The Pretreatment Gut Microbiome Is Associated With Lack of Response to Methotrexate in New-Onset Rheumatoid Arthritis
The Pretreatment Gut Microbiome Is Associated With Lack of Response to Methotrexate in New-Onset Rheumatoid Arthritis
复制标题
DOI：
10.1002/art.41622
复制
发表时间：
2021-05-02
影响因子：
13.3
通讯作者：
Scher, Jose U.
中科院分区：
文献类型：
--
作者：
Artacho, Alejandro;Isaac, Sandrine;Scher, Jose U.
目的尽管口服甲氨蝶呤（MTX）仍然是类风湿性关节炎（RA）的锚定药物，但高达50%的患者未能获得临床充分的结果。此外，在开始给药前缺乏治疗反应的预后工具。本研究旨在探讨人类肠道微生物组的个体间差异是否有助于预测MTX在新发RA中的疗效。方法我们对26例初治RA患者的基线肠道微生物组进行了16S核糖体RNA基因和鸟枪法宏基因组测序。结果在另一个独立队列（n = 21）中得到验证。为了深入了解潜在的微生物机制，我们进行了离体实验，结合代谢组学分析，以评估微生物组驱动的MTX消耗和临床respons.Results之间的关联，我们的分析显示，肠道细菌类群及其基因的丰度与未来的临床反应（q < 0.05），包括与嘌呤和MTX代谢相关的直系同源物的显着关联。机器学习技术被应用于宏基因组数据，产生了一个基于微生物组的模型，该模型预测了一组独立患者对MTX缺乏反应。最后，与来自预处理RA患者的远端肠道样品离体孵育后剩余的MTX水平与未来临床应答的幅度显著相关，表明肠道微生物组对MTX代谢和治疗结果可能有直接影响。这些发现是预测新冠肺炎患者对口服MTX缺乏反应的第一步，并支持肠道微生物组作为可能的预后工具和RA治疗中的潜在靶点的价值。
Objective Although oral methotrexate (MTX) remains the anchor drug for rheumatoid arthritis (RA), up to 50% of patients do not achieve a clinically adequate outcome. In addition, there is a lack of prognostic tools for treatment response prior to drug initiation. This study was undertaken to investigate whether interindividual differences in the human gut microbiome can aid in the prediction of MTX efficacy in new-onset RA.Methods We performed 16S ribosomal RNA gene and shotgun metagenomic sequencing on the baseline gut microbiomes of drug-naive patients with new-onset RA (n = 26). Results were validated in an additional independent cohort (n = 21). To gain insight into potential microbial mechanisms, we conducted ex vivo experiments coupled with metabolomics analysis to evaluate the association between microbiome-driven MTX depletion and clinical response.Results Our analysis revealed significant associations of the abundance of gut bacterial taxa and their genes with future clinical response (q < 0.05), including orthologs related to purine and MTX metabolism. Machine learning techniques were applied to the metagenomic data, resulting in a microbiome-based model that predicted lack of response to MTX in an independent group of patients. Finally, MTX levels remaining after ex vivo incubation with distal gut samples from pretreatment RA patients significantly correlated with the magnitude of future clinical response, suggesting a possible direct effect of the gut microbiome on MTX metabolism and treatment outcomes.Conclusion Taken together, these findings are the first step toward predicting lack of response to oral MTX in patients with new-onset RA and support the value of the gut microbiome as a possible prognostic tool and as a potential target in RA therapeutics.