyrate-producing bacteria; however, whether D2T RA displays more extreme shifts in microbial composition remains unclear. On the other hand, current research on gut microbiota heavily relies on high-throughput sequencing technologies, which are costly and time-consuming, limiting their widespread application in primary healthcare settings. Fecal Gram staining, a rapid and inexpensive morphological assessment method, has proven effective in detecting microbial community shifts across various diseases, yet its use in rheumatic and immunological disorders remains rare. This review will discuss the clinical challenges of D2T RA, its definition and underlying mechanisms, advances in gut-joint axis research, and the current status and limitations of gut microbiota analysis techniques. It will also explore the potential of fecal Gram staining for translating into clinical applications in D2T RA, aiming to provide new insights for rapid screening and primary care management.